CN112641926B - Teicoplanin preparation for injection and its preparing method - Google Patents
Teicoplanin preparation for injection and its preparing method Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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 discloses a teicoplanin preparation for injection and a preparation method thereof, belonging to the technical field of medicine, and comprising an injection preparation containing 0.2g of teicoplanin and an injection preparation containing 0.4g of teicoplanin. The preparation method comprises the following steps: firstly, preparing teicoplanin raw powder, then preparing liquid medicine, filling, and finally carrying out freeze-drying treatment. The teicoplanin prepared by the method has the advantages of obviously improved clarity, color grade, purity, endotoxin qualification rate and yield index, high purity of preparation products, plump appearance, no atrophy, no bubbling, uniform color, porosity, firm structure, high redissolution speed, low residual moisture, light color and greatly improved clarity and stability. Meanwhile, the preparation method has the advantages of low production cost, short production period, contribution to industrial production, advancement and important theoretical significance and application value for the production and clinical application of teicoplanin for injection.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a teicoplanin preparation for injection and a preparation method thereof.
Background
Currently, about 70 million people die worldwide each year from drug-resistant bacterial infections, mostly in developing countries and poor regions. Chinese antibiotics account for about half of the world, with about half being used by people and the rest being used in the food industry. By 2050, antibiotic resistance will result in premature death of 100 million Chinese people each year, with a cumulative loss of 20 trillion dollars to China. The number of deaths caused by antibiotic resistance in the world will rise to 1000 thousands, which is more than that of the deaths caused by the existing malignant tumors. Once drug resistance is developed by Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and other similar intestinal inhabitants, the novel glycopeptide antibiotics vancomycin, teicoplanin and the like having similar chemical structures will be the last line of defense in treating intestinal bacterial infection. Teicoplanin for injection was developed by the company amantadine, approved in italy and france in 1988, and sold under the trade name of tagatose; the uk and germany were marketed in 1989.
Teicoplanin (Teicoplanin), also known as peptomycin (Teicoplanin a2), is a novel glycopeptide antibiotic similar to vancomycin, discovered by pareti, et al 1978, produced by actinoplanes teichomyces. Teicoplanin has strong antibacterial activity mainly against gram-positive aerobic and anaerobic bacteria, sensitive bacteria include staphylococcus aureus and coagulase-positive staphylococcus, streptococcus, enterococcus, mononucleosis liturgil bacteria and micrococcus, and in addition, has good curative effect on penicillin and cephalosporin, macrolide, tetracycline, chloramphenicol, aminoglycoside and other drug-resistant gram-positive bacteria, especially on MRSA-induced infection, and is one of the few clinically available drugs with activity against multidrug-resistant staphylococcus aureus and enterococcus. Compared with the current internationally accepted antibiotic vancomycin resisting drug-resistant bacteria, teicoplanin has the following advantages:
(1) antibacterial activity: the action mechanisms of the teicoplanin and the staphylococcus aureus are the same, but the action of the teicoplanin on most staphylococcus aureus and streptococcus pneumoniae is better than that of vancomycin and norvancomycin, the action on enterococcus is good, and some enterococcus which are resistant to vancomycin are still sensitive to the teicoplanin.
(2) Pharmacokinetics: the lipophilicity of teicoplanin is 30-100 times of that of vancomycin, the teicoplanin is easier to permeate tissues and cells, the half life is long, the teicoplanin can be administrated 1 time a day, and the teicoplanin can be injected intravenously or intramuscularly. Therefore, teicoplanin has more convenient and faster administration route than vancomycin and is more convenient to apply.
(3) Safety: the medicine has the advantages of light adverse reaction, lower toxicity, particularly lower renal toxicity, no occurrence of 'Hongshensyndrome' caused by using vancomycin, no need of conventional blood concentration monitoring, and safety of teicoplanin compared with vancomycin for old people, newborn children and patients with low renal function.
(4) The clinical curative effect is as follows: similar to or better than vancomycin.
(5) The compound has synergistic bactericidal effect on most gram-positive bacteria when being combined with beta-lactam antibiotics, aminoglycosides and carbapenem antibiotics.
The preparation process of the existing teicoplanin for injection is as follows: the teicoplanin raw material is prepared by fermentation, filtration, chromatography and concentration, and then the teicoplanin for injection is prepared by liquid preparation, filling and freeze-drying, but the teicoplanin prepared by the process has the following defects:
1) the teicoplanin raw material has unstable quality and low yield, and has great influence on the clarity and stability of teicoplanin for injection. The existing separation and purification main procedures of teicoplanin comprise ion exchange resin adsorption and desorption, decarburization, chromatography and the like, the existing extraction and purification process cannot meet the higher quality requirements of customers, and the color grade and the content of teicoplanin raw powder are reduced due to oxidation when the teicoplanin raw powder is stored in an aluminum barrel.
2) Teicoplanin for injection has poor color and clarity, especially has large change for a long time and after acceleration, and has poor stability.
3) In order to improve the stability of the teicoplanin for injection and facilitate clinical use, the traditional teicoplanin for injection auxiliary materials are sodium chloride and water for injection, and the prepared teicoplanin for clinical use is isotonic solution which can be directly injected. But the clarity of the solution decreased significantly upon addition of Nacl.
Disclosure of Invention
The invention discloses a teicoplanin preparation for injection and a preparation method thereof, which solve the problems of low purity, low yield, high cost, poor stability, deep color, poor clarity and the like of the existing product.
In order to achieve the purpose, the invention adopts the following technical scheme:
the teicoplanin preparation for injection comprises an injection preparation containing 0.2g of teicoplanin and an injection preparation containing 0.4g of teicoplanin.
The preparation method of the teicoplanin preparation for injection comprises the following steps: firstly, preparing teicoplanin raw powder, then preparing liquid medicine, filling, and finally performing freeze-drying treatment, wherein the method specifically comprises the following steps:
s1, adsorbing and desorbing the teicoplanin fermentation filtrate by macroporous adsorption resin to obtain teicoplanin raw material liquid;
s2: decoloring, namely adding mixed active carbon into the teicoplanin raw material liquid for decoloring, and filtering to obtain teicoplanin filtrate;
s3: performing DAC column chromatography, wherein the DAC column filler is a polymer reversed phase chromatographic filler UniPs30-300, the teicoplanin filtrate is eluted through the column, and the eluent is collected;
s4: concentrating the eluent by a membrane system, performing ultrafiltration and nanofiltration concentration on the eluent, and washing the concentrated solution by purified water to remove residual solvent to obtain a teicoplanin finished product solution;
s5: filtering the teicoplanin finished product solution through a nylon 66 filter element to obtain teicoplanin finished product filtrate;
s6: freeze-drying the teicoplanin finished product filtrate, taking out of a box, and subpackaging to obtain teicoplanin raw powder, wherein an aluminum barrel is subjected to nitrogen replacement in the subpackaging process to reduce the oxygen concentration in the barrel;
s7: adding water for injection and weighed teicoplanin raw powder into a dosing tank, charging nitrogen in the liquid dosing process, fully stirring until the solution is dissolved, sampling and detecting the feed liquid, and performing filter pressing to a liquid storage tank after the feed liquid is qualified;
s8: filling, namely filling the feed liquid into a penicillin bottle, and performing half-corking treatment;
s9: and (4) filling nitrogen, freeze-drying and automatically pressing to obtain a final product.
The technical scheme of the invention is further improved as follows: the mixed activated carbon in the step S2 comprises 767 injection of activated carbon and imported FSAC-01 activated carbon, the dosage of the mixed activated carbon is 0.6% of the teicoplanin raw material, and the ratio of the 767 injection of activated carbon to the imported FSAC-01 activated carbon is 1: 1.
The technical scheme of the invention is further improved as follows: the stirring speed in the step S7 is 400-500 r/min; the detection items of the feed liquid are color, pH and clarity.
The technical scheme of the invention is further improved as follows: the pressure filter used in the pressure filtration process in step S7 was a 0.22 μm filter.
The technical scheme of the invention is further improved as follows: the freeze-drying process in step S9 is: and (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the temperature of a silicone oil inlet to-38 ℃, preserving heat for 1.5-2 hours, cooling the temperature of a cold trap to-38 ℃, starting to pump the vacuum degree to 0.1-0.2mbar, starting to heat up for drying, heating up at the speed of 3-10 ℃/30 minutes, heating up to-8 to-15 ℃, heating up at the speed of 5 ℃/1 hour to-5 ℃, heating up to-5 ℃, opening an air seepage valve, maintaining the vacuum of a box body for 0.2-0.3mbar, maintaining the temperature of-5 ℃ for 8 hours, heating up to 0 ℃, maintaining the temperature of 0 ℃ for 7 hours, heating up to 20 ℃ for 2-4 hours, maintaining the temperature for 5 hours, then vacuumizing the box body to 0.025mbar, maintaining for 1 hour, and then carrying out full-pressure plug air release and discharging out of the box to obtain the finished teicoplanin for injection.
The technical scheme of the invention is further improved as follows: the eluent in the step S3 is selected from any one of methanol, ethanol and isopropanol.
The technical scheme of the invention is further improved as follows: the ultrafiltration membrane has the molecular weight cut-off of 5000-10000 Dalton and the nanofiltration membrane has the molecular weight cut-off of 200-300 Dalton in the step S4.
Due to the adoption of the technical scheme, the invention has the technical effects that:
the teicoplanin prepared by the method has the advantages of obviously improved clarity, color grade, purity, endotoxin qualification rate and yield index, high purity of preparation products, plump appearance, no atrophy, no bubbling, uniform color, porosity, firm structure, high redissolution speed, low residual moisture, light color and greatly improved clarity and stability. The quality and stability of the product are far higher than those of the currently produced product, and the safety of clinical medication is improved. Solves the problem that the clarity of the solution is reduced after NaCl is added when the teicoplanin for injection is clinically used. Meanwhile, the preparation method has the advantages of low production cost, short production period, contribution to industrial production, advancement and important theoretical significance and application value for the production and clinical application of teicoplanin for injection.
Detailed Description
The technical solution of the present invention will be described in detail with reference to examples.
And (3) preparing high-purity teicoplanin.
Example 1
A. Adsorption: the total billion 234 hundred million units of teicoplanin fermentation filtrate is desorbed by macroporous adsorption resin to obtain the total billion 169.7 hundred million of teicoplanin raw material liquid;
B. and (3) decoloring: adding 5.1 kilograms of 767 percent of injection active carbon and 5.1 kilograms of 0.3 percent of imported FSAC-01 active carbon into the teicoplanin raw material liquid for decolorization, wherein the total content of decolorized liquid is 153.4 hundred million;
C. performing DAC column chromatography, wherein the filler is polymer reversed phase chromatography filler UniPs30-300, the teicoplanin filtrate is eluted through the column, and the total billion of eluent is collected and collected to be 83.7 billion;
D. concentrating a membrane system: after the chromatographic solution is subjected to ultrafiltration and nanofiltration concentration, the concentrated solution is washed by purified water to remove residual solvent, and thus 80 hundred million total teicoplanin concentrated solution is prepared;
E. and (4) filtering the concentrated solution by a nylon 66 filter element, further controlling endotoxin, and freeze-drying to obtain a qualified finished product.
Example 2
A. Adsorption: the total billion 255 hundred million units of teicoplanin fermentation filtrate is absorbed and desorbed by macroporous absorption resin to obtain the total billion 208.7 hundred million of desorption solution;
B. and (3) decoloring: 6.2 kilograms of domestic active carbon of 0.3 percent and 6.2 kilograms of imported FSAC-01 active carbon of 0.3 percent are added for decolorization, and the total amount of decolorized liquid is 159 hundred million;
C. performing DAC column chromatography, wherein the filler is polymer reversed phase chromatographic filler UniPs30-300, and the decolorized solution is subjected to chromatography to obtain 83 hundred million of chromatographic solution with proper components;
D. concentrating a membrane system: after the chromatographic solution is subjected to ultrafiltration and nanofiltration concentration, the cutoff molecular weight of an ultrafiltration membrane is 5000-.
E. And (4) filtering the concentrated solution by a nylon 66 filter element, further controlling endotoxin, and freeze-drying to obtain a qualified finished product.
Example 3
A. Adsorption: the total billion 266 hundred million units of teicoplanin fermentation filtrate is absorbed and desorbed by macroporous absorption resin to obtain the total billion 211 hundred million of desorption solution;
B. and (3) decoloring: 6.3 kilograms of domestic active carbon of 0.3 percent and 6.3 kilograms of imported FSAC-01 active carbon of 0.3 percent are added for decolorization, and the total content of decolorized liquid is 157.7 hundred million;
C. chromatography: the decolorized solution is chromatographed to obtain 79 hundred million chromatographic solution with proper components;
D. concentrating a membrane system: after the chromatographic solution is subjected to ultrafiltration and nanofiltration concentration, the cutoff molecular weight of an ultrafiltration membrane is 5000-.
E. And (4) filtering the concentrated solution by a nylon 66 filter element, further controlling endotoxin, and freeze-drying to obtain a qualified finished product.
Example 4
A. Adsorption: the total billion 294 hundred million units of teicoplanin fermentation filtrate is absorbed and desorbed by macroporous absorption resin to obtain total billion 206.9 million of desorption solution;
B. and (3) decoloring: 6.2 kilograms of domestic active carbon of 0.3 percent and 6.2 kilograms of imported FSAC-01 active carbon of 0.3 percent are added for decolorization, and the total decolorization liquid is 156.7 hundred million;
C. DAC column chromatography: chromatographic separation is carried out on the destaining solution to obtain 81 hundred million chromatographic solutions with proper components;
D. concentrating a membrane system: ultrafiltering, then carrying out nanofiltration concentration on the chromatographic solution, and washing the concentrated solution by using purified water to remove residual solvent to obtain 76 hundred million teicoplanin concentrated solution;
E. and (4) filtering the concentrated solution by a nylon 66 filter element, further controlling endotoxin, and freeze-drying to obtain a qualified finished product.
Comparative preparation of teicoplanin
Teicoplanin was produced in 3 batches according to the prior art, comparative example 1, comparative example 2, comparative example 3.
The experimental data of the inventive examples compared with the prior art are shown in table 1.
TABLE 1 comparison of experimental data of the present invention with those of the prior art
Test results show that compared with the teicoplanin prepared by the prior art, the teicoplanin prepared by the invention has obviously improved indexes of clarity, color grade, purity, endotoxin qualification rate and yield.
Preparation of teicoplanin hydrochloride for injection
Example 5
Preparation of medicinal liquid
Adding about 80% of injection water with a pre-prepared volume into a preparation tank, weighing the teicoplanin raw powder, filling nitrogen while stirring in the preparation process, and stirring at a stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the silicone oil inlet to-38 ℃, and then preserving heat for 1.5-2 hours. The temperature of the cold trap is cooled to-38 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 8 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 7 hours at 0 ℃. The temperature is raised to 20 ℃ for another 2 to 4 hours, the temperature is maintained at 20 ℃ for 5 hours, and then the box is evacuated to 0.025mbar for 1 hour. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Example 6
About 80% of the pre-formulation volume of water for injection was added to the dosing tank. And (3) filling nitrogen while stirring in the process of preparing the solution, and stirring at the stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the silicone oil inlet to-38 ℃, and then preserving heat for 1.5-2 hours. The temperature of the cold trap is cooled to-38 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 10 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 9 hours at 0 ℃. The temperature was raised to 20 ℃ for a further 2-4h, the temperature was maintained at 20 ℃ for 7 h, and the chamber was then evacuated to 0.025mbar for a further 2 h. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Example 7
Preparation of medicinal liquid
About 80% of the pre-formulation volume of water for injection was added to the dosing tank. And (3) filling nitrogen while stirring in the process of preparing the solution, and stirring at the stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the silicone oil inlet to-43 ℃, and then preserving heat for 1.5-2 hours. The temperature of the cold trap is cooled to-40 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 8 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 7 hours at 0 ℃. The temperature is raised to 20 ℃ for another 2 to 4 hours, the temperature is maintained at 20 ℃ for 5 hours, and then the box is evacuated to 0.025mbar for 1 hour. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Example 8
About 80% of the pre-formulation volume of water for injection was added to the dosing tank. And (3) filling nitrogen while stirring in the process of preparing the solution, and stirring at the stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the silicone oil inlet to-43 ℃, and then preserving heat for 1.5-2 hours. The temperature of the cold trap is cooled to-40 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 10 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 9 hours at 0 ℃. The temperature was raised to 20 ℃ for a further 2-4h, the temperature was maintained at 20 ℃ for 7 h, and the chamber was then evacuated to 0.025mbar for a further 2 h. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Example 9
Preparation of medicinal liquid
About 80% of the pre-formulation volume of water for injection was added to the dosing tank. And (3) filling nitrogen while stirring in the process of preparing the solution, and stirring at the stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the inlet temperature of the silicone oil to-45 ℃, and then preserving the heat for 1.5-2 hours. The temperature of the cold trap is cooled to-42 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 8 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 7 hours at 0 ℃. The temperature is raised to 20 ℃ for another 2 to 4 hours, the temperature is maintained at 20 ℃ for 5 hours, and then the box is evacuated to 0.025mbar for 1 hour. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Example 10
About 80% of the pre-formulation volume of water for injection was added to the dosing tank. And (3) filling nitrogen while stirring in the process of preparing the solution, and stirring at the stirring speed of 450 revolutions per minute until the raw powder is completely dissolved. Detecting the color, pH value and clarity of the medicinal liquid, aseptically pressing the medicinal liquid after the medicinal liquid is qualified, filtering the prepared medicinal liquid by a 0.22 μm filter, and pressing the medicinal liquid into a stainless steel barrel or an aseptic liquid storage tank. Filling the sterile liquid medicine into a penicillin bottle, and semi-pressing and plugging; note that the control load is in the acceptable range.
Freeze drying
And (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the inlet temperature of the silicone oil to-45 ℃, and then preserving the heat for 1.5-2 hours. The temperature of the cold trap is cooled to-42 ℃, the vacuum degree is started to be pumped to 0.1-0.2mbar, the temperature is started to be increased for drying, the temperature is increased at the speed of 3-10 ℃/30 minutes, the temperature is increased to-8 to-15 ℃, the temperature is increased at the speed of 5 ℃/1 hour, and the temperature is increased to-5 ℃. After the temperature is raised to-5 ℃, the air-permeable valve is opened, the vacuum of the box body is maintained for 0.2-0.3mbar, the temperature is maintained for 10 hours at-5 ℃, the temperature is raised to 0 ℃ and maintained for 9 hours at 0 ℃. The temperature was raised to 20 ℃ for a further 2-4h, the temperature was maintained at 20 ℃ for 7 h, and the chamber was then evacuated to 0.025mbar for a further 2 h. The moisture of the product at the end of drying is below 2.5%, the appearance of the product cannot shrink, and then the product is subjected to full-pressure plug deflation and taken out of the box to obtain 0.2g and 0.4g of teicoplanin finished products for injection.
Examples comparative examples
The teicoplanin prepared by the prior art is adopted as a raw material, 3 batches of teicoplanin for injection are prepared by the prior freeze-drying process and liquid preparation and freeze-drying without nitrogen filling, 2 samples of teicoplanin for each batch are arbitrarily extracted to serve as comparative examples, namely comparative example 4, comparative example 5, comparative example 6, comparative example 7, comparative example 8 and comparative example 9.
Drug clarity, color and pH testing
The clarity, color, content and pH value after redissolution are one of the important quality indexes of the freeze-dried product, in each of examples 5-10 and comparative examples, a bottle of finished product is taken, redissolution solvent is added, after redissolution is completed, the clarity and color of the medicine are observed, and the content and pH value of the test liquid medicine are shown in Table 2. The color and clarity after redissolution meet the requirements, and the content and pH test results also meet the quality standards.
TABLE 2 clarity, color and pH test results after reconstitution
As can be seen from Table 3, the examples are significantly lighter in color and higher in content than the comparative examples.
Moisture content test
The freeze-dried solvent residue is another important index for the success of the preparation of the freeze-dried product, and one of the samples was taken for the detection of the water content in examples 5 to 10 and comparative examples 1 to 6, and the results are shown in Table 3.
Table 3 moisture test results
| The water content is less than or equal to 5.0 percent | |
| Example 5 | 0.94％ |
| Example 6 | 0.97％ |
| Example 7 | 0.94％ |
| Example 8 | 0.91％ |
| Example 9 | 0.99％ |
| Example 10 | 0.93％ |
| Comparative example 4 | 1.21％ |
| Comparative example 5 | 1.23％ |
| Comparative example 6 | 1.25％ |
| Comparative example 7 | 1.24％ |
| Comparative example 8 | 1.21％ |
| Comparative example 9 | 1.20％ |
As can be seen from the above table, the moisture of the inventive examples was lower than that of the comparative examples.
Stability test
The data for the 0 day measurements of examples 5-10 and comparative examples 1-6 are shown in Table 4:
TABLE 40 days of assay data
As can be seen from the above table, the examples are significantly lighter in color, higher in content, and lower in impurity A than the comparative examples.
Accelerated testing of samples of examples 5-10 and comparative examples
Examination conditions were as follows: the test paper is placed at 40 +/-2 ℃ and RH75 +/-5% for 6 months to carry out accelerated test investigation, and various investigation items in the 6 th month are detected, and the detection results are shown in Table 5.
TABLE 5 stability of accelerated test
As can be seen from the above table, the comparative example has poor stability and large changes in color, clarity and content at the time of acceleration for 6 months. The product prepared by the embodiment of the invention has obviously lighter color, higher clarity, higher content and obviously less impurity A.
Long term testing of samples of examples 5-10 and comparative examples
Samples were taken and placed at 25 ℃. + -. 2 ℃ and a relative humidity of 60%. + -. 10% for long-term testing. And detecting each item of investigation in the 12 th month. The results are shown in Table 6.
TABLE 6 stability performance in Long term test
As can be seen from the above table, the comparative examples have poor stability and large variations in color, clarity and content after long-term stability testing. The product prepared by the embodiment of the invention has obviously lighter color, higher clarity, higher content and obviously less impurity A.
In summary, it can be seen from the stability data that after accelerated and long term stability testing, although the comparative examples all meet the standards, the stability is poor, the changes in clarity, color and content are large, and especially the color is poor after accelerated. The injection prepared by the invention has light color, high clarity, high content, low impurity content, small change of color, clarity, content and impurity after long-term and accelerated treatment, good stability and high safety in clinical use.
As can be seen by comparison, the product produced by the new preparation method is far higher than the product produced at present in the aspects of purity, clarity, color, marking amount, moisture, content, related substances, stability and the like.
Claims (5)
1. A method for preparing a teicoplanin preparation for injection, the preparation comprising an injection preparation containing 0.2g teicoplanin and an injection preparation containing 0.4g teicoplanin, comprising the steps of: firstly, preparing teicoplanin raw powder, then preparing liquid medicine, filling, and finally performing freeze-drying treatment, wherein the method comprises the following specific steps:
s1, adsorbing and desorbing the teicoplanin fermentation filtrate by macroporous adsorption resin to obtain teicoplanin raw material liquid;
s2: decoloring, namely adding mixed active carbon into the teicoplanin raw material liquid for decoloring, and filtering to obtain teicoplanin filtrate;
s3: performing DAC column chromatography, wherein the DAC column filler is a polymer reversed phase chromatographic filler UniPs30-300, the teicoplanin filtrate is eluted through the column, and the eluent is collected;
s4: concentrating the eluent by a membrane system, performing ultrafiltration and nanofiltration concentration on the eluent, and washing the concentrated solution by purified water to remove residual solvent to obtain a teicoplanin finished product solution;
s5: filtering the teicoplanin finished product solution through a nylon 66 filter element to obtain teicoplanin finished product filtrate;
s6: freeze-drying the teicoplanin finished product filtrate, taking out of a box, and subpackaging to obtain teicoplanin raw powder, wherein an aluminum barrel is subjected to nitrogen replacement in the subpackaging process to reduce the oxygen concentration in the barrel;
s7: adding water for injection and weighed teicoplanin raw powder into a dosing tank, charging nitrogen in the liquid dosing process, fully stirring until the solution is dissolved, sampling and detecting the feed liquid, and performing filter pressing to a liquid storage tank after the feed liquid is qualified;
s8: filling, namely filling the feed liquid into a penicillin bottle, and performing half-corking treatment;
s9: filling nitrogen, freeze-drying and automatically pressing to obtain a final product;
the mixed activated carbon of the step S2 comprises 767 injection activated carbon and imported FSAC-01 activated carbon, the ultrafiltration membrane cut-off molecular weight of the step S4 is 5000-; the freeze-drying process in step S9 is: and (3) filling nitrogen to prevent oxidation in the freeze-drying process, cooling the temperature of a silicone oil inlet to-38 ℃, preserving heat for 1.5-2 hours, cooling the temperature of a cold trap to-38 ℃, starting to pump the vacuum degree to 0.1-0.2mbar, starting to heat up for drying, heating up at the speed of 3-10 ℃/30 minutes, heating up to-8 to-15 ℃, heating up at the speed of 5 ℃/1 hour to-5 ℃, heating up to-5 ℃, opening an air seepage valve, maintaining the vacuum of a box body for 0.2-0.3mbar, maintaining the temperature of-5 ℃ for 8 hours, heating up to 0 ℃, maintaining the temperature of 0 ℃ for 7 hours, heating up to 20 ℃ for 2-4 hours, maintaining the temperature for 5 hours, then vacuumizing the box body to 0.025mbar, maintaining for 1 hour, and then carrying out full-pressure plug air release and discharging out of the box to obtain the finished teicoplanin for injection.
2. The method for preparing a teicoplanin preparation for injection according to claim 1, characterized in that: the dosage of the mixed active carbon is 0.6 percent of the raw material of the teicoplanin, and the ratio of 767 injection active carbon to imported FSAC-01 active carbon is 1: 1.
3. The method for preparing a teicoplanin preparation for injection according to claim 1, characterized in that: the stirring speed in step S7 is 400-500 rpm.
4. The method for preparing a teicoplanin preparation for injection according to claim 1, characterized in that: the pressure filter used in the pressure filtration process in step S7 was a 0.22 μm filter.
5. The method for preparing a teicoplanin preparation for injection according to claim 1, characterized in that: the eluent in the step S3 is selected from any one of methanol, ethanol and isopropanol.
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| CN101423547B (en) * | 2007-10-31 | 2012-10-17 | 浙江医药股份有限公司新昌制药厂 | Purification method of teicoplanin |
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