CN105055169A - Preparation method of imipenem-cilastatin sodium sterile powder - Google Patents
Preparation method of imipenem-cilastatin sodium sterile powder Download PDFInfo
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- CN105055169A CN105055169A CN201510406024.1A CN201510406024A CN105055169A CN 105055169 A CN105055169 A CN 105055169A CN 201510406024 A CN201510406024 A CN 201510406024A CN 105055169 A CN105055169 A CN 105055169A
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Abstract
The invention provides a preparation method of imipenem-cilastatin sodium sterile powder. With the adoption of the preparation method provided by the present invention, the problem of difficulty in uniform mixing due to big grain diameter difference between imipenem and cilastatin sodium as well as the problem of proneness to oxidation due to sulfur contained in the components in existing preparation technology are solved through the measures of solvent adjusting, spray drying, nitrogen filling, etc.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of method preparing Imipenem and Cilasatin Sodium sterilized powder.
Background technology
Imipenum is hydrocarbon mould carbapenem antibiotic, has antibacterial action to Grain-positive, negative aerobic and anaerobe, is specially adapted to multiple pathogens and makes peace the microbial mixed infection of aerobic/anaerobism and the previous tretament before pathogen is not determined.Cilastatin Sodium is without antibacterial action, and its Main Function is the dehydrogenase suppressing nephrocyte secretion, blocks the metabolism of imipenum in kidney, and imipenum is destroyed from hydrolysis, then increases the concentration without the imipenum changed in urinary tract.Both have played important function with share in the treatment infected control fastbacteria, zymogenic bacteria infection and immune deficient patients of 1:1 ratio, are one of anti-severe infection medicines that clinical evaluation is very high.
The Imipenem and Cilasatin Sodium preparation of current listing is sterilized powder, and its technology of preparing is aseptic subpackaged, is mainly sub-packed in cillin bottle or infusion bottle by after imipenum, Cilastatin Sodium and sodium bicarbonate mix homogeneously, mainly there is following problem in it:
(1) powder diameter of imipenum and Cilastatin Sodium, specific gravity difference are huge, and mix homogeneously difficulty is very large, is difficult to the Homogeneous phase mixing of the special ratios reaching 1: 1 formulation requirements such as grade in process of production.
(2) in imipenum and Cilastatin Sodium all containing sulfur, very easily produce impurity with the combination with oxygen in air, affect drug quality, especially in long-term put procedure, impurity increases rapidly, affects medicine use safety effectiveness.
(3) Chinese patent application CN201110196717.4 provides a kind of Imipenem and Cilasatin Sodium medicinal composition liposome injection, is made up of imipenum, Cilastatin Sodium, sphingo, cholesterol, emulsifying agent and freeze protection agent.Adopt Imipenem and Cilasatin Sodium injection prepared by the method, improve formulation products quality, decrease toxic and side effects, improve the bioavailability of medicine, and there is good preparation stability, in freeze-drying process, liposome can not break because of dehydration, fusion, ice crystal etc., and after hydration is redissolved, liposome keeps good envelop rate equally.
(4) the Imipenem and Cilasatin Sodium prescription of Chinese patent application CN201110454779.0 invention comprises imipenum, Cilastatin Sodium and sodium bicarbonate, wherein imipenum is antibacterial, Cilastatin Sodium is dehydropeptidase inhibitor, sodium bicarbonate is adjuvant, as solubilizing agent (increasing the dissolubility of imipenum) and pH adjusting agent.The preparation technology of the imipenem for injection Cilastatin Sodium that this invention provides comprises the following steps: (1) aseptic mixing; (2) cleaning of cillin bottle, butyl rubber plug, aluminium-plastic cap and sterilizing; (3) subpackage.
(5) Chinese patent application CN201410384863.3 relates to a kind of pharmaceutical composition and the preparation thereof that comprise Imipenem and Cilasatin Sodium.In order to the technical deficiency that the maincenter untoward reaction overcoming the injectable powder of Imipenem and Cilasatin Sodium in prior art is larger, this invention provides a kind of injectable powder comprising Imipenem and Cilasatin Sodium by reasonable compatibility, described injectable powder effectively can reduce the maincenter untoward reaction of Imipenem and Cilasatin Sodium compound preparation when being used for clinical antibacterial therapy, and the stability that can significantly improve after the redissolution of described powder injection formulation, is therefore suitable for being developed to clinical treatment medicine.
Although above-mentioned patent documentation part solves prior art Problems existing, often introduce new problem, as phospholipid, cholesterol, protective agent etc. itself have certain activity in liposome, larger side effect can have been produced.
The problem of patent application CN201110454779.0 and the CN201410384863.3 also large and oxidizable generation impurity of unresolved mixing difficulty.
Summary of the invention
The invention provides a kind of preparation method of Imipenem and Cilasatin Sodium sterilized powder, it is advantageous that the problem solving imipenum and Cilastatin Sodium and evenly mix, also solve the problem of the oxidizable decomposition of active component in long-term put procedure.
The concrete technical scheme of the present invention is as follows:
A preparation method for Imipenem and Cilasatin Sodium sterilized powder, comprises the following steps:
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use;
(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by.
(3) feed liquid in (1) is heated to 50 DEG C-60 DEG C, charging is in spray dryer, and under 50 DEG C of-60 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 350kPa-500kPa.The content of moisture in granule, organic solvent residual and imipenum, Cilastatin Sodium is measured after obtaining single-size.
(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
Above-mentioned Imipenem and Cilasatin Sodium sterilized powder preparation method, solvent for use is the mixed solvent of water and pharmaceutically acceptable organic solvent.Wherein pharmaceutically acceptable organic solvent is acetone, the tert-butyl alcohol or the mixed solvent of the two, and water and pharmaceutically acceptable organic solvent weight ratio are 1:10-1:30, is preferably 1:15-1:25.
Application claims gained sterilized powder moisture is lower than 1.5%, and organic solvent content is lower than 1.0%.Because imipenum facile hydrolysis produces impurity, and the safety of organic solvent influence medication, therefore strictly controlling the moisture of gained sterilized powder and organic solvent, is 1.5% and 1.0% through investigating fixed limit degree respectively.
Spray drying technology is used for the granulation of tablet, capsule etc., and gained granule is evenly crisp, and solubility is good.For sterilized powder, it is uneven that spraying dry perfect can solve the mixing caused due to proportion, size difference between different material, the inaccurate problem of drug dose.But there is no spray drying technology at present for the aseptic subpackaged report of antibiotic and document, reason is that antibiotic is more responsive for moisture, solvent etc., on the one hand easily and moisture react and produce hydrolysis etc. and then cause hydrolysis impurity to increase fast, organic solvent removing as extremely difficult in ethanol, glycerol etc. on the other hand, cause dissolvent residual in powder comparatively large, affect the safety and stability of product.
The present invention, through many experiments, solves the above-mentioned difficult problem that spraying dry is produced for sterilized powder.For Imipenem and Cilasatin Sodium, spraying dry after its merely water-soluble or organic solvent all can be caused moisture or organic solvent residual excessive, exceed pharmacopeia relevant criterion and guideline, affect medicine stability and safety.In the present invention, after water is mixed according to a certain percentage with specific organic solvent, not only increase the dissolubility of Cilastatin Sodium, can reach and the requirement of imipenum according to 1:1 proportioning, can reduce again the absorption of powder to organic solvent makes finished product moisture and dissolvent residual meet related request, be less than 1.5% and 1.0% respectively, greatly reduce its impact on medicine stability and safety.
Spraying dry gained grain diameter is even, regular shape, and mobility is fabulous, greatly reduces the difficulty of Workshop Production and the excessive problem of content uniformity.In spray-drying process, first imipenum and Cilastatin Sodium are dissolved in specific solvent with 1:1 proportioning and form homogeneous solution then common drying, therefore in each granule, both ratios are 1:1, and in gained finished product, two kinds of component ratios are also higher than the uniformity after solids mixing, are better than prior art.In addition, spraying dry gained granule is the dry gained of fine droplets, and the passage that evaporates in dry run forms aperture, is clouded in particle surface and its specific surface area is increased, and long-pending large with water engaging surface during redissolution, redissolution is rapid, is conducive to medical worker and makes up a prescription.
Detailed description of the invention
Elaborate the present invention further with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiments and use.And those skilled in the art can carry out equivalent replacement, combination, improvement to the present invention according to description of the invention or modify, but these all will comprise within the scope of the invention.
Embodiment 1
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use; Solvent for use is water: acetone=1:10.(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by.(3) feed liquid in (1) is heated to 50 DEG C, charging is in spray dryer, and under 50 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 350kPa.The content of moisture in granule, organic solvent residual and imipenum, Cilastatin Sodium is measured after obtaining single-size.(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
Embodiment 2
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use; Solvent for use is water: the tert-butyl alcohol=1:30.(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by.(3) feed liquid in (1) is heated to 55 DEG C, charging is in spray dryer, and under 55 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 450kPa.The content of moisture in granule, organic solvent residual and imipenum, Cilastatin Sodium is measured after obtaining single-size.(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
Embodiment 3
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use; Solvent for use is water: acetone: the tert-butyl alcohol=1:10:10.(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by.(3) feed liquid in (1) is heated to 60 DEG C, charging is in spray dryer, and under 60 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 500kPa.The content of moisture in granule, organic solvent residual and imipenum, Cilastatin Sodium is measured after obtaining single-size.(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
Embodiment 4
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use; Solvent for use is water: acetone: the tert-butyl alcohol=1:5:10.(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by.(3) feed liquid in (1) is heated to 57 DEG C, charging is in spray dryer, and under 57 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 400kPa.The content of moisture in granule, organic solvent residual and imipenum, Cilastatin Sodium is measured after obtaining single-size.(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
Comparative example 1
By imipenum, Cilastatin Sodium according to after 1:1 mixing, be sub-packed in clean cillin bottle, compress plug, roll aluminium lid outward and get final product.
Comparative example 2
(1) aseptic mixing
Cilastatin Sodium, imipenum and sodium bicarbonate are mixed to get aseptic Imipenem and Cilasatin Sodium mixing intermediate in 20 ~ 24 DEG C of local laminar flows, and after inspection, mix homogeneously is stand-by; Wherein imipenum: Cilastatin Sodium: the mass ratio of sodium bicarbonate is 1:1:(0.01-0.1).
(2) cleaning of cillin bottle, butyl rubber plug, aluminium-plastic cap and sterilizing
By cillin bottle after ultrasound wave wash bottle, then rinse, subsequently through tunnel oven more than 350 DEG C sterilizings in 5 minutes with purified water, water for injection; By butyl rubber plug through ultrasonic waves for cleaning, then through 121 DEG C of steam sterilizations 30 minutes, vacuum drying 90 minutes subsequently, 120 DEG C of xeothermic 2h sterilizings; Aluminium-plastic cap was through 120 DEG C of sterilizations 1.5 hours;
(3) subpackage
Aseptic Imipenem and Cilasatin Sodium mixing intermediate is obtained semi-finished product in 20 ~ 24 DEG C of local laminar flows, through lamp inspection, labeling, packs to obtain finished product to be checked, after inspection certified products, warehouse-in.
Checking embodiment 1
Moisture, organic solvent residual measure, and the results are shown in Table 1.
Table 1. organic solvent residual measurement result
| 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 | —— | —— |
Checking embodiment 2
Long-time stability are investigated, and get this product in right amount, accurately weighed, add mobile phase and make the solution about containing imipenum 1.0mg and cilastatin 1.0mg in every 1mL, as need testing solution; Precision measures 1mL, puts in 100mL measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution.According to the chromatographic condition under assay item, get contrast solution 20 μ L, injection liquid chromatography, regulate detection sensitivity, the peak height of imipenum main constituent chromatographic peak is made to be about 20% of monitor full scale, precision measures each 20 μ L of above-mentioned two kinds of solution again, respectively injection liquid chromatography, and record chromatogram is to 4 times of imipenum main peak retention time.If any impurity peaks in need testing solution chromatogram, single impurity peak area is not more than two main peak area sums (1.0%) in contrast solution, and each impurity peak area sum is not more than 2 times (2.0%) of two main peak area sums in contrast solution.
Assay measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Investigation the results are shown in Table 2:
Table 2. long-time stability investigate result
Checking embodiment 3
Uniformity of dosage units is investigated; get this product 10 bottles; add mobile phase respectively by labelled amount and dissolve and quantitatively dilute the solution made containing imipenum 0.5mg and cilastatin 0.5mg in every 1mL; according to the method under assay item; measure, conform with the regulations (Chinese Pharmacopoeia version in 2010 two annex XE) in accordance with the law.Investigation the results are shown in Table 3:
Table 3. uniformity of dosage units investigates result
*: Chinese Pharmacopoeia version in 2010 two middle Content uniformity test regulation A+1.8S must not cross 15.0, and wherein A is the absolute value of the difference of labelled amount and average, and S is the standard deviation between 10 increment product.The less then uniformity of dosage units of A+1.8S is better.
Conclusion, as can be seen from experimental result in checking embodiment 1,2,3, it is good that the technology of the present invention products obtained therefrom has uniformity of dosage units relative to prior art (comparative example) products obtained therefrom, more stable advantage, and moisture and organic solvent residual meet Chinese Pharmacopoeia related request, the safety of medication can be ensured.To the invention solves in existing technology of preparing imipenum and Cilastatin Sodium due to particle diameter difference mix homogeneously more greatly and not easily, sulfur-bearing and easily oxidized problem in component, there is larger novelty and practicality.
Claims (6)
1. a preparation method for Imipenem and Cilasatin Sodium sterilized powder, is characterized in that comprising the following steps:
(1) imipenum and Cilastatin Sodium are dissolved in solvent by the weight ratio of 1:1, by the 0.22um microporous filter membrane aseptic filtration of this solution, for subsequent use;
(2) by the pure hot steam sterilizer of spraying dry cabinet bulk, sterilising temp 121 DEG C, sterilization time is 20 minutes, and after sterilizing, nitrogen dries up, and cools stand-by;
(3) feed liquid in (1) is heated to 50 DEG C-60 DEG C, charging is in spray dryer, and under 50 DEG C of-60 DEG C of conditions and nitrogen purge, carry out spraying dry, in drying baker, pressure is 350kPa-500kPa; Gained granule is measured to the content of moisture, organic solvent residual and imipenum, Cilastatin Sodium;
(4) above-mentioned conforming particle is sub-packed in clean cillin bottle under nitrogen protection, in bottle, after filling nitrogen, compresses plug, roll aluminium lid outward and get final product.
2. Imipenem and Cilasatin Sodium sterilized powder preparation method according to claim 1, is characterized in that solvent for use is the mixed solvent of water and pharmaceutically acceptable organic solvent.
3. Imipenem and Cilasatin Sodium sterilized powder preparation method according to claim 1 and 2, is characterized in that pharmaceutically acceptable organic solvent is acetone, the tert-butyl alcohol or the mixed solvent of the two.
4. Imipenem and Cilasatin Sodium sterilized powder preparation method according to claim 1 and 2, is characterized in that water and pharmaceutically acceptable organic solvent weight ratio are 1:10-1:30, is preferably 1:15-1:25.
5. Imipenem and Cilasatin Sodium sterilized powder preparation method according to claim 1 and 2, it is characterized in that pharmaceutically acceptable organic solvent is the mixed solvent of acetone and the tert-butyl alcohol, acetone and tert-butyl alcohol weight ratio are 5 ~ 10:10.
6. Imipenem and Cilasatin Sodium sterilized powder preparation method according to claim 1, it is characterized in that gained granule moisture level is lower than 1.5%, organic solvent content is lower than 1.0%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106943353A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of injection doripenem and preparation method thereof |
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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106943353A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of injection doripenem and preparation method thereof |
| CN106943353B (en) * | 2016-01-06 | 2022-07-01 | 山东新时代药业有限公司 | Doripenem for injection and preparation method thereof |
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