CN103040819B - A kind of pharmaceutical composition containing mezlocillin sodium compound and preparation method thereof - Google Patents
A kind of pharmaceutical composition containing mezlocillin sodium compound and preparation method thereof Download PDFInfo
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- CN103040819B CN103040819B CN201310008618.8A CN201310008618A CN103040819B CN 103040819 B CN103040819 B CN 103040819B CN 201310008618 A CN201310008618 A CN 201310008618A CN 103040819 B CN103040819 B CN 103040819B
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Abstract
The invention discloses a kind of pharmaceutical composition containing mezlocillin sodium compound, it contains the raw material of following weight parts proportioning: mezlocillin sodium 10-20; Mannitol 1-20; Anhydrous sodium sulfate 1-20.The present invention, by lot of experiments, has filtered out best freeze drying protectant mannitol, makes lyophilized powder solubility excellent, good stability, and after long-term preservation, its related substances is low.Due to the unstability of mezlocillin sodium itself, in lyophilized powder preparation process, easily produce polymer, and polymer easily causes allergic reaction.And applicant passes through lot of experiments, be surprised to find that use sodium sulfate, effectively can reduce the content of mezlocillin sodium polymer in lyophilized preparation, make polymer content all be less than 0.3%, meet the requirement of pharmacopeia, efficiently avoid the risk that polymer causes allergic reaction.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of pharmaceutical composition containing mezlocillin sodium compound and preparation method thereof.
Background technology
Mezlocillin sodium, English name is, Mezlocillin Baypen, its chemical name is (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2 [3-(methylsulfonyl)-2-oxo-1-imidazolidine formamido group]-2-phenylacetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0]-heptane-2-formic acid sodium salt.Be mainly used in the respiratory system in the gram negative bacillis such as escherichia coli, Enterobacter, Bacillus proteus caused by sensitive strain, urinary system, digestive system, gynecological and genitals official rank to infect, as septicemia, purulent meningitis, peritonitis, osteomyelitis, skin and soft tissue infection and Eye Ear Nose And Throat section infect.
The anaphylaxis that Penicillin antibiotics causes annoyings its application in clinical for a long time always.Report according to domestic and international clinical research, sensitization source mainly contained polymer of penicillins kind medicine itself.Thus, the content reducing polymer in penicillin medicine becomes and reduces its hypersensitive important channel.Chinese Pharmacopoeia specify the limit of polymer be≤0.3%.In prior art, usually need that chromatography purification is carried out to mezlocillin sodium product and product just can be made to meet the polymer bound requirements of States Pharmacopoeia specifications.
Up to the present, mezlocillin sodium adopts the method for lyophilizing to obtain usually, and due to the unstability of mezlocillin sodium itself, freeze-drying prods impurity content is comparatively large, and quality is unstable, and dissolubility, clarity is poor.And impurity content height easily causes Clinical practice untoward reaction high, current mezlocillin for inj has occurred occurring that ear is dizzy, tinnitus after patient uses clinically; Anaphylaxis; Anaphylactic shock; The untoward reaction, particularly anaphylaxis such as external genitalia edema and anaphylactic shock are substantially all caused by impurity.Therefore develop a kind of polymer content low, stable, mezlocillin preparation that impurity is few has great importance.
CN200610066226.7 discloses a kind of mezlocillin lyophilized injectable powder, it adds aseptic cosolvent by aseptic mezlocillin and mixes, cosolvent is a kind of or several arbitrarily mixture of sodium carbonate, arginine, sodium bicarbonate, sodium hydroxide, and the part by weight of mezlocillin and cosolvent is 1: 1-1: 0.5.But injectable powder polymer content prepared by this formula is higher, there is potential drug safety sex chromosome mosaicism.
Summary of the invention
In view of the special physico-chemical character of the deficiencies in the prior art and mezlocillin sodium, need to find a kind of formula and preparation method, solve poorly soluble, poor stability, clarity difference when mezlocillin sodium is prepared into injection and the high problem such as easily to cause allergic reaction of polymer content simultaneously.Therefore, the object of the present invention is to provide a kind of pharmaceutical composition (lyophilized injectable powder) containing mezlocillin sodium compound, prior art mezlocillin sodium lyophilized preparation be poorly soluble to solve, poor stability, solubility difference and the problem such as polymer content is high.
A kind of pharmaceutical composition containing mezlocillin sodium compound provided by the invention, it contains the raw material of following weight parts proportioning:
Mezlocillin sodium 10-20;
Mannitol 1-20;
Anhydrous sodium sulfate 1-20.
In the present invention's specific embodiments, described pharmaceutical composition contains the raw material of following weight parts proportioning:
Mezlocillin sodium 15;
Mannitol 5;
Anhydrous sodium sulfate 5.
Pharmaceutical composition provided by the invention is lyophilized injectable powder.Further, the present invention also provides the preparation method of described lyophilized injectable powder, it comprises the steps: to take mezlocillin sodium by formula ratio, mannitol, anhydrous sodium sulfate, use sterile water for injection mix and blend, with saturated sodium bicarbonate solution pH be adjusted to 4.5 ~ 7.5 and continue to stir, the active carbon adding liquor capacity 0.1-0.5% stirs decolouring, 0.22 μm of filter membrane fine straining is used again after coarse filtration, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-45 ~-35 DEG C, 6-8 hour, slowly intensification low-temperature vacuum drying 20-30 is little of-20 DEG C again, continue to be warming up to 10 DEG C, vacuum drying 3-5 hour, gland, obtain.
The present invention, by lot of experiments, has filtered out best freeze drying protectant mannitol, makes lyophilized powder solubility excellent, good stability, and after long-term preservation, its related substances is low.Due to the unstability of mezlocillin sodium itself, in lyophilized powder preparation process, easily produce polymer, and polymer easily causes allergic reaction.And applicant passes through lot of experiments, be surprised to find that use sodium sulfate, effectively can reduce the content of mezlocillin sodium polymer in lyophilized preparation, make polymer content all be less than 0.3%, meet the requirement of pharmacopeia, efficiently avoid the risk that polymer causes allergic reaction.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Formula: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 20g; Mannitol 10g; Anhydrous sodium sulfate 1g.
Take the mezlocillin sodium of above-mentioned weight, mannitol and anhydrous sodium sulfate, with sterile water for injection mixing, with saturated sodium bicarbonate solution, pH value is adjusted to 7.0, after 0.1% activated carbon decolorizing filters, with the membrane filtration of 0.22 μm, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-40 DEG C, 8 hours, more slowly intensification low-temperature vacuum drying 20 is little of-20 DEG C, continue to be warming up to 10 DEG C, vacuum drying 5 hours, gland, to obtain final product.
Embodiment 2
Formula: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 15g; Mannitol 5g; Anhydrous sodium sulfate 5g.
Take the mezlocillin sodium of above-mentioned weight, mannitol and anhydrous sodium sulfate, with sterile water for injection mixing, with saturated sodium bicarbonate solution, pH value is adjusted to 6.0, after 0.3% activated carbon decolorizing filters, with the membrane filtration of 0.22 μm, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-45 DEG C, 6 hours, more slowly intensification low-temperature vacuum drying 30 is little of-20 DEG C, continue to be warming up to 10 DEG C, vacuum drying 4 hours, gland, to obtain final product.
Embodiment 3
Formula: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 10g; Mannitol 1g; Anhydrous sodium sulfate 10g.
Take the mezlocillin sodium of above-mentioned weight, mannitol and anhydrous sodium sulfate, with sterile water for injection mixing, with saturated sodium bicarbonate solution, pH value is adjusted to 5.0, after 0.5% activated carbon decolorizing filters, with the membrane filtration of 0.22 μm, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-35 DEG C, 8 hours, more slowly intensification low-temperature vacuum drying 25 is little of-20 DEG C, continue to be warming up to 10 DEG C, vacuum drying 3 hours, gland, to obtain final product.
Embodiment 4
Formula: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 15g; Mannitol 10g; Anhydrous sodium sulfate 20g.
Take the mezlocillin sodium of above-mentioned weight, mannitol and anhydrous sodium sulfate, with sterile water for injection mixing, with saturated sodium bicarbonate solution, pH value is adjusted to 7.0, after 0.1% activated carbon decolorizing filters, with the membrane filtration of 0.22 μm, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-40 DEG C, 8 hours, more slowly intensification low-temperature vacuum drying 20 is little of-20 DEG C, continue to be warming up to 10 DEG C, vacuum drying 5 hours, gland, to obtain final product.
Comparative example 1
According to injectable powder prepared by the embodiment 1 of CN200610066226.7, specific as follows:
Aseptic mezlocillin 1g and sterile sodium carbonate 0.3g mixture, the procedure operation of injectable powder production technology is carried out routinely.
Test example 1
Measure the content of mezlocillin sodium polymer in the mezlocillin sodium freeze-dried powder injection of embodiment 1-4 and comparative example 1 preparation according to the molecular exclusion chromatography of China's coastal port two annex VH, result is as shown in table 1.
The content of mezlocillin sodium polymer in table 1 sample
| Sample | Polymer content % |
| Embodiment 1 | 0.18 |
| Embodiment 2 | 0.15 |
| Embodiment 3 | 0.17 |
| Embodiment 4 | 0.20 |
| Comparative example 1 | 3.22 |
As can be seen from Table 1, owing to have employed sodium sulfate in mezlocillin sodium freeze-dried powder injection of the present invention, make polymer content wherein far below the polymer content in existing injectable powder, each batch of product is made all to meet the regulation of pharmacopeia, substantially increase the safety of medication, the polymer content of comparative example does not then meet the regulation of pharmacopeia.
Test example 2
Mezlocillin injectable powder prepared by the lyophilized injectable powder prepare embodiment 1-4 and comparative example 1 carries out safety testing investigation, test method and result as follows:
One, vascular stimulation test
Get the healthy rabbit 48 that body weight is 2.0-2.5kg, be divided into blank group, experiment 1-7 group at random, often organize 6, adopt rabbit auricular vein slowly to inject, injection volume is 10ml/kg.Wherein blank group adopts sodium chloride injection, the mezlocillin sodium freeze-dried powder injection that experiment 1-4 group adopts embodiment 1-4 to prepare respectively, tests 5 groups of mezlocillin injectable powder adopting comparative example 1 to prepare.Both are all dissolved in water for injection rear injection.
Once a day, successive administration 7 days, the rabbit ear is cut short after 24 hours in last administration, be placed in 10% formalin fixed preparation, then pathology is sent to carry out histological examination (draw materials at 5 places of the different parts of rabbit auricular vein, namely centripetal end does a section every 1cm from the initial position of injection).
Through rabbit ear edge vein pathological examination, the auricular vein tube wall of blank group and test 1-4 group is complete, and endotheliocyte structure is clear, and without obvious pathological changes, dilatation and congestion that blood vessel is slight, without cell infiltration.Test 5 groups and occur the slight dilatation and congestion of blood vessel, other are normal.
Two, hemolytic experiment
Laboratory observation sodium chloride blank group, experiment 1-5 group are to the hemolysis in vitro effect of family's Sanguis Leporis seu oryctolagi, wherein blank group adopts sodium chloride injection, the mezlocillin sodium freeze-dried powder injection that experiment 1-4 group adopts embodiment 1-4 to prepare respectively, tests 5 groups of mezlocillin injectable powder adopting comparative example 1 to prepare.Both are all dissolved in water for injection rear injection.
Result shows 37 DEG C, 3 hours, test 5 groups and occurred erythrocyte aggregation phenomenon, and all the other experimental grouies and blank group is all without haemolysis, has no erythrocyte aggregation phenomenon and occurs.
Three, allergic experiment
Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, experiment 1-5 group, wherein blank group adopts sodium chloride injection, the mezlocillin sodium freeze-dried powder injection that experiment 1-4 group adopts embodiment 1-4 to prepare respectively, tests 5 groups of mezlocillin injectable powder adopting comparative example 1 to prepare.Both are all dissolved in water for injection rear injection.
Concrete grammar is: laboratory animal every other day gives mezlocillin sodium injection sensitization prepared by lumbar injection comparative example 1, continuous three times, then laboratory animal is divided into blank group, experiment 1-5 group, totally 6 groups, and start in sensitization within the 14th day and 21 days, attack administration respectively, immediately observe 1 hour.
Result shows, and test 5 groups and occurred the phenomenons such as perpendicular hair, dyspnea, sneeze, retch, cough or rale, tic, collapse, death, all the other each group does not occur above-mentioned phenomenon.
The above results shows, the mezlocillin sodium freeze-dried powder injection of preparation of the present invention adds mannitol, anhydrous sodium sulfate, but safety is without any impact.
Test example 3
The solubility of mezlocillin sodium freeze-dried powder injection prepared by comparing embodiment 1 ~ 4 and comparative example 1 and clarity of solution, the results are shown in Table 2.
Table 2 sample redissolution situation
| Sample | Lyophilizing finished product redissolution situation |
| Embodiment 1 | Redissolve fast, solution is clarified |
| Embodiment 2 | Redissolve fast, solution is clarified |
| Embodiment 3 | Redissolve fast, solution is clarified |
| Embodiment 4 | Redissolve fast, solution is clarified |
| Comparative example 1 | Redissolve slow, have a small amount of precipitation |
| Comparative example 2 | Redissolve slow, have a small amount of precipitation |
Test example 4
The sample of comparing embodiment 1 ~ 4 and comparative example 1 keep sample for a long time test (room temperature 25 ± 2 DEG C, under relative humidity 60% ± 10% condition, assay method: national standard WS
1(X-024) 2003Z and WS
1(X-025) 2003Z), investigation project comprises character, clarity of solution and color, pH value, labelled amount, its related substances etc., and result of study is as table 3 ~ 5.
Table 3 keeps sample test 0th month for a long time
Table 4 keeps sample test 6 months for a long time
Table 5 keeps sample test 12 months for a long time
Above-mentioned result of the test sufficient proof, the present invention adopts adjuvant mannitol and sodium sulfate, and the solubility that can solve mezlocillin sodium lyophilized preparation is well poor, poor stability and the high problem of polymer content.As can be seen from result, injectable powder polymer content of the present invention is low, and long-time placement rear stability is high, and the indices changes such as content, related substance, clarity are all not obvious, the comparable existing injectable powder significant prolongation of storage time.And compare with many prior aries, not only adjunct ingredient is simple, and safety, preparation method easily operates.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (3)
1. the pharmaceutical composition containing mezlocillin sodium compound, it is made up of the raw material of following weight parts proportioning:
Mezlocillin sodium 10-20;
Mannitol 1-10;
Anhydrous sodium sulfate 1-20;
Its preparation method is: take mezlocillin sodium by formula ratio, mannitol, anhydrous sodium sulfate, use sterile water for injection mix and blend, with saturated sodium bicarbonate solution pH be adjusted to 4.5 ~ 7.5 and continue to stir, the active carbon adding liquor capacity 0.1-0.5% stirs decolouring, 0.22 μm of filter membrane fine straining is used again after coarse filtration, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-45 ~-35 DEG C, 6-8 hour, slowly intensification low-temperature vacuum drying 20-30 is little of-20 DEG C again, continue to be warming up to 10 DEG C, vacuum drying 3-5 hour, gland, obtain.
2. pharmaceutical composition as claimed in claim 1, it is made up of the raw material of following weight parts proportioning:
Mezlocillin sodium 15;
Mannitol 5;
Anhydrous sodium sulfate 5.
3. the preparation method of the pharmaceutical composition described in claim 1 or 2, it comprises the steps:
Mezlocillin sodium is taken by formula ratio, mannitol, anhydrous sodium sulfate, use sterile water for injection mix and blend, with saturated sodium bicarbonate solution pH be adjusted to 4.5 ~ 7.5 and continue to stir, the active carbon adding liquor capacity 0.1-0.5% stirs decolouring, 0.22 μm of filter membrane fine straining is used again after coarse filtration, be sub-packed in vial by preparation specification under aseptic, send in freezer dryer and carry out lyophilization, pre-freeze-45 ~-35 DEG C, 6-8 hour, slowly intensification low-temperature vacuum drying 20-30 is little of-20 DEG C again, continue to be warming up to 10 DEG C, vacuum drying 3-5 hour, gland, obtain.
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| CN104739781A (en) * | 2015-04-03 | 2015-07-01 | 海南通用康力制药有限公司 | Preparation method of mezlocillin sodium aseptic powder for injection |
| CN107648189A (en) * | 2017-11-13 | 2018-02-02 | 南京正亮医药科技有限公司 | A kind of injection omeprazole sodium and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045050A (en) * | 2006-03-30 | 2007-10-03 | 广东奇方药业有限公司 | Stable antibiotic powder injection |
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045050A (en) * | 2006-03-30 | 2007-10-03 | 广东奇方药业有限公司 | Stable antibiotic powder injection |
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
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