CN110507608A - A kind of fasudil hydrochloride injection preparation process - Google Patents
A kind of fasudil hydrochloride injection preparation process Download PDFInfo
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- CN110507608A CN110507608A CN201910950116.4A CN201910950116A CN110507608A CN 110507608 A CN110507608 A CN 110507608A CN 201910950116 A CN201910950116 A CN 201910950116A CN 110507608 A CN110507608 A CN 110507608A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
- A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
Abstract
A kind of fasudil hydrochloride injection preparation process, is completed by following steps, and water for injection is added in dense preparing tank, puts into glucose or common salt is dissolved in dense preparing tank, and stirring puts into activated carbon adsorption to being completely dissolved, and de- charcoal is simultaneously filled into dilute preparing tank while hot.Fasudic hydrochloride dissolves and is directed into dilute preparing tank, and regulating liquid medicine pH is stirred for, and returns filter, then filling, sterilizing, packaging.The present invention provides the new process for producing of fasudil hydrochloride injection.Process for producing of the invention has good sterilization sterilization effect.
Description
Technical field
The present invention relates to a kind of injection and preparation processes.Belong to injection field of medicine production.
Background technique
Fasudil hydrochloride injection is colourless or yellowish clear liquid, inhibits the flesh ball of smooth muscle contraction terminal stage
Protein light chain phosphorylation, distends the blood vessels.This product only intravenous drip uses, and other approach administrations not can be used.It is adapted to change
Cerebral angiospasm and caused symptoms of cerebral ischemia kind and that prevention subarachnoid hemorrhage is postoperative.
In the production process of injection, sterile production is always the key of injection production, be in the mistake of production injection
Cheng Zhong is repeatedly sterilized, to reach total number of bacteria control within qualified quantity.
It is also the same in fasudil hydrochloride injection production process, it is necessary to control total number of bacteria.Present method of controlling
Predominantly, it in high-cleanness production environment area, completes with after pharmacy industry, activated carbon adsorption degerming of row removes when in dense preparing tank
Impurity.Then de- charcoal is refiltered, sterilizing is completed.When dependent on this kind of mode, to reach better sterilization effect, it is necessary to be addition
The active carbon and active carbon of sufficient amount must be stirred time enough in dense preparing tank, can be only achieved preferably to thin
Bacterium absorption.
As it can be seen that can be adsorbed in dense preparing tank after the amount of activated carbon in dense preparing tank is excessive, and adsorption time is too long
Medicine company effective ingredient, reduce the effective ingredient amount of end product, and if active carbon addition quantity it is excessive, can be to medicine
Liquid forms new pollution, and increases the process and cost of later period de- charcoal.Therefore, it was produced in existing fasudil hydrochloride injection
Cheng Zhong, it is necessary to which the dosage for controlling active carbon is balanced choice on bactericidal effect and activated carbon dosage, and appropriate reduction sterilization is wanted
It asks, it is up to standard within regulation is controlled the size to meet bacterial number, does not control bacterial number further.
For fasudil hydrochloride injection, directly input in blood of human body, wherein the bacterial number contained is got over
It is low, it is theoretically then safer, and the speed of bacterial growth is and not know that the bacterium of type can be in various complexity than faster
Environment in grow, therefore, if the bacterial number being packaged in early period in medical fluid is lower, following period of time medicine of the later period in inventory
The bacterial number grown in liquid is certainly fewer.It is extremely important to effectively being sterilized in liquid in medical fluid production period.
Therefore, in existing note fasudil hydrochloride injection production method, that is, wish preferably to control bacterial number, again
Worry loss drug effect, and increase filtering cost, belongs to insoluble problem contradiction.
Summary of the invention
To solve the above-mentioned problems, the present invention provides a kind of fasudil hydrochloride injection preparation processes.
Fasudil hydrochloride injection preparation process provided by the invention, is completed by following steps,
(1), it is 75 DEG C or more that water temperature is added in dense preparing tank, the water for injection of amount of preparation total volume 45-55%,
(2), the drug for putting into recipe quantity is dissolved in dense preparing tank, stirring to being completely dissolved,
(3), active carbon is put into, steam valve heating is opened and boils, be stirred continuously heat preservation absorption；
(4), starting recycles de- charcoal；
(5), medical fluid is cooled to 50-60 DEG C, is filled into dilute preparing tank while hot.
(6), water for injection is added in dissolving tank, water for injection temperature control system is at 50-60 DEG C；The hydrochloric acid method that recipe quantity is added is relaxed
Ground that, stirs to being completely dissolved, is directed into dilute preparing tank；
(7), plus water for injection to dilute preparing tank to amount of preparation 90%, stir, while dilute hydrochloric acid regulating liquid medicine pH be added extremely
4.0~4.3,50-60 DEG C of regulating liquid medicine temperature supplies water for injection to full dose, is stirred for, returns filter；
(4), intermediate is taken to monitor medical fluid pH；
(5), medical fluid is using filter, filling, sterilizing, packaging.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The drug of the investment recipe quantity is dissolved in dense preparing tank, stirring to being completely dissolved, specifically: stirring 5 minutes until
It is completely dissolved, and then adjusting pH with 0.1mol/L HCl is 2.0~3.0；
The investment active carbon is opened steam valve heating and is boiled, is stirred continuously heat preservation absorption, specifically: investment is overall
The active carbon of product 0.2 ‰ w/v to 0.4 ‰ w/v is opened steam valve heating and is boiled, and heat preservation absorption 10min or more is stirred continuously；
The starting recycles de- charcoal, specifically: de- charcoal recycles 20 minutes；
Described is cooled to 50-60 DEG C for medical fluid, specifically: it opens cooling water valve goalkeeper medical fluid and is cooled to 50-60 DEG C；
The addition dilute hydrochloric acid regulating liquid medicine pH to 4.0~4.3, specially dilute hydrochloric acid are 0.1mol/L；
It after supplying water for injection to full dose, is stirred for 10 minutes, returns filter 25 minutes；
The medical fluid using filter, it is filling, sterilizing, packaging, specifically: filtered through titanium, 0.45 miillpore filter, 0.22 μm is removed
Bacterium filters back that filter is qualified to visible foreign matters and filling after replacing, and filling temperature control is at 50-60 DEG C.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The drug is one of DEXTROSE ANHYDROUS, sodium chloride.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The step further includes before putting into drug in dense preparing tank, first dissolving drug in ultrasonic tank and going forward side by side
Row is sterilized for the first time, specifically:
The water for injection of 5 times of volumes of drug or more is added in ultrasonic tank, and drug is put into ultrasonic tank, ultrasonic sound
Progress first time sterilization in 8-10 minutes is vibrated, and dissolves drug simultaneously in water for injection；The water for injection for dissolving drug is thrown
Enter in dense preparing tank, completes drug and be dissolved in dense preparing tank.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The sonic oscillation parameter are as follows: sound intensity 1-5W/cm2, frequency 30-40KHz, ultrasonic pot bottom generates 10.5 μm
Amplitude；Ultrasonic output power is 45-55w, ultrasonic waveform is impulse wave, pulse width 8-12ms.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The step further includes before investment active carbon investment active carbon, carrying out low-pressure boiled in dense preparing tank and cutting
Cut water sterilization；
Then the low-pressure boiled shearing water sterilization extracts negative pressure extremely specifically, by being heated to 75-80 DEG C in dense preparing tank
It is negative pressure in dense preparing tank, then persistently dense preparing tank is heated, makes to generate boiling in dense preparing tank, the shearing force generated using water boiling
It is sterilized.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The described low-pressure boiled shearing water sterilization specifically, extract negative pressure to concentrated compounding pressure inside the tank be -62KPa to -
54KPa, then persistently to dense preparing tank heat, and continue extract tank in negative pressure, and keep concentrated compounding pressure inside the tank be -62KPa to -
54KPa makes to generate boiling 23 minutes in dense preparing tank with this condition.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
The step further includes, and before taking intermediate to monitor medical fluid pH, recirculation water shearing is carried out in dilute preparing tank and is killed
Bacterium；Recirculation water shearing sterilization is specifically, liquid rotates 20-25 minutes repeatedly in agitation dilute preparing tank.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
Liquid rotates repeatedly in the agitation dilute preparing tank, specifically, first stirring 1-3 points of liquid up time rotation in dilute preparing tank
Clock, then liquid inverse time rotation 1-3 minutes in dilute preparing tank are stirred, it rotates repeatedly, and primary rotation side was converted every 1-3 minutes
To generation high shear force；
The agitating method that liquid rotates repeatedly in agitation dilute preparing tank are as follows: the water outlet of several first group of reflux pump is with clockwise
Direction is simultaneously arranged on dilute preparing tank outer wall from dilute preparing tank inner circle tangential direction, and the water inlet of first group of reflux pump is arranged in dilute preparing tank
First group of reflux pump of bottom, above-mentioned setting completes right handed agitation in dilute preparing tank；
The water outlet of several second group of reflux pump is matched in a counterclockwise direction and from the setting of dilute preparing tank inner circle tangential direction dilute
On tank wall, in dilute preparing tank bottom, second group of reflux pump of above-mentioned setting completes dilute match for the water inlet setting of second group of reflux pump
The agitation rotated counterclockwise in tank；
Above-mentioned first group of reflux pump is alternately and repeatedly opened with second group of reflux pump, rotates liquid in dilute preparing tank repeatedly, is produced
Raw high shear force；
The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
A kind of preparation process of fasudil hydrochloride injection as described above, further explains are as follows:
In pouring process, persistently to the rotational agitation repeatedly of liquid in dilute preparing tank；Specifically, first stirring liquid in dilute preparing tank
Up time rotates 1-3 minutes, then stirs liquid inverse time rotation 1-3 minutes in dilute preparing tank, rotates repeatedly, and every 1-3 minutes
A direction of rotation is converted, high shear force is generated；
Until medicine liquid tank is installed into dilute preparing tank.
The utility model has the advantages that
The present invention provides the new process for producing of fasudil hydrochloride injection.
Process for producing of the invention has good sterilization sterilization effect.
In the case where not putting into more activated carbon adsorptions sterilization, conducive to boiled water shearing in ultrasonic sterilization, dense preparing tank
Power sterilizes, and the sterilizing of recirculation water shearing force, multiple sterilization steps preferably reduce the bacteria total amount in medical fluid in dilute preparing tank.Or
In the case that bacteria total amount of the person in the existing medical fluid of holding is constant and product is qualified, the present invention can put into the use of active carbon less
Amount, and the time of activated carbon adsorption is reduced, to keep the effective ingredient of medical fluid.
Specific embodiment
Step of the present invention includes concentrated compounding, dilution, is finally carried out canned.
Embodiment one:
Prepare the Fasudic hydrochloride glucose injection of 100ml infusion bag.
It matches as follows:
Embodiment two:
Prepare the Fasudic hydrochloride common salt injection of 100ml infusion bag.
It matches as follows:
Embodiment three:
Prepare the Fasudic hydrochloride glucose injection of 100ml infusion bag.Operation is protected from light during preparing process.
According to production ordering and technological parameter requirement, it is 80 DEG C or more amount of preparation total volumes that water temperature is added in dense preparing tank
50% water for injection, the DEXTROSE ANHYDROUS for putting into recipe quantity are dissolved in dense preparing tank, open stirring 5 minutes until be completely dissolved,
Adjusting pH with appropriate 0.1mol/L HCl is 2.0~3.0.
The active carbon of total volume 0.2 ‰ (w/v) is put into, steam valve heating is opened and boils, is stirred continuously heat preservation absorption 15min
Left and right.
De- charcoal recycles 20 minutes, and opens cooling water valve, and medical fluid is cooled to 50-60 DEG C.
It is filled into target dilute preparing tank while hot.
Ultrasonic tank is taken, appropriate water for injection is added, water for injection temperature control system adds the hydrochloric acid of recipe quantity at 50-60 DEG C
Fasudil is sufficiently stirred 10 minutes until Fasudic hydrochloride is completely dissolved, and solution of being subject to is clarified, and it is dilute that target is added immediately
In distribution tank.
Open water for injection valve, add water for injection to target dilute preparing tank to amount of preparation 90%, open stir 10 minutes,
The appropriate regulating liquid medicine pH to 4.0~4.3 of dilute hydrochloric acid (0.1mol/L), 50-60 DEG C of regulating liquid medicine temperature are added simultaneously.
It supplies water for injection to be stirred for 10 minutes to full dose, while starting spray pump and passing through back filter system time filter 25 minutes.
Sample tap sampling, which is sent to intermediate sensing chamber, to be detected.
The qualified intermediate of detection is filtered through titanium, 0.45 miillpore filter, and 0.22 μm of aseptic filtration returns filter to visible foreign matters qualification
And it is filling after replacing, at 50-60 DEG C, the minimum temperature of pouring process must not be lower than 50 DEG C for filling temperature control.
Sterilizing, packaging.
Example IV:
Prepare the Fasudic hydrochloride common salt injection of 100ml infusion bag.Operation is protected from light during preparing process.
According to production ordering and technological parameter requirement, it is 80 DEG C or more amount of preparation total volumes that water temperature is added in dense preparing tank
50% water for injection.
The sodium chloride of investment recipe quantity is dissolved in dense preparing tank, opens stirring 5 minutes until raw material is completely dissolved.
The active carbon of existing volume 0.4 ‰ (w/v) is put into again, is opened steam valve heating and is boiled, is stirred continuously heat preservation absorption
15min or so.
De- charcoal, which recycles 20 minutes and opens cooling water valve goalkeeper's medical fluid, is cooled to 50-60 DEG C, is filled into that target is dilute to match while hot
Tank.
Ultrasonic tank is taken, 5L water for injection is added, water for injection temperature control system adds the hydrochloric acid method of recipe quantity at 50-60 DEG C
Relax ground that, is sufficiently stirred 10 minutes until Fasudic hydrochloride is completely dissolved (solution clarification), immediately in addition target dilute preparing tank.
Open water for injection valve, add water for injection to target dilute preparing tank to amount of preparation 90%, open stir 10 minutes,
The dilute hydrochloric acid or Sodium hydroxide q.s. regulating liquid medicine pH to 5.0~6.0 of 0.1mol/L, regulating liquid medicine temperature 50-60 are added simultaneously
℃。
It supplies water for injection to be stirred for 10 minutes to full dose, while starting spray pump and passing through back filter system time filter 25 minutes.
It send in sample tap sampling to intermediate sensing chamber and is detected.
The qualified intermediate of detection is filtered through titanium, 0.45 miillpore filter, and 0.22 μm of aseptic filtration returns filter to visible foreign matters qualification
And it is filling after replacing, at 50-60 DEG C, the minimum temperature of pouring process must not be lower than 50 DEG C for filling temperature control.
Sterilizing, packaging.
Embodiment five:
Prepare the Fasudic hydrochloride glucose injection of 100ml infusion bag.Operation is protected from light during preparing process.
1, glucose is first dissolved in ultrasonic tank and is carried out first time sterilization, specifically:
The water for injection of 100L or more is added in ultrasonic tank, and glucose is put into ultrasonic tank, ultrasonic sound oscillation
8-10 minutes, the sonic oscillation sound intensity was 1-5W/cm2, frequency 30-40KHz, ultrasonic pot bottom generates 10.5 μm of amplitudes；Ultrasound is defeated
Power is 45-55w out, ultrasonic waveform is impulse wave, pulse width 8-12ms.First time sterilization is carried out with this and dissolves Portugal simultaneously
Grape sugar is in water for injection.
If the quantity for preparing batch is too big, the capacity of primary ultrasound tank can not dissolve glucose, can be by grape sugar
It is arrived respectively in ultrasonic tank twice or repeatedly and sterilizes and dissolve.
2, the water for injection that water temperature is 80 DEG C or more amount of preparation total volumes 50% is added in dense preparing tank, glucose will be dissolved
Water for injection investment dense preparing tank in, open stirring 5 minutes until be completely dissolved.
3, it will be heated to 75-80 DEG C in dense preparing tank to after being completely dissolved in stirring, then extracts negative pressure to dense preparing tank internal pressure
Power is -62KPa to -54KPa, is then persistently heated to dense preparing tank, and continues to extract negative pressure in tank, and keep concentrated compounding pressure inside the tank
Be -62KPa to -54KPa, make to generate boiling 23 minutes in dense preparing tank with this condition, the shearing force generated using water boiling into
Row sterilization.
4, adjusting pH with appropriate 0.1mol/L HCl is 2.0~3.0.
5, the active carbon of total volume 0.2 ‰ (w/v) is put into again, is opened steam valve heating and is boiled, is stirred continuously heat preservation absorption
15min or so.
6, it takes off charcoal to recycle 20 minutes, and opens cooling water valve, medical fluid is cooled to 50-60 DEG C.
It is filled into target dilute preparing tank while hot.
7, ultrasonic tank is taken, 5L water for injection is added, water for injection temperature control system adds the hydrochloric acid of recipe quantity at 50-60 DEG C
Fasudil starts sonic oscillation, sound intensity 1-5W/cm2, frequency 30-40KHz, ultrasonic pot bottom generates 10.5 μm of amplitudes；It is super
Output acoustic power is 45-55w, ultrasonic waveform is impulse wave, pulse width 8-12ms.Sonic oscillation 10 minutes until hydrochloric acid method is relaxed
You are completely dissolved on ground, and solution of being subject to is clarified, and are added in target dilute preparing tank immediately.If the quantity for preparing batch is too big, once
The capacity of ultrasonic tank can not dissolve Fasudic hydrochloride, Fasudic hydrochloride can be arrived respectively in two times or repeatedly in ultrasonic tank
It sterilizes and dissolves.
8, open water for injection valve, add water for injection to target dilute preparing tank to amount of preparation 90%, open stir 10 points
Clock, while the appropriate regulating liquid medicine pH to 4.0~4.3 of dilute hydrochloric acid (0.1mol/L), 50-60 DEG C of regulating liquid medicine temperature is added.
9, water for injection is supplied to full dose, is stirred for 10 minutes, is then stirred liquid in dilute preparing tank and rotate 20-25 points repeatedly
Clock rotates repeatedly are as follows: liquid rotates clockwise 1-3 minutes in agitation dilute preparing tank, then from inversely stirring liquid in dilute preparing tank again
Rotation 1-3 minutes, rotates repeatedly, and every the direction of rotation of conversion in 1-3 minutes, generates high shear force；It flows back
Water shearing sterilization.
The agitating device that rotates repeatedly of liquid in agitation dilute preparing tank are as follows: two groups of reflux pumps are set on dilute preparing tank, first group
Reflux pump is rotated clockwise for stirring liquid in dilute preparing tank, and second group of reflux pump revolves counterclockwise for stirring liquid in dilute preparing tank
Turn.
The water outlet of first group of reflux pump is arranged outside dilute preparing tank in a clockwise direction and from dilute preparing tank inner circle tangential direction
On wall, for example, 5 water outlets are arranged in first group of reflux pump, equably it is distributed on dilute preparing tank outer wall from top to bottom.When this 5
When water outlet high speed sprays into liquid into dilute preparing tank along a tangential direction, the medical fluid that will be stirred in dilute preparing tank is rotated clockwise.
The bottom in dilute preparing tank is arranged in the water inlet of first group of reflux pump, sucks medical fluid from the bottom in dilute preparing tank.Cause
This medical fluid is exactly to pass through first group of reflux pump to be recycled.
The water outlet of second group of reflux pump is arranged outside dilute preparing tank in a counterclockwise direction and from dilute preparing tank inner circle tangential direction
On wall, first group of reflux pump of remaining structural reference.Medical fluid in second group of reflux pump agitation dilute preparing tank rotates counterclockwise.
Above-mentioned first group of reflux pump is alternately and repeatedly opened with second group of reflux pump, rotates liquid in dilute preparing tank repeatedly, is produced
Raw high shear force.
The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
10, starting spray pump passes through back filter system and returns filter 25 minutes.
11, sample tap sampling, which is sent to intermediate sensing chamber, is detected.
12, the qualified intermediate of detection is filtered through titanium, 0.45 miillpore filter, and 0.22 μm of aseptic filtration is returned filter to visible foreign matters and closed
Filling after lattice and displacement, at 50-60 DEG C, the minimum temperature of pouring process must not be lower than 50 DEG C for filling temperature control.
In pouring process, persistently to the rotational agitation repeatedly of liquid in dilute preparing tank；Specifically, liquid in rotation in agitation dilute preparing tank
It 3-5 minutes, then from inversely stirring again in dilute preparing tank liquid in rotation 3-5 minutes, rotates, and turned every 3-5 minutes repeatedly
A direction of rotation is changed, high shear force is generated.The mode of agitation and the above-mentioned mode to the rotational agitation repeatedly of liquid in dilute preparing tank
It is identical.The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
13, it sterilizes, pack.
Embodiment six:
Prepare the Fasudic hydrochloride common salt injection of 100ml infusion bag.Operation is protected from light during preparing process.
1, common salt is first dissolved in ultrasonic tank and is carried out first time sterilization, specifically:
The water for injection of 100L or more is added in ultrasonic tank, and common salt is put into ultrasonic tank, ultrasonic sound oscillation
8-10 minutes, the sonic oscillation sound intensity was 1-5Wcm2, frequency 30-40KHz, and ultrasonic pot bottom generates 10.5 μm of amplitudes；Ultrasound output
Power is 45-55w, ultrasonic waveform is impulse wave, pulse width 8-12ms.First time sterilization is carried out with this and dissolves chlorination simultaneously
It is contained in water for injection.
If the quantity for preparing batch is too big, the capacity of primary ultrasound tank can not dissolve common salt, can be by common salt point
It is arrived respectively in ultrasonic tank twice or repeatedly and sterilizes and dissolve.
2, the water for injection that water temperature is 80 DEG C or more amount of preparation total volumes 50% is added in dense preparing tank, common salt will be dissolved
Water for injection investment dense preparing tank in, open stirring 5 minutes until be completely dissolved.
3, it will be heated to 75-80 DEG C in dense preparing tank to after being completely dissolved in stirring, then extracts negative pressure to dense preparing tank internal pressure
Power is -62KPa to -54KPa, is then persistently heated to dense preparing tank, and continues to extract negative pressure in tank, and keep concentrated compounding pressure inside the tank
Be -62KPa to -54KPa, make to generate boiling 23 minutes in dense preparing tank with this condition, the shearing force generated using water boiling into
Row sterilization.
4, the active carbon of total volume 0.4 ‰ (w/v) is put into again, is opened steam valve heating and is boiled, is stirred continuously heat preservation absorption
15min or so.
5, it takes off charcoal to recycle 20 minutes, and opens cooling water valve, medical fluid is cooled to 50-60 DEG C.
It is filled into target dilute preparing tank while hot.
6, ultrasonic tank is taken, 5L water for injection is added, water for injection temperature control system adds the hydrochloric acid of recipe quantity at 50-60 DEG C
Fasudil starts sonic oscillation, sound intensity 1-5W/cm2, frequency 30-40KHz, ultrasonic pot bottom generates 10.5 μm of amplitudes；It is super
Output acoustic power is 45-55w, ultrasonic waveform is impulse wave, pulse width 8-12ms.Sonic oscillation 10 minutes until hydrochloric acid method is relaxed
You are completely dissolved on ground, and solution of being subject to is clarified, and are added in target dilute preparing tank immediately.If the quantity for preparing batch is too big, once
The capacity of ultrasonic tank can not dissolve Fasudic hydrochloride, Fasudic hydrochloride can be arrived respectively in two times or repeatedly in ultrasonic tank
It sterilizes and dissolves.
7, open water for injection valve, add water for injection to target dilute preparing tank to amount of preparation 90%, open stir 10 points
Clock, while the appropriate regulating liquid medicine pH to 4.0~4.3 of dilute hydrochloric acid (0.1mol/L), 50-60 DEG C of regulating liquid medicine temperature is added.
8, water for injection is supplied to full dose, is stirred for 10 minutes, is then stirred liquid in dilute preparing tank and rotate 20-25 points repeatedly
Clock rotates repeatedly are as follows: liquid rotates clockwise 1-3 minutes in agitation dilute preparing tank, then from inversely stirring liquid in dilute preparing tank again
Rotation 1-3 minutes, rotates repeatedly, and every the direction of rotation of conversion in 1-3 minutes, generates high shear force；It flows back
Water shearing sterilization.
The agitating device that rotates repeatedly of liquid in agitation dilute preparing tank are as follows: two groups of reflux pumps are set on dilute preparing tank, first group
Reflux pump is rotated clockwise for stirring liquid in dilute preparing tank, and second group of reflux pump revolves counterclockwise for stirring liquid in dilute preparing tank
Turn.
The water outlet of first group of reflux pump is arranged outside dilute preparing tank in a clockwise direction and from dilute preparing tank inner circle tangential direction
On wall, for example, 5 water outlets are arranged in first group of reflux pump, equably it is distributed on dilute preparing tank outer wall from top to bottom.When this 5
When water outlet high speed sprays into liquid into dilute preparing tank along a tangential direction, the medical fluid that will be stirred in dilute preparing tank is rotated clockwise.
The bottom in dilute preparing tank is arranged in the water inlet of first group of reflux pump, sucks medical fluid from the bottom in dilute preparing tank.Cause
This medical fluid is exactly to pass through first group of reflux pump to be recycled.
The water outlet of second group of reflux pump is arranged outside dilute preparing tank in a counterclockwise direction and from dilute preparing tank inner circle tangential direction
On wall, first group of reflux pump of remaining structural reference.Medical fluid in second group of reflux pump agitation dilute preparing tank rotates counterclockwise.
Above-mentioned first group of reflux pump is alternately and repeatedly opened with second group of reflux pump, rotates liquid in dilute preparing tank repeatedly, is produced
Raw high shear force.
The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
9, starting spray pump passes through back filter system and returns filter 25 minutes.
10, sample tap sampling, which is sent to intermediate sensing chamber, is detected.
11, the qualified intermediate of detection is filtered through titanium, 0.45 miillpore filter, and 0.22 μm of aseptic filtration is returned filter to visible foreign matters and closed
Filling after lattice and displacement, at 50-60 DEG C, the minimum temperature of pouring process must not be lower than 50 DEG C for filling temperature control.
In pouring process, persistently to the rotational agitation repeatedly of liquid in dilute preparing tank；Specifically, liquid in rotation in agitation dilute preparing tank
It 3-5 minutes, then from inversely stirring again in dilute preparing tank liquid in rotation 3-5 minutes, rotates, and turned every 3-5 minutes repeatedly
A direction of rotation is changed, high shear force is generated.The mode of agitation and the above-mentioned mode to the rotational agitation repeatedly of liquid in dilute preparing tank
It is identical.The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
12, it sterilizes, pack.
In the above embodiment of the present invention, first various be put into ultrasonic tank with material is dissolved, then carries out ultrasonic sterilization.
Ultrasonic wave is to be made of a series of longitudinal wave of density interphases, and propagated around by liquid medium.When sound can be sufficiently high, In
In the loose half period, the attraction between liquid phase molecule is broken, formed cavitation nucleus, the service life of cavitation nucleus is about 0.1 μ S, it
The moment of explosion can produce localized hyperthermia and the hyperbaric environment of about 4000K and 100MPa, and generating speed is about 110m/s tool
There is the microjet of intense impact, microjet effect can form strong mechanical stirring effect between interface, and this effect can
To break through the limitation of wake boundary, thus chemical reaction process and transmittance process between strengthening interface.
Ultrasonic wave is the sound wave that frequency is greater than 20kHz, is a kind of mechanical oscillation propagated in medium.Due to its frequency
Height, wavelength are short, and other than having the characteristics that good directionality, power are big, penetration power is strong, ultrasonic energy causes cavitation and one
The special effects of series, such as mechanics effect, calorifics effect, chemical effect and biological effect.Sterilization effect possessed by ultrasonic wave
Power makes microbial cell content by strong concussion mainly due to cavitation caused by ultrasonic wave, to reach pair
The destruction of microorganism.So-called cavitation is when ultrasonic wave acts in the medium, and intensity is more than a certain air threshold values
When, cavitation phenomenon can be generated, i.e., small air complex is activated under ultrasonic wave effect in liquid, shows as the vibration of complex
A series of dynamic processes such as swing, grow, shrink and collapse.The moment that air bubble shrinks and collapses in insulation steeps interior present
5000 DEG C or more of high temperature and the rate of temperature change of 109K/s generate the strong impact wave for being up to 108N/m2.Utilize ultrasonic air
Change the local instantaneous high-temperature and temperature alternating variation, local instantaneous pressure and pressure change that effect generates in a liquid, makes liquid
In certain bacteriums it is lethal, it is virally inactivated, or even make the cell wall damage of some microorganisms of small volume.
In this example, ultrasonic sterilization effect is as follows:
| Sterilize duration | Output power | Ultrasonic frequency | Sterilization effect |
| 1 minute | 50w | 30KHz | 8% |
| 3 minutes | 50w | 30KHz | 14% |
| 5 minutes | 50w | 30KHz | 17% |
| 7 minutes | 50w | 30KHz | 21.5% |
| 9 minutes | 50w | 30KHz | 22.5% |
| 10 minutes | 50w | 30KHz | 23.3% |
| 13 minutes | 50w | 30KHz | 24.0% |
| 15 minutes | 50w | 30KHz | 24.4% |
In the test of ultrasonic sterilization, sterilization time can have an impact final sterilization effect, when longer sterilizing
Between can bring better sterilization effect, when sterilization time was at 5 minutes or more, sterilization effect can be with significantly increasing, but works as
More than after a certain period of time, 13 minutes or more, sterilization effect was not in that ratio increases, result, it is believed that the sterilizing in 5-10 minutes
Time is most significant.The present invention takes 5-10 minutes ultrasonic sterilization times in an implementation, ultrasonic sound use cost, the time with
It is balanced between sterilizing.
In the above embodiment of the present invention, negative pressure is extracted in dense preparing tank to -62KPa to -54KPa, and to concentrated compounding tank body
Continuous heating makes to generate convection current and boiling in hermetically sealed can, to dense preparing tank bottom-heated using heating outside tank body, passes through infrared ray
The modes such as heating, electromagnetic heating, select electromagnetic heating here.Therefore, when in dense preparing tank vacuum take away, internal pressure is less than big
Air pressure takes -62KPa to -54KPa, preferably -70KPa here, dense in -70KPa according to water for injection boiling point and pressure dependence
Liquid in distribution tank can reach boiling point after 77 DEG C, therefore, temperature is controlled at 75-85 DEG C；Concentrated compounding pot bottom is heated to
More than 80 DEG C, boiling and convection current are produced in dense preparing tank, the very fast Complex Flows generated when using water boiling sterilize.
In the above embodiment of the present invention, stir in dilute preparing tank liquid in rotation 3-5 minutes, then from inversely stirring dilute match again
Pot liquid rotates 3-5 minutes, rotates repeatedly, and every the direction of rotation of conversion in 3-5 minutes.
Volume in dense preparing tank is about 3000L, be conducive to existing air exhauster, can satisfy extract negative pressure to -62KPa extremely -
The ability of 54KPa, and the cost for extracting negative pressure is not high.And the volume of dilute preparing tank is 7000L, extracts the cost mistake of negative pressure
It is high.Therefore the present invention takes dense preparing tank to take out negative pressure boiling sterilizing, the mode that dilute preparing tank takes rotary injection water to sterilize.
And ultrasonic tank volume minimum, it is less than 1000L, therefore can use sonic oscillation, but dense preparing tank and dilute preparing tank volume
Excessive, using sonic oscillation, cost is excessively high.
Because the injection water flow of high-speed circulating allows bacterium that can not be attached to wall surface of the container, and recycles injection water flow tool
There is uncertain sinuous flow, between making water for injection molecule mutual extrusion, generates shearing force, this shearing force, which has cell to destroy, to be made
With.Therefore achieve the effect that certain.
But the shearing force sterilizing for being conducive to the injection water flow of high-speed circulating should not cross for a long time, because of medical fluid people of the invention
The canned time prepared is unsuitable too long, it is necessary to complete in 16 hours so canned.Therefore it must be strictly controlled each step process
Time, second is that water for injection shearing force bactericidal effect is limited, and after circulation time being more than 30 minutes, sterilization effect decline is prolonged
Become meaningless for a long time.Therefore the water for injection shearing force sterilization cycles time of the present invention takes 20-25 minutes.
In canning process, persistently to the rotational agitation repeatedly of liquid in dilute preparing tank, until medicine liquid tank is installed into dilute preparing tank.
Bacterium is further suppressed to grow during this period.
Process conditions: whole operation operates under 10000 grades of 100 grades of part laminar flow hoods；Film, interface, sealing cover send operation
Between before must through surface cleaning, disinfection treatment；Must first be checked before driving the name of an article of printing die plate, specification whether with production ordering
Unanimously.Whether the batch number of verification first three bag of lettering, date of manufacture, validity period are correct after driving.
The Fasudic hydrochloride common salt of 100ml infusion bag and the Fasudic hydrochloride glucose injection of 100ml infusion bag
Liquid final product quality:
Above-mentioned is exemplary illustration of the present invention, does not represent protection scope of the present invention.
Claims (10)
1. a kind of preparation process of fasudil hydrochloride injection, which is characterized in that it is completed by following steps,
(1), it is 75 DEG C or more that water temperature is added in dense preparing tank, the water for injection of amount of preparation total volume 45-55%,
(2), the drug for putting into recipe quantity is dissolved in dense preparing tank, stirring to being completely dissolved,
(3), active carbon is put into, steam valve heating is opened and boils, be stirred continuously heat preservation absorption；
(4), starting recycles de- charcoal；
(5), medical fluid is cooled to 50-60 DEG C, is filled into dilute preparing tank while hot.
(6), water for injection is added in dissolving tank, water for injection temperature control system is at 50-60 DEG C；The hydrochloric acid method that recipe quantity is added relaxes ground
You, stirs to being completely dissolved, is directed into dilute preparing tank；
(7), plus water for injection to dilute preparing tank to amount of preparation 90%, stir, at the same be added dilute hydrochloric acid regulating liquid medicine pH to 4.0~
4.3,50-60 DEG C of regulating liquid medicine temperature supplies water for injection to full dose, is stirred for, returns filter；
(4), intermediate is taken to monitor medical fluid pH；
(5), medical fluid is using filter, filling, sterilizing, packaging.
2. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that
The drug of the investment recipe quantity is dissolved in dense preparing tank, stirring to being completely dissolved, specifically: stirring 5 minutes until completely
Dissolution, and then adjusting pH with 0.1mol/L HCl is 2.0~3.0；
The investment active carbon is opened steam valve heating and is boiled, is stirred continuously heat preservation absorption, specifically: investment total volume
The active carbon of 0.2 ‰ w/v to 0.4 ‰ w/v is opened steam valve heating and is boiled, and heat preservation absorption 10min or more is stirred continuously；It is described
Starting recycle de- charcoal, specifically: de- charcoal recycles 20 minutes；
Described is cooled to 50-60 DEG C for medical fluid, specifically: it opens cooling water valve goalkeeper medical fluid and is cooled to 50-60 DEG C；
The addition dilute hydrochloric acid regulating liquid medicine pH to 4.0~4.3, specially dilute hydrochloric acid are 0.1mol/L；
It after supplying water for injection to full dose, is stirred for 10 minutes, returns filter 25 minutes；
The medical fluid using filter, it is filling, sterilizing, packaging, specifically: filtered through titanium, 0.45 miillpore filter, 0.22 μm of degerming
It is to visible foreign matters qualification and filling after replacing to filter back filter, filling temperature control is at 50-60 DEG C.
3. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that the drug
For one of DEXTROSE ANHYDROUS, sodium chloride.
4. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that the step
It further include before putting into drug in dense preparing tank, drug being dissolved in ultrasonic tank first and carries out first time sterilization, specifically
Are as follows:
The water for injection of 5 times of volumes of drug or more is added in ultrasonic tank, and drug is put into ultrasonic tank, ultrasonic sound oscillation
Progress first time sterilization in 8-10 minutes, and drug is dissolved simultaneously in water for injection；The water for injection investment for dissolving drug is dense
In distribution tank, completes drug and be dissolved in dense preparing tank.
5. a kind of preparation process of fasudil hydrochloride injection as claimed in claim 4, which is characterized in that the ultrasound
Parameter of oscillation are as follows: sound intensity 1-5W/cm2, frequency 30-40KHz, ultrasonic pot bottom generates 10.5 μm of amplitudes；Ultrasonic output power
It is impulse wave, pulse width 8-12ms for 45-55w, ultrasonic waveform.
6. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that the step
It further include that before investment active carbon investment active carbon, low-pressure boiled shearing water sterilization is carried out in dense preparing tank；
Then the low-pressure boiled shearing water sterilization extracts negative pressure to concentrated compounding specifically, by being heated to 75-80 DEG C in dense preparing tank
It is negative pressure in tank, then persistently dense preparing tank is heated, make to generate boiling in dense preparing tank, is carried out using the shearing force that water boiling generates
Sterilization.
7. a kind of preparation process of fasudil hydrochloride injection as claimed in claim 6, which is characterized in that the low pressure
Boiling shearing water sterilization is specifically, extracting negative pressure to concentrated compounding pressure inside the tank is -62KPa to -54KPa, then persistently to dense preparing tank
Heating, and continue to extract negative pressure in tank, and keeping concentrated compounding pressure inside the tank is -62KPa to -54KPa, is made in dense preparing tank in this condition
Lower generation is boiled 23 minutes.
8. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that the step
It further include that before taking intermediate to monitor medical fluid pH, recirculation water shearing sterilization is carried out in dilute preparing tank；Recirculation water shearing sterilization tool
Body is to stir liquid in dilute preparing tank to rotate repeatedly 20-25 minutes.
9. a kind of preparation process of fasudil hydrochloride injection as claimed in claim 8, which is characterized in that the agitation
Liquid rotates repeatedly in dilute preparing tank, rotates 1-3 minutes specifically, first stirring liquid up time in dilute preparing tank, then stir in dilute preparing tank
The liquid inverse time rotates 1-3 minutes, rotates repeatedly, and every the direction of rotation of conversion in 1-3 minutes, generates high shear force；
The agitating method that liquid rotates repeatedly in agitation dilute preparing tank are as follows: the water outlet of several first group of reflux pump is in a clockwise direction
And be arranged on dilute preparing tank outer wall from dilute preparing tank inner circle tangential direction, the water inlet of first group of reflux pump is arranged at dilute preparing tank bottom
First group of reflux pump in portion, above-mentioned setting completes right handed agitation in dilute preparing tank；
The water outlet of several second group of reflux pump is arranged outside dilute preparing tank in a counterclockwise direction and from dilute preparing tank inner circle tangential direction
On wall, in dilute preparing tank bottom, second group of reflux pump of above-mentioned setting is completed in dilute preparing tank for the water inlet setting of second group of reflux pump
The agitation rotated counterclockwise；
Above-mentioned first group of reflux pump is alternately and repeatedly opened with second group of reflux pump, rotates liquid in dilute preparing tank repeatedly, is generated high
Shearing force；
The water outlet parameter of the water outlet are as follows: flow is greater than 50L/min, flow velocity 2-3.5m/s.
10. a kind of preparation process of fasudil hydrochloride injection as described in claim 1, which is characterized in that in filling mistake
Cheng Zhong, persistently to the rotational agitation repeatedly of liquid in dilute preparing tank；It is rotated 1-3 minutes specifically, first stirring liquid up time in dilute preparing tank,
Stirring in dilute preparing tank the liquid inverse time again rotates 1-3 minutes, rotates repeatedly, and every the direction of rotation of conversion in 1-3 minutes,
Generate high shear force；
Until medicine liquid tank is installed into dilute preparing tank.
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