CN104739780A - Ertapenem disodium pharmaceutical composition and preparation method thereof - Google Patents
Ertapenem disodium pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN104739780A CN104739780A CN201310750967.7A CN201310750967A CN104739780A CN 104739780 A CN104739780 A CN 104739780A CN 201310750967 A CN201310750967 A CN 201310750967A CN 104739780 A CN104739780 A CN 104739780A
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Abstract
The invention relates to a solid Ertapenem disodium pharmaceutical composition and a preparation method thereof. The pharmaceutical composition contains Ertapenem disodium as shown in formula I and a compound as shown in formula II or a sodium salt, a hydrate or a solvate thereof and pharmaceutically acceptable additives. In the solid Ertapenem disodium pharmaceutical composition provided by the invention, the proportion of the compound as shown in formula II or the sodium salt, the hydrate or the solvate thereof is higher than 80%, and thus the stability of a final Ertapenem disodium preparation is greatly improved.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of ertapenem sodium pharmaceutical composition and preparation method thereof.
Background technology
Ertapenem (Ertapenem sodium; structural formula is such as formula 1); chemistry is by name: (1R; 5S; 6S; 8R; 2S*; 4S*)-2-[2-[3-carboxyl-phenyl carbamoyl]-pyrrolidinyl-4-sulfo-]-6-(1-ethoxy)-1-beta-methyl carbapenem-3-formic acid list sodium salt; for the New-type wide-spectrum carbapenem antibiotic of Merck company and Astrazeneca AB's joint development, to comprising gram positive bacteria and Negative aerobe and anaerobe, all there is good antibacterial activity.
The commodity of ertapenem listing formulation products by name " happy ten thousand it " are aseptic freeze-dried powder.Also containing 175mg sodium bicarbonate in per unit ertapenem formulation products, pH is regulated to be 7.5 with sodium hydroxide.
First CN1198162A discloses ertapenem stable form as shown in Equation 2,
The preparation method of the compound of formula 2 disclosed in this patent is, is mixed by formula 1 compound, and is dissolved by this mixture, usually can obtain formula 2 compound with carbon dioxide source (as sodium carbonate or sodium bicarbonate).But compositions exists in liquid form disclosed in it, formula 2 compound can not be present in compositions with fixed proportion.
CN1481385A discloses the preparation method of the final formulation product of a kind of formula 2 compound or its pharmaceutically useful salt, hydrate or solvate, and described final preparation is lyophilized powder.In this patent specification, mention the high conversion that alkali metal salt (such as single sodium salt) that its method provides carbapenem is converted into formula 2 compound, but in this patent, do not mention that above-mentioned high conversion is how many.
The structural identification data of all unexposed formula 2 compound and detection method in above-mentioned 2 sections of documents.
To sum up, in the final preparation of ertapenem disclosed in prior art, with no specific disclosure of formula 2 compound or its pharmaceutically useful salt, hydrate or solvate proportion wherein.Because formula 2 compound is the stable form of ertapenem, its in the final formulation proportion determine the stability of final preparation, therefore, need to study the preparation technology of the final preparation of ertapenem, improve the ratio of final preparation Chinese style 2 compound or its pharmaceutically useful salt, hydrate or solvate, thus improve the stability of the final preparation of ertapenem.
Summary of the invention
The present inventor has carried out large quantity research to ertapenem preparation prescription technique, finally have found a kind of method that can improve the conversion ratio of final preparation Chinese style 2 compound, final preparation Chinese style 2 compound obtained or its pharmaceutically useful salt, hydrate or solvate proportion, up to more than 80%, substantially increase the stability of the final preparation of ertapenem.
Therefore, one aspect of the present invention provides a kind of solid pharmaceutical composition, it is characterized in that: it contains the ertapenem shown in formula 1, and the compound shown in formula 2 or its sodium salt, hydrate or solvate, and pharmaceutically acceptable adjuvant,
Wherein:
Compound shown in formula 2 or its pharmaceutically acceptable salt, hydrate or solvate, the percentage ratio accounting for the total amount of the ertapenem shown in itself and formula 1, for being not less than 80%, being preferably not less than 85%, being more preferably and being not less than 90%.
Compound sodium salt shown in described formula 2 is selected from next group:
Compound sodium salt shown in above-mentioned formula 2-a to 2-g is referred to as carbaminate.
The present invention provides a kind of preparation method of pharmaceutical composition as above on the other hand, it is characterized in that, comprises the steps:
(1) prepare sodium bicarbonate ethanol water: be dissolved in the ethanol water of 5 ~ 10% by the sodium bicarbonate of recipe quantity, obtained sodium bicarbonate concentration is 2-12%, is preferably 3-7%(w/w) sodium bicarbonate ethanol water, be cooled to-5 ~ 0 DEG C, for subsequent use;
At (2)-5 ~ 0 DEG C of temperature, the ertapenem sodium raw materials of recipe quantity is slowly joined in the sodium bicarbonate ethanol water of the step (1) accounting for total consumption 40 ~ 70%, stir, slowly add the sodium bicarbonate ethanol water of surplus (30 ~ 60%) immediately, optionally, appropriate sodium hydroxide solution can be dripped, to maintain pH value of reaction system between 7.0 ~ 8.0;
(3) optionally, by the process of step (2) gained solution with activated carbon, filter, then aseptic filtration, obtain sterile solution;
(4) step (2) gained solution is carried out lyophilization, obtain solid pharmaceutical composition of the present invention; Or the sterile solution that step (3) obtains is carried out lyophilization, obtain aseptic solid pharmaceutical composition of the present invention.
Wherein:
In described step (2), the mol ratio of the total consumption of sodium bicarbonate and ertapenem sodium raw materials is 3 ~ 1.5:1, is preferably 2.5 ~ 2:1.
In step (2), the initial content of sodium bicarbonate ethanol water preferably accounts for 45 ~ 60% of total consumption; Concentration of sodium hydroxide solution (w/w) is 1-10%, is preferably 2-5%; Reaction system pH preferably maintains 7.3 ~ 7.7, is more preferably 7.4 ~ 7.6.
In described step (3), activated carbon dosage is 0.05% ~ 0.2%(w/w), within the scope of this, absorption 60min medicinal liquid content has no significant effect.Aseptic filtration is preferably the microporous filter membrane of 0.22um, described microporous filter membrane be selected from polyvinylidene fluoride microporous filter membrane and polyethersulfone millipore filter one or both.
Step (4) is preferably: by the solution quantitative separating that obtains in step (2) in injection bottle, then carry out lyophilization, obtain solid pharmaceutical composition of the present invention; Or by the sterile solution quantitative separating that obtains in step (3) in injection bottle, then carry out lyophilization, obtain aseptic solid pharmaceutical composition of the present invention.Described injection bottle is preferably the lyophilizing cillin bottle of neutral boron silica glass material.
Described lyophilization, in general, require that bottle was about-45 ~-40 DEG C of equal heat treatments about 3 ~ 5 hours, then maintain this temperature, lyophilized machine chamber pressure maintains about 2 ~ 4 hours under 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy is to about-30 ~-25 DEG C, and lyophilized machine chamber pressure maintains about 26 ~ 40 hours under about 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy temperature to about 0 DEG C, and maintains about 4 ~ 8 hours at about 20 ~ 30 handkerchiefs; Be warming up to 20 DEG C again, and maintain about 10 ~ 15 hours at about 10 handkerchiefs; Then be warming up to 40 DEG C, and maintain about 8 ~ 12 hours at about 10 handkerchiefs; Then freeze dryer flaggy is cooled to room temperature.Before taking out from freeze dryer, bottle seals completely under the partial vacuum of about 20 ~ 30 handkerchiefs or power at low pressure.Under the partial vacuum of≤10 handkerchief pressure, by injection bottle tamponade, take out from freeze dryer.
Also the solution obtained in (2) can be carried out lyophilizing in batch, then gained powder be carried out subpackage, obtain solid pharmaceutical composition of the present invention; Or the sterile solution obtained in (3) is carried out lyophilizing in batch, then gained powder is carried out aseptic subpackaged, obtain aseptic solid pharmaceutical composition of the present invention.
The present invention also relates on the other hand solid pharmaceutical composition of the present invention for the preparation of the application in anti-infectives.
In ertapenem solid pharmaceutical composition provided by the invention, compound 2 or its pharmaceutically useful salt, hydrate or solvate proportion are up to more than 80%, and through the long term test of 24 months, related substance increased seldom, and sample stability is good; Compared with commercialized product " happy ten thousand it ", impurity increase is relatively less, and character is more stable, and be more conducive to storing, clinical application is safer.
Detailed description of the invention
Following embodiment is only to illustrate in greater detail the present invention, instead of restriction the present invention.
Carbaminate detection method of content:
Instrument: Bruker Advance600 type nuclear magnetic resonance spectrometer
Solvent: D
2o
Detection method: to detection sample carry out 1H-13C heteronuclear multiple-bond be correlated with two-dimensional spectrum (HMBC) experiment.
Embodiment 1: the preparation of ertapenem solid pharmaceutical composition
Table 1: ertapenem solid pharmaceutical composition prescription (1000 bottles of amounts, specification: 1g)
| Supplementary material title | Consumption (g) |
| Ertapenem | 1046g |
| Sodium bicarbonate | 353g |
| Ethanol | 350g |
| Sodium hydroxide | In right amount |
| Water for injection | Add to 11000g |
| By every bottle of 11g subpackage, make 1000 bottles altogether |
Preparation technology:
(1) prepare the ethanol water of 5%: joined in 6650g water for injection by 350g ethanol, fully mix, place, for subsequent use; Be dissolved in above-mentioned ethanol water by the sodium bicarbonate of recipe quantity, be cooled to-5 ~ 0 DEG C, obtained sodium bicarbonate ethanol water is for subsequent use.
(2) the sodium bicarbonate ethanol water of total amount 50% is taken, at-5 ~ 0 DEG C, by the ertapenem sodium raw materials (HPLC purity is 99.1%) of recipe quantity, slowly join in above-mentioned solution, stir, drip the sodium bicarbonate ethanol water of surplus (i.e. total amount 50%) immediately, again with 2%(w/w) sodium hydroxide solution regulate and maintain solution ph to 7.5, stir, mend and inject water to 11000g, stir; Time used is 1 hour.
Following steps are carried out under hundred grades of clean environments:
(3) medicinal liquid is through the aseptic filtration of two-stage 0.22 μm of microporous filter membrane (filter element); Time used is 0.5 hour.(4) adopt 20ml cleaning, aseptic control lyophilizing cillin bottle subpackage medicinal liquid, theoretical loading amount is 11g/ bottle, and half tamponade, the sample after half tamponade is transferred to immediately the freeze dryer of pre-cooling drying baker to-5 DEG C, the time used is 2 hours; Start lyophilizing program, freeze-drying curve is as follows:
Table 2 embodiment 1 freeze-drying curve
(5) tamponade, rolls aluminium-plastic cap, and inspection, labeling, obtains solid pharmaceutical composition of the present invention.
Get finished product sample D
2o dissolves and is mixed with 200mg/mL solution, and carry out carbaminate content detection, the ratio of carbaminate and ertapenem is 95:5.
Embodiment 2 ~ 9: the preparation (reaction system pH investigation) of ertapenem solid pharmaceutical composition
With reference to the formulation and technology of embodiment 1, just change the dosing pH value in step (2), experimental result sees the following form:
The experimental result of table 3 embodiment 2 ~ 9
| Embodiment | Medicinal liquid pH value | The ratio of finished product carbaminate and ertapenem |
| 2 | 7.0 | 80:20 |
| 3 | 7.2 | 83:17 |
| 4 | 7.3 | 86:14 |
| 5 | 7.4 | 91:9 |
| 6 | 7.6 | 90:10 |
| 7 | 7.7 | 85:15 |
| 8 | 7.8 | 82:18 |
| 9 | 8.0 | 80:20 |
Experimental result shows, during drug solution preparing, pH value controls between 7.0 ~ 8.0, and in final dried frozen aquatic products, carbamic acid salt content is more than 80%; When medicinal liquid pH value is 7.3 ~ 7.7, carbamic acid salt content is more than 85%; When medicinal liquid pH value is 7.4 ~ 7.6, carbamic acid salt content is more than 90%; When medicinal liquid pH value is 7.5, carbamic acid salt content can reach 95%(and see embodiment 1).
Embodiment 10 ~ 14: the preparation (investigation of sodium bicarbonate consumption) of ertapenem solid pharmaceutical composition
With reference to the formulation and technology of embodiment 1, just change the consumption of sodium bicarbonate in step (1), experimental result sees the following form:
The experimental result of table 4 embodiment 10 ~ 14
Experimental result shows, sodium bicarbonate and ertapenem mol ratio are between 1.5 ~ 3, and in final dried frozen aquatic products, carbamic acid salt content is more than 80%; When mol ratio is between 1.8 ~ 2.5, carbamic acid salt content is more than 85%; When mol ratio is between 2.2 ~ 2.0, carbamic acid salt content is (see embodiment 1,12) more than 90%.
Embodiment 15: the preparation (investigation of sodium bicarbonate ethanol water initial content) of ertapenem solid pharmaceutical composition
With reference to the formulation and technology of embodiment 1, just change the initial content of sodium bicarbonate ethanol water in step (2), experimental result sees the following form:
Table 5 embodiment 15 ~ 21 experimental result
Experimental result shows, in step (2), sodium bicarbonate ethanol water initial content is between 40 ~ 70% of total consumption, and in final dried frozen aquatic products, carbamic acid salt content is more than 80%; When consumption is between 45 ~ 60% of total consumption, carbamic acid salt content is more than 85%; When consumption is between 50 ~ 55% of total consumption, carbamic acid salt content is (see embodiment 1,18) more than 90%.
Embodiment 22: long-term stable experiment
Get the embodiment of the present invention 1,2,6 and 7 sample, simulation listing packaging, temperature 25 ± 2 DEG C, under relative humidity 60% ± 10% condition, lucifuge is placed, and detects, detect by stability high spot reviews project and assay method in 0,3,6,9,12,18,24 sampling at the end of month, separately get keeping sample under this condition by imitative product happy ten thousand, in the sampling of same time point, investigate related substance situation of change, the results are shown in Table 6.
Table 6 ertapenem solid pharmaceutical composition long-term stable experiment result
Table 6-1
Table 6-2
Table 6-3
Result of the test shows: ertapenem solid pharmaceutical composition of the present invention, and through the long term test of 24 months, related substance increased seldom, and sample stability is good; Compared with commercialized product " happy ten thousand it ", impurity increase is relatively less, and character is more stable, and be more conducive to storing, clinical application is safer.
Claims (9)
1. a solid pharmaceutical composition, is characterized in that: it contains the ertapenem shown in formula 1, and the compound shown in formula 2 or its sodium salt, hydrate or solvate, and pharmaceutically acceptable adjuvant,
2. pharmaceutical composition as claimed in claim 1, it is characterized in that: the compound shown in formula 2 or its pharmaceutically acceptable salt, hydrate or solvate account for the percentage by weight of the total amount of the ertapenem shown in itself and formula 1 for being not less than 80%, preferably be not less than 85%, be more preferably and be not less than 90%.
3. pharmaceutical composition as claimed in claim 1 or 2, is characterized in that: the sodium salt of the compound shown in described formula 2 is selected from the group of the composition of compound shown in following formula 2-a to formula 2-g:
4. a preparation method for pharmaceutical composition as claimed in claim 1 or 2, is characterized in that: comprise the steps:
(1) prepare sodium bicarbonate ethanol water: be dissolved in the ethanol water of 5 ~ 10% by the sodium bicarbonate of recipe quantity, obtained sodium bicarbonate concentration is 2-12%, is preferably 3-7%(w/w) sodium bicarbonate ethanol water, be cooled to-5 ~ 0 DEG C, for subsequent use;
At (2)-5 ~ 0 DEG C of temperature, the ertapenem sodium raw materials of recipe quantity is slowly joined in the sodium bicarbonate ethanol water of step (1) of initial content, this initial content is 40 ~ 70(w/w of total consumption) %, stir, slowly add the sodium bicarbonate ethanol water of surplus immediately, optionally, drip appropriate sodium hydroxide solution, to maintain pH value of reaction system between 7.0 ~ 8.0;
(3) optionally, by the process of step (2) gained solution with activated carbon, filter, then carry out aseptic filtration, obtain sterile solution;
(4) step (2) gained solution is carried out lyophilization, obtain solid pharmaceutical composition; Or the sterile solution that step (3) obtains is carried out lyophilization, obtain sterile solid pharmaceutical composition.
5. the preparation method of pharmaceutical composition as claimed in claim 4, is characterized in that: in described step (2), the mol ratio of the total consumption of sodium bicarbonate and ertapenem sodium raw materials is 1.5 ~ 3:1, is preferably 2.5 ~ 2:1.
6. the preparation method of pharmaceutical composition as claimed in claim 4, is characterized in that: in step (2), the initial content of sodium bicarbonate ethanol water is 45 ~ 60(w/w of total consumption) %.
7. the preparation method of pharmaceutical composition as claimed in claim 4, is characterized in that: in step (2), reaction system pH maintains 7.3 ~ 7.7, is preferably 7.4 ~ 7.6.
8. the preparation method of pharmaceutical composition as claimed in claim 4, is characterized in that: step (4) is the solution will obtained in step (2), or by the sterile solution quantitative separating that obtains in step (3) in injection bottle, then carries out lyophilization;
Described freezing dry process is: injection bottle was-45 ~-40 DEG C of equal heat treatments 3 ~ 5 hours, and then maintain this temperature, lyophilized machine chamber pressure maintains 2 ~ 4 hours under 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy is to-30 ~-25 DEG C, and lyophilized machine chamber pressure maintains 26 ~ 40 hours under 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy temperature to 0 DEG C, and maintain 4 ~ 8 hours at 20 ~ 30 handkerchiefs; Be warming up to 20 DEG C again, and maintain 10 ~ 15 hours at 10 handkerchiefs; Then be warming up to 40 DEG C, and maintain 8 ~ 12 hours at 10 handkerchiefs; Then freeze dryer flaggy is cooled to room temperature; Under the partial vacuum of≤10 handkerchief pressure, by injection bottle tamponade, take out from freeze dryer.
9. the solid pharmaceutical composition that the pharmaceutical composition described in any one of claim 1-3 or the method described in any one of claim 4-8 obtain is preparing the application in anti-infectives.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310750967.7A CN104739780A (en) | 2013-12-31 | 2013-12-31 | Ertapenem disodium pharmaceutical composition and preparation method thereof |
| CN201810683783.6A CN109134469B (en) | 2013-12-31 | 2013-12-31 | Ertapenem sodium pharmaceutical composition and preparation method thereof |
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| CN201310750967.7A CN104739780A (en) | 2013-12-31 | 2013-12-31 | Ertapenem disodium pharmaceutical composition and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012066492A1 (en) * | 2010-11-16 | 2012-05-24 | Ranbaxy Laboratories Limited | Processes for the preparation of carbapenem antibiotic composition |
| EP2505191A1 (en) * | 2008-06-11 | 2012-10-03 | Ranbaxy Laboratories Limited | Lyophilized Carbapenem antibiotic composition |
| CN103181904A (en) * | 2011-12-27 | 2013-07-03 | 石药集团中奇制药技术（石家庄）有限公司 | Ertapenem sodium freeze-dried preparation and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6548492B1 (en) * | 1999-10-29 | 2003-04-15 | Merck & Co., Inc. | Process for formulation of carbapenem antibiotic compositions |
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- 2013-12-31 CN CN201310750967.7A patent/CN104739780A/en active Pending
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2505191A1 (en) * | 2008-06-11 | 2012-10-03 | Ranbaxy Laboratories Limited | Lyophilized Carbapenem antibiotic composition |
| WO2012066492A1 (en) * | 2010-11-16 | 2012-05-24 | Ranbaxy Laboratories Limited | Processes for the preparation of carbapenem antibiotic composition |
| CN103181904A (en) * | 2011-12-27 | 2013-07-03 | 石药集团中奇制药技术（石家庄）有限公司 | Ertapenem sodium freeze-dried preparation and preparation method thereof |
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