CN103040819A - Drug composition containing mezlocillin sodium compound and preparation method of drug composition - Google Patents
Drug composition containing mezlocillin sodium compound and preparation method of drug composition Download PDFInfo
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- CN103040819A CN103040819A CN2013100086188A CN201310008618A CN103040819A CN 103040819 A CN103040819 A CN 103040819A CN 2013100086188 A CN2013100086188 A CN 2013100086188A CN 201310008618 A CN201310008618 A CN 201310008618A CN 103040819 A CN103040819 A CN 103040819A
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- mezlocillin
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Abstract
The invention discloses a drug composition containing a mezlocillin sodium compound, which comprises the following raw materials in parts by weight: 10-20 parts of mezlocillin sodium, 1-20 parts of mannitol and 1-20 parts of anhydrous sodium sulfate. According to the drug composition, an optimal freeze-drying protective agent mannitol is screened out by a large number of tests, freeze-dried powder is excellent in re-dissolubility and good in stability, and contents of relevant substances are low after long-term storage. As mezlocillin sodium is instable, a polymer is generated easily during preparation of the freeze-dried powder, and the polymer causes anaphylactic reaction easily. The applicant accidentally find that sodium sulfate can effectively reduce the content of a mezlocillin sodium polymer in the lyophilized agent to be less than 0.3%, through a large number of tests, so that the requirements of the pharmacopeia are met, and the risk of anaphylactic reaction caused by the polymer is avoided effectively.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition that contains the 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]-the 2-phenylacetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0]-heptane-2-formic acid sodium salt.Be mainly used in the respiratory system due to the sensitive strain in the gram negative bacillis such as escherichia coli, Enterobacter, Bacillus proteus, urinary system, digestive system, gynecological and genitals official rank and infect, infect such as septicemia, purulent meningitis, peritonitis, osteomyelitis, skin and soft tissue infection and Eye Ear Nose And Throat section.
Its application in clinical is being perplexed in the anaphylaxis that Penicillin antibiotics causes for a long time always.According to domestic and international clinical research report, the sensitization source of penicillins kind medicine mainly is contained polymer itself.Thereby the content that reduces polymer in the penicillin medicine becomes and reduces its hypersensitive important channel.The limit of Chinese Pharmacopoeia regulation polymer is≤0.3%.In the prior art, usually need that the mezlocillin sodium product is carried out chromatography purification and just can make product satisfy the polymer limit requirement of pharmacopeia regulation.
Up to the present, mezlocillin sodium adopts the method for lyophilizing to obtain usually, because the unstability of mezlocillin sodium itself, the freeze-drying prods impurity content is larger, and quality is unstable, dissolubility, and clarity is poor.And the impurity content height easily causes clinical use untoward reaction high, and at present mezlocillin for inj has occurred clinically occurring after the patient uses that ear is dizzy, tinnitus; Anaphylaxis; Anaphylactic shock; The untoward reaction, particularly anaphylaxis such as external genitalia edema and anaphylactic shock substantially all are to be caused by impurity.Therefore developing a kind of polymer content mezlocillin preparation low, stable, 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 any several mixture of sodium carbonate, arginine, sodium bicarbonate, sodium hydroxide, and the part by weight of mezlocillin and cosolvent is 1: 1-1: 0.5.The injectable powder polymer content that can be somebody's turn to do the prescription preparation is higher, and potential drug safety problem is arranged.
Summary of the invention
Special physico-chemical character in view of the deficiencies in the prior art and mezlocillin sodium, need to find a kind of prescription and preparation method, poorly soluble, the poor stability when solving simultaneously mezlocillin sodium and being prepared into injection, clarity is poor and the high problem such as easily cause allergic reaction of polymer content.Therefore, the object of the present invention is to provide a kind of pharmaceutical composition (lyophilized injectable powder) that contains the mezlocillin sodium compound, the problems such as prior art mezlocillin sodium lyophilized preparation is poorly soluble to solve, poor stability, solubility is poor and polymer content is high.
A kind of pharmaceutical composition that contains the 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 specific embodiments of the present invention, 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 by weighing mezlocillin sodium by formula ratio, mannitol, anhydrous sodium sulfate, use the sterile water for injection mix and blend, with saturated sodium bicarbonate solution pH being transferred to 4.5～7.5 also continues to stir, the active carbon that adds liquor capacity 0.1-0.5% stirs decolouring, use again 0.22 μ m filter membrane fine straining after the coarse filtration, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, 6-8 hour, slowly heated up low-temperature vacuum drying 20-30 hour to-20 ℃ again in pre-freeze-45～-35 ℃, continue to be warming up to 10 ℃, vacuum drying 3-5 hour, gland, and get final product.
The present invention has filtered out best freeze drying protectant mannitol by lot of experiments, makes the lyophilized powder solubility excellent, good stability, and its related substances is low after the long preservation.Because the unstability of mezlocillin sodium itself easily produce polymer in the lyophilized powder preparation process, and polymer causes allergic reaction easily.And the applicant passes through lot of experiments, be surprised to find that use sodium sulfate, can effectively reduce the content of mezlocillin sodium polymer in the lyophilized preparation, make polymer content all less than 0.3%, satisfy the requirement of pharmacopeia, the risk of effectively having avoided polymer to cause allergic reaction.
The specific embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Prescription: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 20g; Mannitol 10g; Anhydrous sodium sulfate 1g.
Take by weighing mezlocillin sodium, mannitol and the anhydrous sodium sulfate of above-mentioned weight, mix with sterile water for injection, with saturated sodium bicarbonate solution pH value is transferred to 7.0, after 0.1% activated carbon decolorizing filters, with the membrane filtration of 0.22 μ m, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, pre-freeze-40 ℃, 8 hours, low-temperature vacuum drying 20 hours to-20 ℃ more slowly heated up, continue to be warming up to 10 ℃, vacuum drying 5 hours, gland, and get final product.
Embodiment 2
Prescription: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 15g; Mannitol 5g; Anhydrous sodium sulfate 5g.
Take by weighing mezlocillin sodium, mannitol and the anhydrous sodium sulfate of above-mentioned weight, mix with sterile water for injection, with saturated sodium bicarbonate solution pH value is transferred to 6.0, after 0.3% activated carbon decolorizing filters, with the membrane filtration of 0.22 μ m, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, pre-freeze-45 ℃, 6 hours, low-temperature vacuum drying 30 hours to-20 ℃ more slowly heated up, continue to be warming up to 10 ℃, vacuum drying 4 hours, gland, and get final product.
Embodiment 3
Prescription: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 10g; Mannitol 1g; Anhydrous sodium sulfate 10g.
Take by weighing mezlocillin sodium, mannitol and the anhydrous sodium sulfate of above-mentioned weight, mix with sterile water for injection, with saturated sodium bicarbonate solution pH value is transferred to 5.0, after 0.5% activated carbon decolorizing filters, with the membrane filtration of 0.22 μ m, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, pre-freeze-35 ℃, 8 hours, low-temperature vacuum drying 25 hours to-20 ℃ more slowly heated up, continue to be warming up to 10 ℃, vacuum drying 3 hours, gland, and get final product.
Embodiment 4
Prescription: mezlocillin of the present invention sodium pharmaceutical composition comprises component: mezlocillin sodium 15g; Mannitol 10g; Anhydrous sodium sulfate 20g.
Take by weighing mezlocillin sodium, mannitol and the anhydrous sodium sulfate of above-mentioned weight, mix with sterile water for injection, with saturated sodium bicarbonate solution pH value is transferred to 7.0, after 0.1% activated carbon decolorizing filters, with the membrane filtration of 0.22 μ m, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, pre-freeze-40 ℃, 8 hours, low-temperature vacuum drying 20 hours to-20 ℃ more slowly heated up, continue to be warming up to 10 ℃, vacuum drying 5 hours, gland, and get final product.
Comparative Examples 1
According to the injectable powder of embodiment 1 preparation 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 Examples 1 preparation according to the molecular exclusion chromatography of two appendix VH of Chinese Pharmacopoeia version in 2005, the 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 Examples 1 | 3.22 |
As can be seen from Table 1, in the mezlocillin sodium freeze-dried powder injection of the present invention owing to having adopted sodium sulfate, make wherein polymer content far below the polymer content in the existing injectable powder, make each batch product all meet the regulation of pharmacopeia, greatly improved the safety of medication, the polymer content of Comparative Examples does not then meet the regulation of pharmacopeia.
Test example 2
The lyophilized injectable powder of embodiment 1-4 preparation and the mezlocillin injectable powder of Comparative Examples 1 preparation are carried out the safety testing investigation, and test method and result are as follows:
One, vascular stimulation test
Get body weight and be 48 of the healthy rabbits of 2.0-2.5kg, be divided at random blank group, experiment 1-7 group, 6 every group, adopt rabbit ear edge vein slowly to inject, injection volume is 10ml/kg.Wherein the blank group adopts sodium chloride injection, and experiment 1-4 group adopts respectively the mezlocillin sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of mezlocillin injectable powder that adopt Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
Once a day, successive administration 7 days, cut short the rabbit ear in last administration after 24 hours, place 10% formalin fixed preparation, then send pathology to carry out histological examination (5 places at the different parts of rabbit ear edge vein draw materials, and namely begin centripetal end and do a section every 1cm from injecting initial position).
Through rabbit ear edge vein pathological examination, the auricular vein tube wall of blank group and test 1-4 group is complete, and the endotheliocyte structure is clear, and without obvious pathological changes, the slight dilatation and congestion of blood vessel is without cell infiltration.Test 5 groups and the slight dilatation and congestion of blood vessel occurs, other are normal.
Two, hemolytic experiment
Laboratory observation sodium chloride blank group, the experiment 1-5 group external haemolysis to family's Sanguis Leporis seu oryctolagi, wherein the blank group adopts sodium chloride injection, experiment 1-4 group adopts respectively the mezlocillin sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of mezlocillin injectable powder that adopt Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
The result shows 37 ℃, 3 hours, test 5 groups and the erythrocyte aggregation phenomenon occurred, and all the other experimental grouies and blank group has no the erythrocyte aggregation phenomenon and occurs all without haemolysis.
Three, allergic experiment
Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, experiment 1-5 group, wherein the blank group adopts sodium chloride injection, experiment 1-4 group adopts respectively the mezlocillin sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of mezlocillin injectable powder that adopt Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
Concrete grammar is: laboratory animal every other day gives the mezlocillin sodium injection sensitization of lumbar injection Comparative Examples 1 preparation, continuous three times, then laboratory animal is divided into blank group, experiment 1-5 group, totally 6 groups, and the 14th day and 21 days of beginning in sensitization attack respectively administration, observed immediately 1 hour.
The result shows, tests 5 groups and the phenomenons such as perpendicular hair, dyspnea, sneeze, retch, cough or rale, tic, collapse, death occurred, and above-mentioned phenomenon does not appear in all the other each groups.
The above results shows, the mezlocillin sodium freeze-dried powder injection of preparation of the present invention has added mannitol, anhydrous sodium sulfate, but safety is without any impact.
Test example 3
Solubility and the clarity of solution of the mezlocillin sodium freeze-dried powder injection of comparing embodiment 1～4 and Comparative Examples 1 preparation the results are shown in Table 2.
Table 2 sample redissolution situation
| Sample | Lyophilizing finished product redissolution situation |
| Embodiment 1 | Redissolve soon the solution clarification |
| Embodiment 2 | Redissolve soon the solution clarification |
| Embodiment 3 | Redissolve soon the solution clarification |
| Embodiment 4 | Redissolve soon the solution clarification |
| Comparative Examples 1 | Redissolve slowly, a small amount of precipitation is arranged |
| Comparative Examples 2 | Redissolve slowly, a small amount of precipitation is arranged |
Test example 4
The sample of comparing embodiment 1～4 and Comparative Examples 1 keep sample for a long time test (25 ± 2 ℃ of room temperatures, under relative humidity 60% ± 10% condition, assay method: national standard WS
1(X-024) 2003Z and WS
1(X-025) 2003Z), the investigation project comprises character, clarity of solution and color, pH value, labelled amount, its related substances etc., result of study such as table 3～5.
Table 3 keeps sample for a long time and tested 0th month
Table 4 keeps sample for a long time and tested 6 months
Table 5 keeps sample for a long time and tested 12 months
Above-mentioned result of the test sufficient proof, the present invention adopts adjuvant mannitol and sodium sulfate, and the solubility that can solve well the mezlocillin sodium lyophilized preparation is poor, poor stability and the high problem of polymer content.Can find out from the result, injectable powder polymer content of the present invention is low, places for a long time rear stability high, and the indices such as content, related substance, clarity change all not obvious, the comparable existing injectable powder significant prolongation of storage time.And with many prior art relatively, not only adjunct ingredient is simple, safety, preparation method easily operates.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away 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 (4)
1. pharmaceutical composition that contains the 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.
2. pharmaceutical composition as claimed in claim 1, it contains the raw material of following weight parts proportioning:
Mezlocillin sodium 15;
Mannitol 5;
Anhydrous sodium sulfate 5.
3. pharmaceutical composition as claimed in claim 1 or 2, it is lyophilized injectable powder.
4. the preparation method of each described pharmaceutical composition of claim 1～3, it comprises the steps:
Take by weighing mezlocillin sodium by formula ratio, mannitol, anhydrous sodium sulfate, use the sterile water for injection mix and blend, with saturated sodium bicarbonate solution pH being transferred to 4.5～7.5 also continues to stir, the active carbon that adds liquor capacity 0.1-0.5% stirs decolouring, use again 0.22 μ m filter membrane fine straining after the coarse filtration, under aseptic, be sub-packed in the vial by the preparation specification, send into and carry out lyophilization in the freezer dryer, 6-8 hour, slowly heated up low-temperature vacuum drying 20-30 hour to-20 ℃ again in pre-freeze-45～-35 ℃, continue to be warming up to 10 ℃, vacuum drying 3-5 hour, gland, and get final product.
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| CN201310008618.8A CN103040819B (en) | 2013-01-10 | 2013-01-10 | A kind of pharmaceutical composition containing mezlocillin sodium compound and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2013
- 2013-01-10 CN CN201310008618.8A patent/CN103040819B/en active Active
Patent 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| CN103040819B (en) | 2015-09-30 |
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