CN110538146A - levoornidazole sodium chloride injection and preparation process thereof - Google Patents
levoornidazole sodium chloride injection and preparation process thereof Download PDFInfo
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Abstract
The invention relates to a levo-ornidazole sodium chloride injection and a preparation process thereof, wherein the levo-ornidazole sodium chloride injection is prepared from levo-ornidazole, 0.1M hydrochloric acid, sodium chloride and water for injection. The preparation process comprises adding 0.1M hydrochloric acid, sodium chloride, and levoornidazole into water for injection, stirring, and dissolving. Adsorbing with activated carbon, removing carbon, adding the medicinal liquid into diluting tank, adjusting pH, adding water for injection to full volume, inspecting intermediate, and packaging. The levoornidazole sodium chloride injection has better treatment effect. The invention provides a new production and preparation process of a levoornidazole sodium chloride injection. The production and preparation process has better sterilization effect.
Description
Technical Field
the present invention relates to an injection and its preparation process. Belongs to the field of injection medicine production.
Background
the levoornidazole sodium chloride injection is used for treating various infectious diseases caused by sensitive anaerobic bacteria such as bacteroides fragilis, bacteroides dieldii, bacteroides ovatus, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium, eubacterium, streptococcus digestans, helicobacter pylori, bacteroides melanoides, clostridium, C02 weaves phage bacteria, gingivostomidae and the like, and is used for preventing infection before operation and treating anaerobic bacteria infection after operation. The preparation proportion of the levo-ornidazole sodium chloride injection has no better proportion all the time, so that the prior levo-ornidazole sodium chloride injection has low drug effect and the treatment effect needs to be further improved.
In the production process of injection, aseptic production is always the key of injection production, and multiple times of sterilization are carried out in the process of producing injection so as to control the total number of bacteria within the qualified number.
the same is true in the production process of the levoornidazole sodium chloride injection, and the total number of bacteria must be controlled. The existing control method mainly comprises the steps of carrying out once activated carbon adsorption, degerming and impurity removal in a thick preparation tank after the preparation pharmaceutical industry is finished in a high-cleanness production environment area. Then filtering and decarburizing to finish sterilization. Depending on the mode, to achieve better sterilization, a sufficient amount of activated carbon must be added, and the activated carbon must be stirred and mixed in the concentration tank for a sufficient time to achieve better bacteria adsorption.
however, when the amount of the activated carbon in the concentration tank is too large and the adsorption time is too long, the active ingredients in the pharmaceutical industry in the concentration tank can be adsorbed, so that the amount of the active ingredients in the final product is reduced, and if the amount of the activated carbon is too large, new pollution is caused to the liquid medicine, and the procedure and cost for later-stage decarburization are increased. Therefore, in the existing production process of the levoornidazole sodium chloride injection, the consumption of the active carbon must be controlled, the balance between the sterilization effect and the consumption of the active carbon is taken, the sterilization requirement is properly reduced, the requirement that the bacterial quantity reaches the standard within the specified control quantity is met, and the bacterial quantity is not further controlled.
for the injection of the levoornidazole and the sodium chloride, the injection is directly input into human blood, the lower the number of bacteria contained in the injection is, the safer the injection is theoretically, the growth speed of the bacteria is faster, and the unknown bacteria can grow in various complex environments, so that if the number of the bacteria packaged in the liquid medicine at the early stage is lower, the number of the bacteria growing in the liquid medicine at the later stage in a period of inventory is certainly lower. In the production period of the liquid medicine, it is very important to effectively sterilize the liquid.
Therefore, in the existing production mode of the injection of the levoornidazole and the sodium chloride, the bacteria quantity is hoped to be better controlled, the medicine effect is improved and lost, and the filtering cost is increased, which belongs to the problem contradiction which is difficult to solve.
disclosure of Invention
In order to solve the problems, the invention provides a levoornidazole sodium chloride injection and a preparation process thereof.
The invention relates to a levoornidazole sodium chloride injection, which comprises the following components in parts by weight:
Adding water for injection, levoornidazole, 0.1M hydrochloric acid, and sodium chloride.
The injection of the levoornidazole and the sodium chloride is further explained as follows according to the weight parts: 100 parts of water for injection, 0.25 part of ornidazole, 0.5-1.1 parts of 0.1M hydrochloric acid and 0.87 part of sodium chloride.
The injection of the levoornidazole and the sodium chloride is further explained as follows according to the weight parts: 100 parts of water for injection, 0.5 part of ornidazole and 0.83 part of sodium chloride.
A preparation process of a levoornidazole sodium chloride injection is completed by the following steps,
(1) Adding water for injection into a thick preparation tank, sequentially adding 0.1M hydrochloric acid, sodium chloride and levoornidazole according to the prescription amount, and stirring for dissolving.
(2) adding active carbon, stirring and adsorbing;
(2) Removing carbon;
(3) Injecting the liquid medicine into a diluting preparation tank, flushing the concentrating preparation tank with injection water, injecting the flushing water into the diluting preparation tank, and adjusting the pH value with 0.1M hydrochloric acid;
(4) Adding water for injection to the full amount;
(5) and checking an intermediate: measuring pH value, the content of the ornidazole, the content of sodium chloride and bacterial endotoxin;
(6) filtering the liquid medicine through a filter until the visible foreign matters are qualified;
(7) filling, sterilizing and packaging.
the preparation process of the levoornidazole sodium chloride injection comprises the following specific steps:
Injecting water for injection into the concentration tank, specifically, adding 80% of the injection water according to the prescription amount into the concentration tank, and controlling the temperature of the water for injection in the concentration tank to be 50-60 ℃;
The method comprises the following steps of (1) adding activated carbon, stirring and adsorbing, and specifically comprises the following steps: firstly wetting the activated carbon with water for injection until the water content is more than 5%, then adding the activated carbon with the diluted ligand volume of 0.03% into a concentrated preparation tank, and stirring for 15 minutes at 50-60 ℃;
The decarbonization is specifically that the liquid medicine in the concentration tank is decarbonized through a titanium rod filter;
The method comprises the following steps of flushing a thickening tank with injection water and pumping flushing water into a diluting tank, wherein the thickening tank is flushed with the injection water for 2-3 times, and the flushing water is completely conveyed into the diluting tank through a titanium rod filter;
The pH value is adjusted by 0.1M hydrochloric acid, in particular to the pH value is adjusted to 3.4 to 3.6 by 0.1M hydrochloric acid,
The intermediate inspection specifically comprises that the qualified value of the measured pH value is 3.3-3.7, the content of the levoornidazole is 95-105%, and the content of the sodium chloride is 95-105%;
The liquid medicine is filtered by a filter until the visible foreign matters are qualified, specifically, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
The sterilization comprises the following steps: sterilizing with superheated water bath at 121 deg.C for 8 min;
The packaging comprises the following steps: packaging is started about 2 hours after sterilization.
The preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
Adding 0.1M hydrochloric acid, sodium chloride and levoornidazole, stirring and dissolving, specifically, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole into an ultrasonic tank, performing ultrasonic sterilization and simultaneous dissolution, more specifically, adding water for injection into the ultrasonic tank, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole into the ultrasonic tank, performing ultrasonic oscillation for 8-10 min to perform primary sterilization, simultaneously dissolving ingredients in the water for injection, and adding 0.1M hydrochloric acid, sodium chloride and levoornidazole subjected to ultrasonic sterilization and dissolution into a concentration tank.
The preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
The ultrasonic oscillation parameters are as follows: the sound intensity is 1-5W/cm2, the frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 μm amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
the preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
before the activated carbon is put into the tank for stirring and adsorption, low-pressure boiling shearing water sterilization is carried out, specifically, negative pressure is extracted to the concentration tank to be negative pressure of-88 Kpa to-81 Kpa, then the concentration tank is continuously heated at the temperature of more than 60 ℃, the negative pressure in the tank is continuously extracted, the pressure in the concentration tank is kept to be-88 Kpa to-81 Kpa, the concentration tank is boiled for 23 minutes under the condition, and the shearing force generated by water boiling is utilized for sterilization.
The preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
the step also comprises the step of carrying out reflux water shearing sterilization in the diluting preparation tank after adding the injection water to the full amount; the reflux water shearing sterilization is specifically that the liquid in the blending tank is stirred and repeatedly rotated for 20-25 minutes.
The preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
The liquid in the stirring diluting and blending tank rotates repeatedly, specifically, the liquid in the stirring diluting and blending tank rotates for 1-3 minutes, then the liquid in the stirring diluting and blending tank rotates for 1-3 minutes in the opposite direction, and the rotating direction is changed every 1-3 minutes to generate high shearing force;
The further explanation is that: the water outlets of a plurality of first group of reflux pumps are arranged on the outer wall of the diluting preparation tank in a clockwise direction and from the tangential direction of the inner circle of the diluting preparation tank, the water inlets of the first group of reflux pumps are arranged at the bottom of the diluting preparation tank, and the arranged first group of reflux pumps complete the stirring of the clockwise rotation in the diluting preparation tank;
The water outlets of a plurality of second groups of reflux pumps are arranged on the outer wall of the diluting preparation tank in the anticlockwise direction and from the tangential direction of the inner circle of the diluting preparation tank, the water inlets of the second groups of reflux pumps are arranged at the bottom of the diluting preparation tank, and the arranged second groups of reflux pumps complete the stirring of the anticlockwise rotation in the diluting preparation tank;
The first group of reflux pumps and the second group of reflux pumps are repeatedly and alternately started to enable the liquid in the diluting preparation tank to repeatedly rotate to generate high shearing force;
the water outlet parameters of the water outlet are as follows: the flow rate is more than 50L/min, and the flow speed is 2-3.5 m/s.
The preparation process of the injection of the l-ornidazole and the sodium chloride is further explained as follows,
In the filling process, the liquid in the diluting preparation tank is continuously and repeatedly rotated and stirred; stirring the liquid in the diluting and blending tank for 1-3 minutes, then stirring the liquid in the diluting and blending tank for 1-3 minutes from the reverse direction, repeatedly rotating in the way, and converting the rotating direction every 1-3 minutes to generate high shearing force;
Until the liquid medicine in the diluting preparation tank is canned.
Has the advantages that:
The invention provides a new proportioning component of a levoornidazole sodium chloride injection and a proportioning proportion. The levoornidazole sodium chloride injection has better treatment effect.
The invention provides a new production and preparation process of a levoornidazole sodium chloride injection.
the production and preparation process has better sterilization effect.
under the condition of not adding more active carbon for adsorption sterilization, ultrasonic sterilization, sterilization by the shearing force of boiling water in the concentrated preparation tank, sterilization by the shearing force of reflux water in the diluted preparation tank and multiple sterilization steps are facilitated, so that the total amount of bacteria in the liquid medicine is better reduced. Or under the condition of keeping the total amount of bacteria in the existing liquid medicine unchanged and qualified products, the invention can reduce the dosage of the active carbon and reduce the adsorption time of the active carbon so as to keep the effective components of the liquid medicine.
Detailed Description
The first embodiment is as follows:
100ml of infusion bag of the injection of the levoornidazole and the sodium chloride with the content of 250mg is prepared.
The mixture ratio is as follows:
| prescription | Input amount |
| Levoornidazole | 0.25g |
| 0.1M hydrochloric acid | 0.9ml |
| Sodium chloride | 0.87g |
| Water for injection | 100ml |
Example two:
Prepare 100ml infusion bag of the injection of the levoornidazole and the sodium chloride with the content of 500 mg.
The mixture ratio is as follows:
example three:
and (3) preparing the infusion bag of the levoornidazole sodium chloride injection.
Concentration and preparation: adding 80% of injection water in a prescription amount into a concentration tank, keeping the water temperature at 50 ℃, sequentially adding 0.1M hydrochloric acid (1ml/100ml), sodium chloride in the prescription amount and the levoornidazole, and stirring to completely dissolve.
The activated carbon was wetted with water for injection to a water content of 7%, then 0.03% diluted activated carbon was added to the thick compounding tank and stirred at 50 ℃ for 15 minutes.
diluting and preparing: decarburizing the liquid medicine in the concentration tank through a titanium rod filter, completely conveying the liquid medicine to a diluting tank, flushing the concentrating tank with injection water for 2 times, completely conveying the flushing water to the diluting tank through the titanium rod filter, adjusting the pH value to 3.4-3.6 by using 0.1M hydrochloric acid, and adding injection water to full dose.
Checking an intermediate: measuring pH value (3.6), the content of the ornidazole (97-100%), the content of the sodium chloride (97-100%) and bacterial endotoxin.
after the semi-finished product is inspected to be qualified, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
filling: each bag is filled with 100ml of liquid medicine, and the opening is sealed and the cover is pressed.
And (3) sterilization: sterilizing at 121 deg.C for 8 min (water bath type sterilizing cabinet). And (6) checking, packaging and warehousing.
Example four:
And (3) preparing the infusion bag of the levoornidazole sodium chloride injection.
Concentration and preparation: adding 80% of injection water according to the prescription amount into a concentration tank, keeping the water temperature at 60 ℃, sequentially adding 0.1M hydrochloric acid (0.9ml/100ml), sodium chloride according to the prescription amount and the levoornidazole, and stirring to completely dissolve.
the activated carbon is wetted by water for injection to the water content of 8 percent, and then the activated carbon with the diluted ligand volume of 0.03 percent is added into a concentrated preparation tank and stirred for 15 minutes at the temperature of 60 ℃.
diluting and preparing: decarburizing the liquid medicine in the concentration tank through a titanium rod filter, completely conveying the liquid medicine to a diluting tank, flushing the concentrating tank with injection water for 3 times, completely conveying the flushing water to the diluting tank through the titanium rod filter, adjusting the pH value to 3.4-3.6 by using 0.1M hydrochloric acid, and adding injection water to full dose.
checking an intermediate: measuring pH value (3.5-3.6), content of ornidazole (100-105%), content of sodium chloride (100-105%) and bacterial endotoxin.
After the semi-finished product is inspected to be qualified, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
Filling: each bag is filled with 100ml of liquid medicine, and the opening is sealed and the cover is pressed.
And (3) sterilization: sterilizing at 121 deg.C for 8 min (water bath type sterilizing cabinet). And (6) checking, packaging and warehousing.
And (3) preparing the infusion bag of the levoornidazole sodium chloride injection.
Example five:
1. Firstly, 0.1M hydrochloric acid, sodium chloride and levoornidazole are put into an ultrasonic tank for ultrasonic sterilization and dissolution at the same time.
The method for sterilizing and simultaneously dissolving comprises the following steps: adding 100L of water for injection into an ultrasonic tank, adding half of the total amount of materials (0.1M hydrochloric acid, sodium chloride and levoornidazole) into the ultrasonic tank, performing ultrasonic oscillation for 8 minutes to perform first sterilization, dissolving the materials in the water for injection, and adding the 0.1M hydrochloric acid, sodium chloride and levoornidazole which are subjected to ultrasonic sterilization and dissolution into a concentration tank. In this process, the ultrasound parameters were: the sound intensity is 1-5W/cm2, the frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 μm amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
Then 100L of water for injection is added into the ultrasonic tank, and the other half of the materials are put into the ultrasonic tank to be vibrated, sterilized and dissolved, and then put into a concentration tank. And the ultrasonic tank is flushed with the injection, and the flushing water is also put into the thickening tank.
2. Concentration and preparation: adding 80% of water for injection at a prescription amount into a concentration tank, keeping the water temperature at 50 deg.C, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole which are subjected to ultrasonic sterilization and dissolution into the concentration tank, and stirring to completely dissolve.
extracting negative pressure until the pressure in the thick preparation tank is negative pressure of-88 Kpa, continuously heating the thick preparation tank at a temperature of above 60 ℃, continuously extracting the negative pressure in the tank, keeping the pressure in the thick preparation tank at-88 Kpa, boiling the thick preparation tank for 23 minutes under the condition, and sterilizing by utilizing the shearing force generated by water boiling.
3. The activated carbon is wetted with water for injection to a water content of 10%, then the activated carbon with a diluted ligand volume of 0.03% is added into a concentrated preparation tank, and stirred for 15 minutes at 50 ℃.
Diluting and preparing: decarburizing the liquid medicine in the concentration tank through a titanium rod filter, completely conveying the liquid medicine to the diluting tank, washing the concentrating tank with injection water for 3 times, completely conveying the washing water to the diluting tank through the titanium rod filter, and adjusting the pH value to 3.4-3.6 by using 0.1M hydrochloric acid.
adding water for injection to full volume, stirring the liquid in the diluting preparation tank, and repeatedly rotating for 25 minutes to carry out reflux water shearing sterilization.
Firstly stirring the liquid in the diluting and blending tank to rotate for 1 minute, then stirring the liquid in the diluting and blending tank to rotate for 1 minute from the reverse direction, repeating the rotation, and converting the rotation direction once every 1 minute to generate high shear force.
The stirring method for stirring the liquid in the diluting preparation tank to rotate repeatedly comprises the following steps: the delivery port of a plurality of first set of backwash pumps sets up on the tank outer wall is joined in marriage to the rarefied with clockwise and from the circle tangential direction in the tank of rare joining in marriage, and the water inlet setting of first set of backwash pump is in the tank bottom portion is joined in marriage to the rarefied, and the rotatory stirring of clockwise in the tank is joined in marriage to the first set of backwash pump of above-mentioned setting is accomplished to the rarefied.
The delivery port of a plurality of second group's backwash pumps sets up on the tank outer wall is joined in marriage to the rare direction and from the circle tangential direction in the rare jar of joining in marriage, and the water inlet setting of second group's backwash pump is in the bottom of the rare jar of joining in marriage, and the rotatory stirring of anticlockwise in the jar is accomplished to the backwash pump of the second group of above-mentioned setting.
The first group of reflux pumps and the second group of reflux pumps are repeatedly and alternately started to ensure that liquid in the diluting preparation tank is repeatedly rotated to generate high shearing force, and the reflux parameters are as follows: the flow rate is more than 50L/min, and the flow speed is 2-3.5 m/s.
checking an intermediate: measuring pH value (3.3-3.7), ornidazole content (100-105%), sodium chloride content (100-105%) and bacterial endotoxin.
After the semi-finished product is inspected to be qualified, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
filling: each bag is filled with 100ml of liquid medicine, and the opening is sealed and the cover is pressed. In the filling process, the liquid in the diluting preparation tank is continuously and repeatedly rotated and stirred; stirring the liquid in the diluting and blending tank for 4 minutes, then stirring the liquid in the diluting and blending tank for 4 minutes from the reverse direction, repeatedly rotating in the way, and converting the rotating direction once every 4 minutes to generate high shear force;
Until the liquid medicine in the diluting preparation tank is canned.
And (3) sterilization: sterilizing at 121 deg.C for 8 min (water bath type sterilizing cabinet). And (6) checking, packaging and warehousing.
the stirring device for stirring the liquid in the diluting preparation tank to rotate repeatedly is as follows: set up two sets of backwash pumps on the tank is joined in marriage to the rare, and first set of backwash pump is used for stirring the interior liquid clockwise rotation of tank is joined in marriage to the rare, and the second set of backwash pump is used for stirring the interior liquid anticlockwise rotation of tank is joined in marriage to the rare.
The delivery port of first set of backwash pump sets up on the tank outer wall of rare matching with clockwise and from the circle tangential direction in the rare matching jar, for example, first set of backwash pump sets up 5 delivery ports, evenly from the top down distributes on the tank outer wall of rare matching. When the 5 water outlets spray liquid into the diluting preparation tank at a high speed along the tangential direction, the liquid medicine in the diluting preparation tank is stirred to rotate clockwise.
The water inlet of the first set of reflux pump is arranged at the bottom of the diluting preparation tank, and the liquid medicine is sucked from the bottom of the diluting preparation tank. Therefore, the liquid medicine is circulated by the first group of reflux pumps.
The water outlet of the second group of reflux pumps is arranged on the outer wall of the diluting preparation tank in the anticlockwise direction and in the tangential direction of the inner circle of the diluting preparation tank, and the first group of reflux pumps is referred to by other structures. The second group of reflux pumps agitates the liquid medicine in the diluting preparation tank to rotate anticlockwise.
the first set of reflux pump and the second set of reflux pump are alternately started repeatedly to make the liquid in the diluting preparation tank rotate repeatedly to generate high shearing force. The reflux parameters were: the flow rate is more than 50L/min, and the flow speed is 2-3.5 m/s.
Example six:
1. Firstly, 0.1M hydrochloric acid, sodium chloride and levoornidazole are put into an ultrasonic tank for ultrasonic sterilization and dissolution at the same time.
the method for sterilizing and simultaneously dissolving comprises the following steps: adding 100L of water for injection into an ultrasonic tank, adding half of the total amount of materials (0.1M hydrochloric acid, sodium chloride and levoornidazole) into the ultrasonic tank, performing ultrasonic vibration for 25 min to perform first sterilization, dissolving the materials in the water for injection, and adding 0.1M hydrochloric acid, sodium chloride and levoornidazole which are subjected to ultrasonic sterilization and dissolution into a concentration tank. In this process, the ultrasound parameters were: the sound intensity is 1-5W/cm2, the frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 μm amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
then 100L of water for injection is added into the ultrasonic tank, and the other half of the materials are put into the ultrasonic tank to be vibrated, sterilized and dissolved, and then put into a concentration tank. And the ultrasonic tank is flushed with the injection, and the flushing water is also put into the thickening tank.
2. Concentration and preparation: adding 80% of water for injection at the prescribed dose into a concentration tank, keeping the water temperature at 60 deg.C, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole which are subjected to ultrasonic sterilization and dissolution into the concentration tank, and stirring to completely dissolve.
Injecting water for injection into a thick preparation tank, sequentially adding 0.1M hydrochloric acid, sodium chloride and levoornidazole according to the prescription amount, stirring and dissolving, and then carrying out low-pressure boiling shearing water sterilization, specifically, extracting negative pressure until the negative pressure in the thick preparation tank is negative pressure of-81 Kpa, continuously heating the thick preparation tank at the temperature of more than 60 ℃, continuously extracting the negative pressure in the tank, keeping the pressure in the thick preparation tank at-81 Kpa, boiling the thick preparation tank for 20 minutes under the condition, and sterilizing by utilizing the shearing force generated by water boiling.
3. The activated carbon is wetted by water for injection to the water content of 8 percent, and then the activated carbon with the diluted ligand volume of 0.03 percent is added into a concentrated preparation tank and stirred for 20 minutes at the temperature of 60 ℃.
Diluting and preparing: decarburizing the liquid medicine in the concentration tank through a titanium rod filter, completely conveying the liquid medicine to the dilution tank, washing the concentration tank with injection water for 2 times, completely conveying the washing water to the dilution tank through the titanium rod filter, and adjusting the pH value to 3.4-3.6 by using 0.1M hydrochloric acid.
Adding water for injection to full volume, stirring the liquid in the diluting preparation tank, and repeatedly rotating for 20 minutes to carry out reflux water shearing sterilization.
Firstly stirring the liquid in the diluting and blending tank for 3 minutes, then stirring the liquid in the diluting and blending tank for 3 minutes from the reverse direction, repeating the rotation, and converting the rotation direction once every 3 minutes to generate high shear force.
The stirring method for stirring the liquid in the diluting preparation tank to rotate repeatedly comprises the following steps: the delivery port of a plurality of first set of backwash pumps sets up on the tank outer wall is joined in marriage to the rarefied with clockwise and from the circle tangential direction in the tank of rare joining in marriage, and the water inlet setting of first set of backwash pump is in the tank bottom portion is joined in marriage to the rarefied, and the rotatory stirring of clockwise in the tank is joined in marriage to the first set of backwash pump of above-mentioned setting is accomplished to the rarefied.
The delivery port of a plurality of second group's backwash pumps sets up on the tank outer wall is joined in marriage to the rare direction and from the circle tangential direction in the rare jar of joining in marriage, and the water inlet setting of second group's backwash pump is in the bottom of the rare jar of joining in marriage, and the rotatory stirring of anticlockwise in the jar is accomplished to the backwash pump of the second group of above-mentioned setting.
The first set of reflux pump and the second set of reflux pump are alternately started repeatedly to make the liquid in the diluting preparation tank rotate repeatedly to generate high shearing force. The water outlet parameters of the water outlet are as follows: the flow rate is more than 50L/min, and the flow speed is 2-3.5 m/s.
Checking an intermediate: measuring pH value (3.3-3.7), ornidazole content (100-105%), sodium chloride content (100-105%) and bacterial endotoxin.
after the semi-finished product is inspected to be qualified, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
filling: each bag is filled with 100ml of liquid medicine, and the opening is sealed and the cover is pressed. In the filling process, the liquid in the diluting preparation tank is continuously and repeatedly rotated and stirred; stirring the liquid in the diluting and blending tank for 3 minutes, then stirring the liquid in the diluting and blending tank again in the reverse direction for 3 minutes, repeatedly rotating in the way, and converting the rotating direction once every 3 minutes to generate high shear force;
Until the liquid medicine in the diluting preparation tank is canned.
and (3) sterilization: sterilizing at 121 deg.C for 8 min (water bath type sterilizing cabinet). And (6) checking, packaging and warehousing.
The stirring device for stirring the liquid in the diluting preparation tank to rotate repeatedly is as follows: set up two sets of backwash pumps on the tank is joined in marriage to the rare, and first set of backwash pump is used for stirring the interior liquid clockwise rotation of tank is joined in marriage to the rare, and the second set of backwash pump is used for stirring the interior liquid anticlockwise rotation of tank is joined in marriage to the rare.
the delivery port of first set of backwash pump sets up on the tank outer wall of rare matching with clockwise and from the circle tangential direction in the rare matching jar, for example, first set of backwash pump sets up 5 delivery ports, evenly from the top down distributes on the tank outer wall of rare matching. When the 5 water outlets spray liquid into the diluting preparation tank at a high speed along the tangential direction, the liquid medicine in the diluting preparation tank is stirred to rotate clockwise.
the water inlet of the first set of reflux pump is arranged at the bottom of the diluting preparation tank, and the liquid medicine is sucked from the bottom of the diluting preparation tank. Therefore, the liquid medicine is circulated by the first group of reflux pumps.
The water outlet of the second group of reflux pumps is arranged on the outer wall of the diluting preparation tank in the anticlockwise direction and in the tangential direction of the inner circle of the diluting preparation tank, and the first group of reflux pumps is referred to by other structures. The second group of reflux pumps agitates the liquid medicine in the diluting preparation tank to rotate anticlockwise.
the first set of reflux pump and the second set of reflux pump are alternately started repeatedly to make the liquid in the diluting preparation tank rotate repeatedly to generate high shearing force.
In the embodiment of the invention, various ingredients are firstly put into the ultrasonic tank for dissolution, and then ultrasonic sterilization is carried out. The ultrasonic wave is composed of a series of longitudinal waves with alternate density and is transmitted to the periphery through a liquid medium. When the sound energy is high enough, the attractive force among liquid phase molecules is broken in a loose half period to form a cavitation nucleus, the service life of the cavitation nucleus is about 0.1 mu S, the cavitation nucleus can generate local high-temperature and high-pressure environments of about 4000K and 100MPa at the moment of explosion, and generates microjet with strong impact at the speed of about 110m/S, the action of the microjet can form strong mechanical stirring effect among interfaces, and the effect can break through the limit of laminar boundary, so that the chemical reaction process and the transfer process among the interfaces are strengthened.
ultrasonic waves are sound waves with a frequency greater than 20kHz and are mechanical vibrations that propagate in a medium. Due to the high frequency and short wavelength, the ultrasonic wave can cause cavitation and a series of special effects such as mechanical effect, thermal effect, chemical effect and biological effect besides the characteristics of good directivity, high power, strong penetrating power and the like. The sterilization effect of the ultrasonic wave is mainly due to the cavitation effect generated by the ultrasonic wave, so that the contents of the microbial cells are strongly vibrated, and the destruction effect on the microbes is achieved. The cavitation is a cavitation phenomenon that when ultrasonic waves act in a medium and the intensity of the ultrasonic waves exceeds a certain air threshold value, tiny bubble nuclei in liquid are activated under the action of the ultrasonic waves and show a series of dynamic processes such as oscillation, growth, shrinkage and collapse of the bubble nuclei. At the moment of adiabatic shrinkage and collapse, the air bubbles have a high temperature of 5000 ℃ or higher and a temperature change rate of 109K/s, and generate strong shock waves of 108N/m 2. The ultrasonic cavitation effect is utilized to generate local instantaneous high temperature, temperature alternation change, local instantaneous high pressure and pressure change in the liquid, so that certain bacteria in the liquid are killed, viruses are inactivated, and even cell walls of a few microorganisms with small volume are damaged.
in this example, the ultrasonic sterilization effect is as follows:
In the ultrasonic sterilization test, the sterilization time affects the final sterilization effect, and a longer sterilization time brings a better sterilization effect, and when the sterilization time is 5 minutes or more, the sterilization effect is greatly increased, but when the sterilization time exceeds a certain time, the sterilization effect is not increased in proportion to 13 minutes or more, so that the sterilization time within 5 to 10 minutes is considered to be most significant. The invention takes 5-10 minutes of ultrasonic sterilization time in the implementation, and balances the use cost and time of ultrasonic sound and sterilization.
in the above embodiment of the invention, the negative pressure is extracted from the thickening tank to-88 KPa to-81 KPa, the thickening tank is continuously heated to generate convection and boiling in the sealing tank, the bottom of the thickening tank is heated by heating the outside of the tank, and electromagnetic heating is selected here by infrared heating, electromagnetic heating and the like. Therefore, when the vacuum in the concentration tank is pumped away, the internal pressure is less than the atmospheric pressure, and-88 KPa to-81 KPa is taken, according to the relation between the boiling point of the water for injection and the pressure, the boiling point of the liquid in the concentration tank can be reached after 50 ℃ to 60 ℃ according to the pressure relation between-88 KPa and-81 KPa, so that the temperature is controlled to be 50 ℃ to 60 ℃; the bottom of the concentration tank is heated to over 60 ℃, and boiling and convection are generated in the concentration tank. For example, according to the relationship between the boiling point of the water for injection and the pressure, the boiling point can be reached after the liquid in the concentration tank is 55 ℃ at-85 KPa. Sterilization is performed using the very fast flow generated when the water boils.
in the embodiment of the invention, the liquid in the stirring and diluting tank rotates for 1-3 minutes, then the liquid in the stirring and diluting tank rotates for 1-3 minutes from the reverse direction, the rotation is repeated, and the rotation direction is changed every 1-3 minutes.
the volume in the thick matching tank is about 3000L, the existing air extractor is facilitated, the capacity of extracting negative pressure from-88 KPa to-81 KPa can be met, and the cost of extracting the negative pressure is not high. The volume of the diluting preparation tank is 7000L, and the cost of extracting negative pressure is too high. Therefore, the invention adopts the way that the concentrated preparation tank is sterilized by boiling under negative pressure, and the diluted preparation tank is sterilized by rotating water for injection.
The volume of the ultrasonic tank is the minimum and is less than 1000L, so that ultrasonic oscillation can be utilized, but the volumes of the concentration tank and the diluting tank are too large, and the cost is too high due to the adoption of ultrasonic oscillation.
Because the high-speed circulating water flow for injection prevents bacteria from adhering to the wall surface of the container, and the circulating water flow for injection has uncertain turbulence, molecules of water for injection are squeezed to each other to generate shearing force, and the shearing force has destructive effect on cells. Thereby achieving a certain effect.
but the shearing force sterilization of the injection water flow which is beneficial to high-speed circulation is not suitable for too long time, and the canning is completed within 16 hours because the canning time of the liquid medicine prepared by the liquid medicine person of the invention is not suitable for too long time. Therefore, the time of each step of the process must be strictly controlled, secondly, the shearing force sterilization effect of the injection water is limited, and when the circulation time exceeds 30 minutes, the sterilization effect is reduced, and the extension time becomes meaningless. Therefore, the water shearing force sterilization cycle time for injection is 20-25 minutes.
In the canning process, the liquid in the diluting preparation tank is continuously and repeatedly rotated and stirred until the liquid medicine in the diluting preparation tank is canned. Further inhibiting bacterial growth during this period.
The foregoing is illustrative of the present invention and does not represent the scope of the invention.
Claims (11)
1. the levoornidazole sodium chloride injection is characterized by comprising the following components in parts by weight:
Adding water for injection, levoornidazole, 0.1M hydrochloric acid, and sodium chloride.
2. the levoornidazole sodium chloride injection as claimed in claim 1, wherein the proportions by weight are as follows: 100 parts of water for injection, 0.25 part of ornidazole, 0.5-1.1 parts of 0.1M hydrochloric acid and 0.87 part of sodium chloride.
3. the levoornidazole sodium chloride injection as claimed in claim 1, wherein the proportions by weight are as follows: 100 parts of water for injection, 0.5 part of ornidazole and 0.83 part of sodium chloride.
4. a preparation process of a levoornidazole sodium chloride injection, which is characterized by comprising the following steps of,
(1) Adding water for injection into a thick preparation tank, sequentially adding 0.1M hydrochloric acid, sodium chloride and levoornidazole according to the prescription amount, and stirring for dissolving.
(2) Adding active carbon, stirring and adsorbing;
(2) Removing carbon;
(3) injecting the liquid medicine into a diluting preparation tank, flushing the concentrating preparation tank with injection water, injecting the flushing water into the diluting preparation tank, and adjusting the pH value with 0.1M hydrochloric acid;
(4) Adding water for injection to the full amount;
(5) and checking an intermediate: measuring pH value, the content of the ornidazole, the content of sodium chloride and bacterial endotoxin;
(6) Filtering the liquid medicine through a filter until the visible foreign matters are qualified;
(7) Filling, sterilizing and packaging.
5. the preparation process of the levoornidazole sodium chloride injection as claimed in claim 4, is characterized by comprising the following steps:
Injecting water for injection into the concentration tank, specifically, adding 80% of the injection water according to the prescription amount into the concentration tank, and controlling the temperature of the water for injection in the concentration tank to be 50-60 ℃;
The method comprises the following steps of (1) adding activated carbon, stirring and adsorbing, and specifically comprises the following steps: firstly wetting the activated carbon with water for injection until the water content is more than 5%, then adding the activated carbon with the diluted ligand volume of 0.03% into a concentrated preparation tank, and stirring for 15 minutes at 50-60 ℃;
The decarbonization is specifically that the liquid medicine in the concentration tank is decarbonized through a titanium rod filter;
the method comprises the following steps of flushing a thickening tank with injection water and pumping flushing water into a diluting tank, wherein the thickening tank is flushed with the injection water for 2-3 times, and the flushing water is completely conveyed into the diluting tank through a titanium rod filter;
The pH value is adjusted by 0.1M hydrochloric acid, in particular to the pH value is adjusted to 3.4 to 3.6 by 0.1M hydrochloric acid,
The intermediate inspection specifically comprises that the qualified value of the measured pH value is 3.3-3.7, the content of the levoornidazole is 95-105%, and the content of the sodium chloride is 95-105%;
The liquid medicine is filtered by a filter until the visible foreign matters are qualified, specifically, the liquid medicine is filtered by a 0.22 mu m microporous filter until the visible foreign matters are qualified.
The sterilization comprises the following steps: sterilizing with superheated water bath at 121 deg.C for 8 min;
the packaging comprises the following steps: packaging is started about 2 hours after sterilization.
6. the preparation process of the levoornidazole sodium chloride injection as claimed in claim 4, wherein,
Adding 0.1M hydrochloric acid, sodium chloride and levoornidazole, stirring and dissolving, specifically, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole into an ultrasonic tank, performing ultrasonic sterilization and simultaneous dissolution, more specifically, adding water for injection into the ultrasonic tank, adding 0.1M hydrochloric acid, sodium chloride and levoornidazole into the ultrasonic tank, performing ultrasonic oscillation for 8-10 min to perform primary sterilization, simultaneously dissolving ingredients in the water for injection, and adding 0.1M hydrochloric acid, sodium chloride and levoornidazole subjected to ultrasonic sterilization and dissolution into a concentration tank.
7. The preparation process of the levoornidazole sodium chloride injection as claimed in claim 6, wherein the ultrasonic oscillation parameters are as follows: the sound intensity is 1-5W/cm2, the frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 μm amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
8. The process for preparing ringer's bicarbonate injection according to claim 5,
Before the activated carbon is put into the tank for stirring and adsorption, low-pressure boiling shearing water sterilization is carried out, specifically, negative pressure is extracted to the concentration tank to be negative pressure of-88 Kpa to-81 Kpa, then the concentration tank is continuously heated at the temperature of more than 60 ℃, the negative pressure in the tank is continuously extracted, the pressure in the concentration tank is kept to be-88 Kpa to-81 Kpa, the concentration tank is boiled for 23 minutes under the condition, and the shearing force generated by water boiling is utilized for sterilization.
9. The process for preparing the injection of the levoornidazole and the sodium chloride as claimed in claim 4, wherein the steps further comprise the step of shearing and sterilizing the injection water in the dilution tank by refluxing water after the injection water is added to the full amount; the reflux water shearing sterilization is specifically that the liquid in the blending tank is stirred and repeatedly rotated for 20-25 minutes.
10. The preparation process of the levoornidazole sodium chloride injection as claimed in claim 8, wherein the liquid in the agitation dilution tank is repeatedly rotated, specifically, the liquid in the agitation dilution tank is rotated for 1-3 minutes, then the liquid in the agitation dilution tank is reversely rotated for 1-3 minutes, and the rotation direction is switched every 1-3 minutes to generate high shear force;
the further explanation is that: the water outlets of a plurality of first group of reflux pumps are arranged on the outer wall of the diluting preparation tank in a clockwise direction and from the tangential direction of the inner circle of the diluting preparation tank, the water inlets of the first group of reflux pumps are arranged at the bottom of the diluting preparation tank, and the arranged first group of reflux pumps complete the stirring of the clockwise rotation in the diluting preparation tank;
The water outlets of a plurality of second groups of reflux pumps are arranged on the outer wall of the diluting preparation tank in the anticlockwise direction and from the tangential direction of the inner circle of the diluting preparation tank, the water inlets of the second groups of reflux pumps are arranged at the bottom of the diluting preparation tank, and the arranged second groups of reflux pumps complete the stirring of the anticlockwise rotation in the diluting preparation tank;
the first group of reflux pumps and the second group of reflux pumps are repeatedly and alternately started to enable the liquid in the diluting preparation tank to repeatedly rotate to generate high shearing force;
The water outlet parameters of the water outlet are as follows: the flow rate is more than 50L/min, and the flow speed is 2-3.5 m/s.
11. the preparation process of the levoornidazole sodium chloride injection as claimed in claim 4, wherein in the filling process, the liquid in the diluting and dispensing tank is continuously and repeatedly rotated and stirred; stirring the liquid in the diluting and blending tank for 1-3 minutes, then stirring the liquid in the diluting and blending tank for 1-3 minutes from the reverse direction, repeatedly rotating in the way, and converting the rotating direction every 1-3 minutes to generate high shearing force;
until the liquid medicine in the diluting preparation tank is canned.
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Application publication date: 20191206 |