CN105055169B - A method of preparing Imipenem and Cilasatin Sodium aseptic powdery - Google Patents
A method of preparing Imipenem and Cilasatin Sodium aseptic powdery Download PDFInfo
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- CN105055169B CN105055169B CN201510406024.1A CN201510406024A CN105055169B CN 105055169 B CN105055169 B CN 105055169B CN 201510406024 A CN201510406024 A CN 201510406024A CN 105055169 B CN105055169 B CN 105055169B
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Abstract
The present invention provides a kind of preparation method of Imipenem and Cilasatin Sodium aseptic powdery, this method by adjusting the measures such as solvent, spray drying, filling nitrogen overcome in existing technology of preparing Imipenem and Cilastatin Sodium due to partial size difference is larger and be not easy to be uniformly mixed, in component sulfur-bearing and the problem of be easily oxidized.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of side for preparing Imipenem and Cilasatin Sodium aseptic powdery
Method.
Background technique
Imipenem is hydrocarbon mould carbapenem antibiotic, has antibacterial action to Grain-positive, negative aerobic and anaerobic bacteria,
Especially suitable for caused by multiple pathogens and aerobic/anaerobic bacteria caused by mixed infection, and pathogen do not determine before before
Phase treatment.For Cilastatin Sodium without antibacterial action, main function is the dehydrogenase for inhibiting nephrocyte secretion, and Imipenem is blocked to exist
Metabolism in kidney destroys Imipenem from hydrolysis, then increases the concentration of the Imipenem in the urinary tract without alteration.
The two is played in the treatment of control drug-fast bacteria, zymogenic bacteria infection and immune deficient patients' infection with sharing for 1:1 ratio
Important function is one of very high anti-severe infection drug of clinical evaluation.
The Imipenem and Cilasatin Sodium preparation listed at present is aseptic powdery, and technology of preparing is aseptic subpackaged, master
If Imipenem, Cilastatin Sodium and sodium bicarbonate are sub-packed in after mixing in cillin bottle or infusion bottle, mainly deposit
In following problems:
(1) powder diameter of Imipenem and Cilastatin Sodium, specific gravity difference are huge, and it is difficult to be uniformly mixed, in life
The uniform mixing for the special ratios that wait formulation requirements at 1: 1 is extremely difficult to during producing.
(2) contain sulphur in Imipenem and Cilastatin Sodium, impurity is generated easily in conjunction with the oxygen in air, influence
Drug quality, especially in long-term placement process, impurity increases rapidly, influences drug and uses safety and effectiveness.
(3) Chinese patent application CN201110196717.4 provides a kind of Imipenem and Cilasatin Sodium medicinal composition lipid
Liposome injection is made of Imipenem, Cilastatin Sodium, sphingo, cholesterol, emulsifier and freeze protection agent.Using
The Imipenem and Cilasatin Sodium injection of this method preparation, improves formulation products quality, reduces toxic side effect, improve
The bioavilability of drug, and there is good preparation stability, liposome will not be because of dehydration, fusion, ice in freeze-drying process
Crystalline substance etc. ruptures, and after hydration is redissolved, liposome equally keeps good encapsulation rate.
It (4) include imines in the Imipenem and Cilasatin Sodium prescription of Chinese patent application CN201110454779.0 invention
Training south, Cilastatin Sodium and sodium bicarbonate, wherein Imipenem is antibacterial agent, and Cilastatin Sodium is dehydropeptidase inhibitor,
Sodium bicarbonate is auxiliary material, as solubilizer (solubility for increasing Imipenem) and pH adjusting agent.The injection that the invention provides
The preparation process of Imipenem and Cilasatin Sodium is the following steps are included: (1) sterile mixing；(2) cillin bottle, butyl rubber plug, plastic-aluminum
The cleaning and sterilizing of lid；(3) it dispenses.
(5) Chinese patent application CN201410384863.3 is related to a kind of medicine group comprising Imipenem and Cilasatin Sodium
Close object and its preparation.In order to overcome the maincenter adverse reaction of the powder-injection of Imipenem and Cilasatin Sodium in the prior art biggish
Technical deficiency, the invention provide a kind of powder-injection comprising Imipenem and Cilasatin Sodium, the powder needle by reasonable compatibility
Agent is used to can be effectively reduced the maincenter adverse reaction of Imipenem and Cilasatin Sodium compound preparation when clinical antibacterial therapy, and
It can be obviously improved the stability after the powder injection formulation redissolves, therefore be suitable for developing into clinical treatment drug.
Although above patent document part solves the problems, such as of the existing technology, new problem has often been introduced,
Phosphatide, cholesterol, protective agent itself have certain activity in such as liposome, can generate larger side effect.
It is greatly and oxidizable that patent application CN201110454779.0 and CN201410384863.3 do not solve mixing difficulty yet
Lead to the problem of impurity.
Summary of the invention
The present invention provides a kind of preparation method of Imipenem and Cilasatin Sodium aseptic powdery, it is advantageous that solving Asia
The problem of amine training south is uniformly mixed with Cilastatin Sodium, also solves asking for the oxidizable decomposition of active constituent in long-term placement process
Topic.
Specific technical solution of the present invention is as follows:
A kind of preparation method of Imipenem and Cilasatin Sodium aseptic powdery, comprising the following steps:
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by solution 0.22um micropore
Filter membrane aseptic filtration, it is spare；
(2) it will be spray-dried box body pure steam pressure sterilizing, 121 DEG C of sterilising temp, sterilization time is 20 minutes, is gone out
It is dried with nitrogen after bacterium, it is cooling stand-by.
(3) feed liquid in (1) is heated to 50 DEG C -60 DEG C, fed in spray dryer, in 50 DEG C of -60 DEG C of conditions and nitrogen
Air-blowing is spray-dried under sweeping, and pressure is 350kPa-500kPa in drying box.Water in particle is measured after obtaining single-size
Divide, the content of organic solvent residual and Imipenem, Cilastatin Sodium.
(4) above-mentioned conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses glue after filling nitrogen in bottle
Plug, rolls aluminium lid outside to obtain the final product.
Above-mentioned Imipenem and Cilasatin Sodium aseptic powdery preparation method, solvent for use are that water has with pharmaceutically acceptable
The mixed solvent of solvent.Wherein pharmaceutically acceptable organic solvent be acetone, the tert-butyl alcohol or both mixed solvent, water with
Pharmaceutically acceptable organic solvent weight ratio is 1:10-1:30, preferably 1:15-1:25.
The present invention claims gained aseptic powdery moisture contents to be lower than 1.5%, and organic solvent content is lower than 1.0%.Due to Asia
Amine trains southern facile hydrolysis and generates impurity, and the safety of organic solvent influence medication, thus to the moisture of gained aseptic powdery with have
Solvent carries out strict control, and being investigated fixed limit degree respectively is 1.5% and 1.0%.
Spray drying technology is chiefly used in the granulation of tablet, capsule etc., and gained particle is crisp uniformly, and solubility is good.For
For aseptic powdery, spray drying can be solved perfectly due to mixing caused by specific gravity, particle size difference between different material not
Uniformly, drug dose inaccuracy problem.But the report and text that there is no spray drying technology aseptic subpackaged for antibiotic at present
It offers, reason is that antibiotic is more sensitive for moisture, solvent etc., and being on the one hand easy to react with moisture generates hydrolysis
Deng so cause hydrolysis impurity quickly to increase, the extremely difficult removing such as another aspect organic solvent such as ethyl alcohol, glycerol causes molten in powder
Agent residual is larger, influences the safety and stability of product.
The present invention passes through many experiments, solves above-mentioned problem of the spray drying for aseptic powdery production.For imines
It trains for southern Cilastatin Sodium, it, which is dissolved in being spray-dried after water or organic solvent merely, can cause moisture or organic solvent residual
Stay it is excessive, be more than pharmacopeia relevant criterion and guideline, influence medicine stability and safety.In the present invention, by water and spy
Determine to not only increase the solubility of Cilastatin Sodium after organic solvent mixes according to a certain percentage, can reach and imines
The requirement that south is matched according to 1:1 is trained, and can be reduced powder to make finished product moisture content and dissolvent residual to the absorption of organic solvent
Meet related request, be respectively smaller than 1.5% and 1.0%, greatly reduces its influence to medicine stability and safety.
Spray drying gained grain diameter is uniform, and regular shape, mobility is fabulous, greatly reduces the difficulty of Workshop Production
The excessive problem with content uniformity.In spray-drying process, Imipenem is dissolved in first with 1:1 proportion specific with Cilastatin Sodium
It is then common dry that homogeneous solution is formed in solvent, therefore ratio is 1:1 both in each particle, in gained finished product two kinds at
Divide ratio also higher than the uniformity after solid mixing, is better than the prior art.In addition, spray drying gained particle is dry for fine droplets
Dry gained, the channel that evaporates in drying process form aperture, and being clouded in particle surface increases its specific surface area, when redissolution with
Water engaging surface product is big, redissolves rapidly, is conducive to medical worker and makes up a prescription.
Specific embodiment
It is further elaborated on the present invention referring to embodiment, it should be appreciated to those skilled in the art that the present invention is not
The preparation method for being limited to these embodiments and using.Moreover, those skilled in the art's description according to the present invention can be to this
Invention is equivalently replaced, combines, improves or modifies, but these are intended to be included in the scope of the present invention.
Embodiment 1
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by solution 0.22um micropore
Filter membrane aseptic filtration, it is spare；Solvent for use is water: acetone=1:10.(2) spray drying box body is gone out with pure steam hot pressing
Bacterium, 121 DEG C of sterilising temp, sterilization time is 20 minutes, is dried with nitrogen after sterilizing, cooling stand-by.(3) feed liquid in (1) is heated
It to 50 DEG C, feeds in spray dryer, is spray-dried under 50 DEG C of conditions and nitrogen purging, pressure is in drying box
350kPa.Obtain the content that moisture, organic solvent residual and Imipenem, Cilastatin Sodium in particle are measured after single-size.
(4) above-mentioned conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses rubber plug after filling nitrogen in bottle, rolls aluminium outside
It covers to obtain the final product.
Embodiment 2
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by solution 0.22um micropore
Filter membrane aseptic filtration, it is spare；Solvent for use is water: the tert-butyl alcohol=1:30.(2) spray drying box body is gone out with pure steam hot pressing
Bacterium, 121 DEG C of sterilising temp, sterilization time is 20 minutes, is dried with nitrogen after sterilizing, cooling stand-by.(3) feed liquid in (1) is heated
It to 55 DEG C, feeds in spray dryer, is spray-dried under 55 DEG C of conditions and nitrogen purging, pressure is in drying box
450kPa.Obtain the content that moisture, organic solvent residual and Imipenem, Cilastatin Sodium in particle are measured after single-size.
(4) above-mentioned conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses rubber plug after filling nitrogen in bottle, rolls aluminium outside
It covers to obtain the final product.
Embodiment 3
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by solution 0.22um micropore
Filter membrane aseptic filtration, it is spare；Solvent for use is water: acetone: the tert-butyl alcohol=1:10:10.(2) the pure steaming of box body will be spray-dried
Vapour pressure sterilizing, 121 DEG C of sterilising temp, sterilization time is 20 minutes, is dried with nitrogen after sterilizing, cooling stand-by.It (3) will be in (1)
Feed liquid is heated to 60 DEG C, feeds in spray dryer, is spray-dried under 60 DEG C of conditions and nitrogen purging, in drying box
Pressure is 500kPa.Obtain measuring after single-size moisture, organic solvent residual and Imipenem in particle, Cilastatin Sodium
Content.(4) above-mentioned conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses rubber plug after filling nitrogen in bottle,
Roll aluminium lid outside to obtain the final product.
Embodiment 4
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by solution 0.22um micropore
Filter membrane aseptic filtration, it is spare；Solvent for use is water: acetone: the tert-butyl alcohol=1:5:10.(2) the pure steaming of box body will be spray-dried
Vapour pressure sterilizing, 121 DEG C of sterilising temp, sterilization time is 20 minutes, is dried with nitrogen after sterilizing, cooling stand-by.It (3) will be in (1)
Feed liquid is heated to 57 DEG C, feeds in spray dryer, is spray-dried under 57 DEG C of conditions and nitrogen purging, in drying box
Pressure is 400kPa.Obtain measuring after single-size moisture, organic solvent residual and Imipenem in particle, Cilastatin Sodium
Content.(4) above-mentioned conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses rubber plug after filling nitrogen in bottle,
Roll aluminium lid outside to obtain the final product.
Comparative example 1
It after Imipenem, Cilastatin Sodium are mixed according to 1:1, is sub-packed in clean cillin bottle, compresses rubber plug, roll aluminium outside
It covers to obtain the final product.
Comparative example 2
(1) sterile mixing
Cilastatin Sodium, Imipenem and sodium bicarbonate are mixed to get sterile imines training in 20~24 DEG C of local laminar flows
Southern Cilastatin Sodium mixing intermediate is uniformly mixed stand-by after examining；Wherein Imipenem: Cilastatin Sodium: sodium bicarbonate
Mass ratio be 1:1:(0.01-0.1).
(2) cleaning and sterilizing of cillin bottle, butyl rubber plug, aluminium-plastic cap
By cillin bottle after ultrasonic wave wash bottle, then rinsed with purified water, water for injection, after through 350 DEG C of tunnel oven with
Sterilizing upper 5 minute；By butyl rubber plug through ultrasonic cleaning, then through 121 DEG C steam sterilizing 30 minutes, then vacuum drying 90 points
Clock, 120 DEG C of xeothermic 2h sterilizings；Aluminium-plastic cap sterilizes 1.5 hours through 120 DEG C；
(3) it dispenses
Sterile Imipenem and Cilasatin Sodium mixing intermediate is obtained into semi-finished product in 20~24 DEG C of local laminar flows, through lamp
Inspection, labeling pack to obtain finished product to be checked, and qualified product, storage are obtained after inspection.
Verify embodiment 1
Moisture, organic solvent residual measurement, the results are shown in Table 1.
1. organic solvent residual measurement result of table
| Moisture (%) | Acetone (%) | The tert-butyl alcohol (%) | |
| Embodiment 1 | 0.55 | 0.22 | —— |
| Embodiment 2 | 0.64 | —— | 0.15 |
| Embodiment 3 | 0.50 | 0.20 | 0.12 |
| Embodiment 4 | 0.48 | 0.17 | 0.13 |
| Comparative example 1 | 1.35 | —— | —— |
| Comparative example 2 | 1.62 | —— | —— |
Verify embodiment 2
Long-time stability are investigated, and take this product appropriate, accurately weighed, and mobile phase is added to be made in every 1mL containing about Imipenem
The solution of 1.0mg and cilastatin 1.0mg, as test solution；Precision measures 1mL, sets in 100mL measuring bottle, uses mobile phase
It is diluted to scale, is shaken up, as contrast solution.According to the chromatographic condition under content determination item, 20 μ L of contrast solution is taken, injects liquid phase
Chromatograph adjusts detection sensitivity, and making the peak height of Imipenem principal component chromatographic peak is about the 20% of recorder full scale, then essence
It is close to measure above two each 20 μ L of solution, it is injected separately into liquid chromatograph, record chromatogram to Imipenem main peak retention time
4 times.If any impurity peaks in test solution chromatogram, single impurity peak area no more than two main peak areas in contrast solution it
(1.0%), 2 times (2.0%) of the sum of each impurity peak area no more than the sum of two main peak areas in contrast solution.
Assay is measured according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010).
Investigation the results are shown in Table 2:
2. long-time stability of table investigate result
Verify embodiment 3
Uniformity of dosage units is investigated, and takes 10 bottles of this product, is added flowing phased soln respectively by labelled amount and is quantified dilution every 1mL is made
In the solution of 0.5mg containing Imipenem and cilastatin 0.5mg measured in accordance with the law according to the method under content determination item, meet regulation
(two annex X E of Chinese Pharmacopoeia version in 2010).Investigation the results are shown in Table 3:
3. uniformity of dosage units of table investigates result
*: Chinese Pharmacopoeia version two middle Content uniformity test regulation A+1.8S in 2010 must not cross 15.0, and wherein A is mark
The absolute value of the difference of the amount of showing and mean value, S are the standard deviation between 10 parts of samples.The smaller then uniformity of dosage units of A+1.8S is better.
Conclusion, the technology of the present invention products obtained therefrom is relative to existing it can be seen from experimental result in verifying embodiment 1,2,3
The advantage that technology (comparative example) products obtained therefrom has uniformity of dosage units good, more stable, and moisture meets with organic solvent residual
Chinese Pharmacopoeia related request can guarantee the safety of medication.The present invention solves Imipenem and west in existing technology of preparing
Si Tading sodium due to partial size difference it is larger and be not easy to be uniformly mixed, in component sulfur-bearing and the problem of be easily oxidized, have biggish
Innovation and practicality.
Claims (2)
1. a kind of preparation method of Imipenem and Cilasatin Sodium aseptic powdery, it is characterised in that the following steps are included:
(1) Imipenem and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1,0.22 μm of micropore of the solution is filtered
Film aseptic filtration, it is spare；
(2) it will be spray-dried box body pure steam pressure sterilizing, 121 DEG C of sterilising temp, sterilization time is 20 minutes, sterilizing
After be dried with nitrogen, it is cooling stand-by；
(3) feed liquid in (1) is heated to 50 DEG C -60 DEG C, feeds in spray dryer, is blown in 50 DEG C of -60 DEG C of conditions and nitrogen
It is spray-dried under sweeping, pressure is 350kPa-500kPa in drying box；Moisture, organic solvent residual are measured to gained particle
And the content of Imipenem, Cilastatin Sodium；
(4) conforming particle is sub-packed under nitrogen protection in clean cillin bottle, compresses rubber plug after filling nitrogen in bottle, rolls outside
Aluminium lid to obtain the final product；
The solvent refers to water and acetone, the mixed solvent of water and the tert-butyl alcohol or water and acetone and the tert-butyl alcohol；
Wherein the weight ratio of the mixed solvent of water and acetone or water and the tert-butyl alcohol or water and acetone and the tert-butyl alcohol is 1:10-1:
30, when organic solvent is the mixed solvent of acetone and the tert-butyl alcohol, acetone and tert-butyl alcohol weight ratio are 5~10:10；
Gained granule moisture level is lower than 1.5%, and organic solvent content is lower than 1.0%.
2. method according to claim 1, which is characterized in that the water and acetone or water and the tert-butyl alcohol or water and acetone and
The weight ratio of the mixed solvent of the tert-butyl alcohol is 1:15-1:25.
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| CN201510406024.1A CN105055169B (en) | 2015-07-11 | 2015-07-11 | A method of preparing Imipenem and Cilasatin Sodium aseptic powdery |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2096599A (en) * | 1981-04-10 | 1982-10-20 | Bristol Myers Co | Production of sodium amoxicillin by spray-drying |
| CN1568975A (en) * | 2004-04-28 | 2005-01-26 | 济南久创化学有限责任公司 | Preparing method of freeze-dried antibiotic formulation |
| CN1608624A (en) * | 2003-10-21 | 2005-04-27 | 北京维科瑞医药技术研究所 | Cefpoxime proxetil for clinical injection |
| WO2006055950A1 (en) * | 2004-11-18 | 2006-05-26 | Nektar Therapeutics | Pharmaceutical dry powder formulation on the basis particles comprising multiple active agents |
-
2015
- 2015-07-11 CN CN201510406024.1A patent/CN105055169B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2096599A (en) * | 1981-04-10 | 1982-10-20 | Bristol Myers Co | Production of sodium amoxicillin by spray-drying |
| CN1608624A (en) * | 2003-10-21 | 2005-04-27 | 北京维科瑞医药技术研究所 | Cefpoxime proxetil for clinical injection |
| CN1568975A (en) * | 2004-04-28 | 2005-01-26 | 济南久创化学有限责任公司 | Preparing method of freeze-dried antibiotic formulation |
| WO2006055950A1 (en) * | 2004-11-18 | 2006-05-26 | Nektar Therapeutics | Pharmaceutical dry powder formulation on the basis particles comprising multiple active agents |
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Denomination of invention: A method for preparing sterile powder of imipenem cilastatin sodium Effective date of registration: 20230117 Granted publication date: 20190122 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |