CN110721153A - Moxifloxacin hydrochloride sodium chloride injection and preparation process thereof - Google Patents
Moxifloxacin hydrochloride sodium chloride injection and preparation process thereof Download PDFInfo
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- CN110721153A CN110721153A CN201910950649.2A CN201910950649A CN110721153A CN 110721153 A CN110721153 A CN 110721153A CN 201910950649 A CN201910950649 A CN 201910950649A CN 110721153 A CN110721153 A CN 110721153A
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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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention provides a moxifloxacin hydrochloride sodium chloride injection and a preparation process thereof, wherein the moxifloxacin hydrochloride sodium chloride injection is prepared according to the following preparation ratio: 0.437 parts of moxifloxacin hydrochloride and 2 parts of sodium chloride are added into 250 parts of water for injection. The preparation process comprises the following steps: passivating a stainless steel container device, filling injection water, adding moxifloxacin hydrochloride into the injection water, stirring to dissolve, adding sodium chloride, stirring to dissolve, adsorbing the added activated carbon, and filtering to remove the carbon to obtain a primary filtrate; detecting the content of the intermediate, and adding water for injection to the prescription amount; fine filtering, filling and sterilizing. The invention provides a new proportioning component of moxifloxacin hydrochloride sodium chloride injection and a proportioning proportion. The production and preparation process has good 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
Moxifloxacin hydrochloride sodium chloride injection is applicable to upper respiratory tract infection and lower respiratory tract infection of adults (more than or equal to 18 years old), such as: acute sinusitis, acute episodes of chronic bronchitis, community-acquired pneumonia; and skin and soft tissue infections. Complex peritoneal infections include mixed bacterial infections such as abscesses. The preparation proportion of the moxifloxacin hydrochloride sodium chloride injection has not been better, so that the existing moxifloxacin hydrochloride 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 moxifloxacin hydrochloride 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 stainless steel container equipment after finishing the pharmaceutical industry 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 a stainless steel container apparatus for a sufficient time to achieve better bacterial adsorption.
Therefore, when the amount of the activated carbon in the stainless steel container equipment is too much and the adsorption time is too long, the active ingredients in the pharmaceutical industry in the stainless steel container equipment can be adsorbed, so that the amount of the active ingredients of the final finished product is reduced, and if the amount of the added activated carbon is too much, new pollution is caused to the liquid medicine, and the procedure and cost for later-stage decarburization are increased. Therefore, in the production process of the conventional moxifloxacin hydrochloride sodium chloride injection, the consumption of the activated carbon needs to be controlled, the balance between the sterilization effect and the consumption of the activated 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 moxifloxacin hydrochloride sodium chloride injection, the moxifloxacin hydrochloride sodium chloride injection is directly input into human blood, the lower the number of bacteria contained in the moxifloxacin hydrochloride sodium chloride injection is, the safer the moxifloxacin hydrochloride sodium chloride injection is theoretically, the growth speed of the bacteria is higher, and the unknown bacteria can grow in various complex environments, so that if the number of bacteria packaged in the liquid medicine at the early stage is lower, the number of bacteria growing in the liquid medicine in a certain period of time in stock at the later stage 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 moxifloxacin hydrochloride injection, the quantity of bacteria is hoped to be better controlled, the medicine effect is improved and lost, and the filtering cost is increased, so that the method belongs to the problem contradiction which is difficult to solve.
Disclosure of Invention
In order to solve the problems, the invention provides a moxifloxacin hydrochloride sodium chloride injection and a preparation process thereof.
The invention relates to a moxifloxacin hydrochloride sodium chloride injection which comprises the following components in percentage by weight:
adding moxifloxacin hydrochloride and sodium chloride into water for injection. The weight portions of the components are as follows: 250 parts of water for injection, 0.437 part of moxifloxacin hydrochloride and 2 parts of sodium chloride.
The invention provides a preparation process of moxifloxacin hydrochloride sodium chloride injection, which comprises the following steps of;
(1) passivating the stainless steel container equipment, and cleaning the passivated equipment;
(2) filling water for injection into a stainless steel container device, adding moxifloxacin hydrochloride with the prescription amount into the water for injection, and stirring to dissolve the moxifloxacin hydrochloride to obtain a solution;
(3) adding the sodium chloride with the prescription amount into the solution, and stirring to dissolve;
(4) adding the activated carbon into the solution, and stirring;
(5) adjusting the pH value of the solution to be between 4.2 and 4.45;
(6) filtering the solution to remove carbon to obtain primary filtrate;
(7) detecting the content of the intermediate, and adding water for injection to the prescription amount;
(8) fine filtering, filling and sterilizing.
The preparation process of the moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
passivating the stainless steel container equipment, and cleaning the passivated equipment; the method comprises the following specific steps: injecting 65-75 ℃ of injection water into the stainless steel container equipment, wherein the volume of the injection water accounts for 60-75% of the total volume of the stainless steel container equipment; weighing EDTA-2Na, adding into a tank, and stirring until the EDTA-2Na is dissolved; stopping stirring, continuously adding injection water to a full tank state, filling the solution in a stainless steel container device, and passivating at the passivation temperature of 70 ℃ for 1 h; then, discharging the solution from the stainless steel container equipment, and cleaning the passivated equipment;
the stainless steel container equipment is filled with water for injection, and specifically, the water for injection at 55-65 ℃ is added;
adding the activated carbon into the solution, and stirring; concretely, 0.01% (W/V)767 type needle activated carbon is added into stainless steel container equipment and stirred for 15 min;
the pH value of the adjusting solution is specifically adjusted to be between 4.2 and 4.45 by using one of 1M sodium hydroxide solution and 1M hydrochloric acid.
The fine filtration is fine filtration by using a 0.22 mu m microporous membrane;
the sterilization is carried out for 15 minutes by a superheated water bath at 121 ℃.
The preparation process of the moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
the method comprises the following steps of taking moxifloxacin hydrochloride with a prescription amount, adding the moxifloxacin hydrochloride into water for injection, specifically, adding more than 5 times of the volume of the water for injection into an ultrasonic tank, putting the moxifloxacin hydrochloride into the ultrasonic tank, carrying out ultrasonic oscillation for 8-10 minutes to carry out primary sterilization, dissolving a moxifloxacin hydrochloride substance into the water for injection, and then introducing the water for injection in which the moxifloxacin hydrochloride is dissolved into stainless steel container equipment;
adding the sodium chloride with the prescription amount into the solution, specifically, adding injection water with the volume of more than 5 times of the sodium chloride into an ultrasonic tank, putting the sodium chloride into the ultrasonic tank, oscillating for 8-10 minutes by ultrasonic sound to perform secondary sterilization, dissolving the sodium chloride in the injection water, and then introducing the injection water dissolved with the sodium chloride into a stainless steel container device.
The preparation process of the moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
the ultrasonic oscillation parameters are as follows: the sound intensity is 1-5W/cm2The frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 mu m amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
7. The process for preparing moxifloxacin hydrochloride sodium chloride injection according to claim 3, wherein the steps further comprise:
after sodium chloride with the prescription amount is added into the solution and stirred to be dissolved, the step of sterilizing by low-pressure boiling shear water is also carried out, which specifically comprises the following steps: heating the inside of the stainless steel container equipment to 55-65 ℃, then pumping negative pressure until the inside of the stainless steel container equipment is negative pressure, then continuously heating the stainless steel container equipment to ensure that the inside of the stainless steel container equipment is boiled, and sterilizing by utilizing the shearing force generated by boiling water.
The preparation process of the moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
the low-pressure boiling shearing water sterilization is specifically to extract negative pressure until the pressure in the stainless steel container equipment is-85 KPa to-76 KPa, then continuously heat the stainless steel container equipment, continuously extract the negative pressure in the tank, and keep the pressure in the stainless steel container equipment to be-85 KPa to-76 KPa, so that the stainless steel container equipment is boiled for 23 minutes under the conditions.
The preparation process of the moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
the fine filtration is that the solution in the stainless steel container equipment is fine-filtered to a diluting preparation tank, and then reflux water shearing sterilization is carried out in the diluting preparation tank; 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 moxifloxacin hydrochloride sodium chloride injection 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 from the reverse direction, the rotation is repeated, and the rotation direction is changed once every 1-3 minutes to generate high shearing force;
the stirring method for stirring the liquid in the diluting preparation tank to rotate repeatedly comprises the following steps: 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 moxifloxacin hydrochloride sodium chloride injection is further explained as follows:
the filling is that in the filling process, the liquid in the diluting preparation tank is continuously rotated and stirred repeatedly; stirring the liquid in the diluting and blending tank for 3-5 minutes, then reversely stirring the liquid in the diluting and blending tank for 3-5 minutes, repeatedly rotating in the way, and converting the rotating direction every 3-5 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 moxifloxacin hydrochloride sodium chloride injection and a proportioning proportion. The moxifloxacin hydrochloride sodium chloride injection provided by the invention has a better treatment effect.
The invention provides a novel production and preparation process of moxifloxacin hydrochloride sodium chloride injection.
The production and preparation process has good 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 stainless steel container equipment, sterilization by the shearing force of reflux water in a diluting 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: moxifloxacin hydrochloride sodium chloride injection for 250ml infusion bags is prepared.
| Raw and auxiliary materials | Manufacturer of the product | g/bag |
| Moxifloxacin hydrochloride | Shenyang Zhonghai pharmaceutical Co Ltd | 0.437 |
| Sodium chloride | 2.0g(W/V0.8％) | |
| Water for injection | 250ml |
Example two:
preparing moxifloxacin hydrochloride sodium chloride injection.
1. Prior to sample preparation, stainless steel containment devices were passivated with a 1% EDTA-2Na solution. The passivation method comprises the following steps: injecting 65-66 ℃ of injection water into the stainless steel container equipment, wherein the volume of the injection water accounts for 60% of the total volume of the stainless steel container equipment; EDTA-2Na is weighed and added into a pot to be stirred until being dissolved. Stopping stirring, continuously adding water for injection to a full tank state, filling the stainless steel container equipment with the solution, and passivating at 70 ℃ for 1 h. The solution was then drained from the stainless steel container apparatus and the passivated apparatus was cleaned.
2. Weighing moxifloxacin hydrochloride with the prescription amount, adding the moxifloxacin hydrochloride with the prescription amount into injection water with the prescription amount, heating the water to 60 ℃, and stirring to dissolve.
3. The prescribed amount of sodium chloride was weighed out and added to the above solution and stirred to dissolve.
4. 0.01% (W/V)767 type needle activated carbon is weighed, added to the above solution, and stirred for 15 min.
5. The solution pH was adjusted between 4.2 and 4.45 with 1M sodium hydroxide solution.
6. Filtering the solution with filter paper to remove carbon to obtain primary filtrate.
7. Detecting the content of the intermediate, (the detection method is shown in the attached page) determining whether water needs to be supplemented, and adding the water for injection to the prescription amount.
8. Fine filtering with 0.22 μm microporous membrane, and packaging.
9. Sterilized at 121 ℃ for 15 minutes.
Example three:
preparing moxifloxacin hydrochloride sodium chloride injection.
1. Prior to sample preparation, stainless steel containment devices were passivated with a 1% EDTA-2Na solution. The passivation method comprises the following steps: injecting 70-73 ℃ of injection water into the stainless steel container equipment, wherein the volume of the injection water accounts for 70% of the total volume of the stainless steel container equipment; EDTA-2Na is weighed and added into a pot to be stirred until being dissolved. Stopping stirring, continuously adding water for injection to a full tank state, filling the stainless steel container equipment with the solution, and passivating at 70 ℃ for 1 h. The solution was then drained from the stainless steel container apparatus and the passivated apparatus was cleaned.
2. Moxifloxacin hydrochloride with the prescription amount is weighed, added into injection water with the prescription amount of 65 ℃, and stirred to be dissolved.
3. The prescribed amount of sodium chloride was weighed out and added to the above solution and stirred to dissolve.
4. 0.01% (W/V)767 type needle activated carbon is weighed, added to the above solution, and stirred for 15 min.
5. The pH of the solution was adjusted to between 4.2 and 4.45 with 1M hydrochloric acid.
6. Filtering the solution with filter paper to remove carbon to obtain primary filtrate.
7. Detecting the content of the intermediate, (the detection method is shown in the attached page) determining whether water needs to be supplemented, and adding the water for injection to the prescription amount.
8. Fine filtering with 0.22 μm microporous membrane, and packaging.
9. Sterilized at 121 ℃ for 15 minutes.
Example four:
preparing moxifloxacin hydrochloride sodium chloride injection.
1. Prior to sample preparation, stainless steel containment devices were passivated with a 1% EDTA-2Na solution. The passivation method comprises the following steps: injecting 70-73 ℃ of injection water into the stainless steel container equipment, wherein the volume of the injection water accounts for 70% of the total volume of the stainless steel container equipment; EDTA-2Na is weighed and added into a pot to be stirred until being dissolved. Stopping stirring, continuously adding water for injection to a full tank state, filling the stainless steel container equipment with the solution, and passivating at 70 ℃ for 1 h. The solution was then drained from the stainless steel container apparatus and the passivated apparatus was cleaned.
2. Adding 65 ℃ of water for injection into a stainless steel container device, wherein the adding amount is 70-90% of the amount of the prescription.
3. Adding 30L of water for injection of the moxifloxacin hydrochloride into an ultrasonic tank, putting the moxifloxacin hydrochloride into the ultrasonic tank, oscillating for 8-10 minutes by ultrasonic sound to perform primary sterilization, dissolving the moxifloxacin hydrochloride in the water for injection, and introducing the water for injection in which the moxifloxacin hydrochloride is dissolved into a stainless steel container device.
Adding 100L of water for injection into the ultrasonic tank, adding sodium chloride into the ultrasonic tank, performing ultrasonic vibration for 20-25 min for secondary sterilization, dissolving sodium chloride in water for injection, and introducing the water for injection with sodium chloride dissolved into stainless steel container.
When the preparation amount for one time is too large, the moxifloxacin hydrochloride or the sodium chloride is required to be added, and the injection water in the ultrasonic tank is filled completely and cannot be completely dissolved, the moxifloxacin hydrochloride or the sodium chloride can be added into the ultrasonic tank in multiple batches, a part of moxifloxacin hydrochloride or the sodium chloride is added into the injection water once, the mixture is led into a stainless steel container after being dissolved and sterilized, and then a part of moxifloxacin hydrochloride or the sodium chloride is added into the ultrasonic tank.
After the last liquid medicine in the ultrasonic tank is introduced into the stainless steel container, the ultrasonic tank should be cleaned with water for injection, and the cleaning water should be introduced into the stainless steel container.
In the first sterilization and the second sterilization, the ultrasonic oscillation parameters are as follows: the sound intensity is 1-5W/cm2The frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 mu m amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
4. Keeping the temperature in the stainless steel container equipment at 55-65 ℃, then extracting negative pressure until the pressure in the stainless steel container equipment is negative pressure from-85 KPa to-76 KPa, then continuously heating the stainless steel container equipment at the temperature higher than 65 ℃, continuously extracting the negative pressure in the tank, keeping the pressure in the stainless steel container equipment at-85 KPa to-76 KPa, boiling the stainless steel container equipment for 23 minutes under the condition, and sterilizing by utilizing the shearing force generated by water boiling.
5. 0.01% (W/V)767 type needle activated carbon is weighed, added to the above solution, and stirred for 15 min.
6. The pH of the solution is adjusted between 4.2 and 4.45 with 1M sodium hydroxide solution or 1M hydrochloric acid.
7. Filtering the solution with filter paper to remove carbon to obtain primary filtrate. Detecting the content of the intermediate, and adding water for injection to the prescription amount; fine filtering to a diluting preparation tank.
8. Carrying out reflux water shearing sterilization in a diluting preparation tank; the reflux water shearing sterilization is specifically that the liquid in the blending tank is stirred and repeatedly rotated for 20-25 minutes. Stirring the liquid in the diluting and blending tank to rotate for 1-3 minutes clockwise, stirring the liquid in the diluting and blending tank to rotate for 1-3 minutes anticlockwise, repeatedly rotating in the way, and converting the rotating direction once every 1-3 minutes to generate high shearing force;
the stirring method for stirring the liquid in the diluting preparation tank to rotate repeatedly comprises the following steps: 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 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 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.
9. Filling, wherein in the filling process, the liquid in the diluting preparation tank is subjected to repeated rotary stirring by referring to the stirring mode; 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.
10. Sterilizing with superheated water bath at 121 deg.C for 15 min.
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 its high frequency and short wavelength, it has good directivity, high power and strong penetrating powerUltrasonic energy causes cavitation and a series of special effects such as mechanical, thermal, chemical and biological effects. 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 deg.C or higher and a temperature change rate of 109K/s, and generate a temperature as high as 108N/m2Strong shock waves. 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:
| duration of sterilization | Output power | Frequency of ultrasonic waves | Sterilizing 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 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 the ultrasonic and the sterilization.
In the above embodiment of the present invention, the negative pressure is pumped to-85 KPa to-76 KPa in the stainless steel container apparatus, the stainless steel container apparatus body is continuously heated to generate convection and boiling in the sealed tank, the bottom of the stainless steel container apparatus is heated by 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 stainless steel container equipment is pumped away, the internal pressure is lower than the atmospheric pressure, wherein the pressure is-85 KPa to-76 KPa, preferably-80 KPa, and according to the relation between the boiling point of water for injection and the pressure, the liquid in the stainless steel container equipment can reach the boiling point after 60 ℃ according to-80 KPa, so that the temperature is controlled to be 55-65 ℃; the bottom of the stainless steel container device is heated to over 65 ℃, and boiling and convection are generated in the stainless steel container device. The convection makes the liquid generate complex movement, and has bacteriostasis and efficacy.
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 stainless steel container equipment is about 3000L, the existing air extractor is facilitated, the capacity of extracting negative pressure from-85 KPa to-76 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 stainless steel container equipment for boiling sterilization under negative pressure, and the diluting preparation tank adopts a rotary water for injection sterilization.
The ultrasonic tank has a volume of 100L, so that ultrasonic oscillation can be utilized, but the stainless steel container equipment and the diluting preparation tank have overlarge volumes, and the ultrasonic oscillation is adopted, so that the cost is overlarge.
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 moxifloxacin hydrochloride sodium chloride injection is characterized by comprising the following components in parts by weight:
adding moxifloxacin hydrochloride and sodium chloride into water for injection.
2. The moxifloxacin hydrochloride sodium chloride injection as claimed in claim 1, which is characterized in that the mixture ratio by weight parts is as follows: 250 parts of water for injection, 0.437 part of moxifloxacin hydrochloride and 2 parts of sodium chloride.
3. A preparation process of moxifloxacin hydrochloride sodium chloride injection is characterized by comprising the following steps;
(1) passivating the stainless steel container equipment, and cleaning the passivated equipment;
(2) filling water for injection into a stainless steel container device, adding moxifloxacin hydrochloride with the prescription amount into the water for injection, and stirring to dissolve the moxifloxacin hydrochloride to obtain a solution;
(3) adding the sodium chloride with the prescription amount into the solution, and stirring to dissolve;
(4) adding the activated carbon into the solution, and stirring;
(5) adjusting the pH value of the solution to be between 4.2 and 4.45;
(6) filtering the solution to remove carbon to obtain primary filtrate;
(7) detecting the content of the intermediate, and adding water for injection to the prescription amount;
(8) fine filtering, filling and sterilizing.
4. The preparation process of moxifloxacin hydrochloride sodium chloride injection as claimed in claim 3, wherein,
passivating the stainless steel container equipment, and cleaning the passivated equipment; the method comprises the following specific steps: injecting 65-75 ℃ of injection water into the stainless steel container equipment, wherein the volume of the injection water accounts for 60-75% of the total volume of the stainless steel container equipment; weighing EDTA-2Na, adding into a tank, and stirring until the EDTA-2Na is dissolved; stopping stirring, continuously adding injection water to a full tank state, filling the solution in a stainless steel container device, and passivating at the passivation temperature of 70 ℃ for 1 h; then, discharging the solution from the stainless steel container equipment, and cleaning the passivated equipment;
the stainless steel container equipment is filled with water for injection, and specifically, the water for injection at 55-65 ℃ is added;
adding the activated carbon into the solution, and stirring; concretely, 0.01% (W/V)767 type needle activated carbon is added into stainless steel container equipment and stirred for 15 min;
the pH value of the adjusting solution is specifically adjusted to be between 4.2 and 4.45 by using one of 1M sodium hydroxide solution and 1M hydrochloric acid.
The fine filtration is fine filtration by using a 0.22 mu m microporous membrane;
the sterilization is carried out for 15 minutes by a superheated water bath at 121 ℃.
5. The preparation process of moxifloxacin hydrochloride sodium chloride injection as claimed in claim 3, wherein,
the method comprises the following steps of taking moxifloxacin hydrochloride with a prescription amount, adding the moxifloxacin hydrochloride into water for injection, specifically, adding the water for injection with more than 5 times of the volume of the moxifloxacin hydrochloride into an ultrasonic tank, putting the moxifloxacin hydrochloride into the ultrasonic tank, oscillating for 8-10 minutes by ultrasonic sound to perform first sterilization, dissolving a moxifloxacin hydrochloride substance into the water for injection, and then introducing the water for injection with the moxifloxacin hydrochloride dissolved into stainless steel container equipment;
adding the sodium chloride with the prescription amount into the solution, specifically, adding injection water with more than 5 times of the volume of the sodium chloride into an ultrasonic tank, putting the sodium chloride into the ultrasonic tank, carrying out ultrasonic oscillation for 8-10 minutes to carry out secondary sterilization, dissolving the sodium chloride in the injection water, and then introducing the injection water dissolved with the sodium chloride into stainless steel container equipment.
6. The preparation process of moxifloxacin hydrochloride sodium chloride injection according to claim 5, wherein the ultrasonic oscillation parameters are as follows: the sound intensity is 1-5W/cm2The frequency is 30-40KHz, and the bottom of the ultrasonic tank generates 10.5 mu m amplitude; the ultrasonic output power is 45-55w, the ultrasonic wave is pulse wave, and the pulse width is 8-12 ms.
7. The process for preparing moxifloxacin hydrochloride sodium chloride injection according to claim 3, wherein the steps further comprise:
after sodium chloride with the prescription amount is added into the solution and stirred to be dissolved, the step of sterilizing by low-pressure boiling shear water is also carried out, which specifically comprises the following steps: heating the inside of the stainless steel container equipment to 55-65 ℃, then pumping negative pressure until the inside of the stainless steel container equipment is negative pressure, then continuously heating the stainless steel container equipment to ensure that the inside of the stainless steel container equipment is boiled, and sterilizing by utilizing the shearing force generated by boiling water.
8. The preparation process of moxifloxacin hydrochloride sodium chloride injection according to claim 7, wherein the low-pressure boiling and shearing water sterilization is specifically that negative pressure is extracted until the pressure in a stainless steel container device is-85 KPa to-76 KPa, then the stainless steel container device is continuously heated, the negative pressure in the tank is continuously extracted, the pressure in the stainless steel container device is kept at-85 KPa to-76 KPa, and the stainless steel container device is boiled for 23 minutes under the condition.
9. The preparation process of moxifloxacin hydrochloride sodium chloride injection according to claim 3, wherein the fine filtration comprises fine filtration of the solution in a stainless steel container device to a dilution tank, and then reflux water shear sterilization in the dilution tank; 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 moxifloxacin hydrochloride sodium chloride injection according to claim 9, wherein the liquid in the stirring dilution tank is repeatedly rotated, specifically, the liquid in the stirring dilution tank is rotated for 1-3 minutes, then the liquid in the stirring dilution tank is again rotated for 1-3 minutes from the reverse direction, the rotation is repeated, and the rotation direction is changed once every 1-3 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 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 process for preparing moxifloxacin hydrochloride sodium chloride injection according to claim 3, wherein the filling step is that the liquid in the dilution tank is continuously rotated and stirred repeatedly during the filling process; stirring the liquid in the diluting and blending tank for 3-5 minutes, then reversely stirring the liquid in the diluting and blending tank for 3-5 minutes, repeatedly rotating in the way, and converting the rotating direction every 3-5 minutes to generate high shearing force;
until the liquid medicine in the diluting preparation tank is canned.
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| WO2021184699A1 (en) * | 2020-03-19 | 2021-09-23 | 石家庄四药有限公司 | Moxifloxacin hydrochloride and sodium chloride injection and preparation method therefor |
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