CN109134469A - A kind of ertapenem sodium pharmaceutical composition and preparation method thereof - Google Patents
A kind of ertapenem sodium pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN109134469A CN109134469A CN201810683783.6A CN201810683783A CN109134469A CN 109134469 A CN109134469 A CN 109134469A CN 201810683783 A CN201810683783 A CN 201810683783A CN 109134469 A CN109134469 A CN 109134469A
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Abstract
The present invention relates to a kind of ertapenem solid pharmaceutical composition and preparation method thereof, described pharmaceutical composition contains ertapenem shown in formula 1 and 2 compound represented of formula or its sodium salt, hydrate or solvate and pharmaceutically acceptable auxiliary material.2 compound of ertapenem solid pharmaceutical composition Chinese style provided by the invention or its pharmaceutical salt, hydrate or solvate proportion are up to 80% or more, substantially increase the stability of ertapenem final preparation.
Description
The application be the applying date be on December 31st, 2013, application No. is 201310750967.7, it is entitled " a kind of
The divisional application of the application for a patent for invention of ertapenem sodium pharmaceutical composition and preparation method thereof ".
Technical field
The invention belongs to field of medicaments, and in particular to a kind of ertapenem sodium pharmaceutical composition and preparation method thereof.
Background technique
Ertapenem (Ertapenem sodium, structural formula such as formula 1), chemical name are as follows: (1R, 5S, 6S, 8R, 2S*,
4S*) -2- [2- [3- carboxyl-phenyl carbamoyl]-pyrrolidinyl -4- is thio] -6- (1- ethoxy) -1- methyl carbon mould
Alkene -3- formic acid mono-sodium salt is the New-type wide-spectrum Carbapenems antibiosis of United States Merck company and Astrazeneca AB's joint development
Element all has good antibacterial activity with Negative aerobe and anaerobic bacteria to including gram positive bacteria.
Ertapenem lists the trade name " happy ten thousand it " of formulation products, is aseptic freeze-dried powder.Per unit ertapenem
Also contain 175mg sodium bicarbonate in preparation of sodium product, adjusting pH with sodium hydroxide is 7.5.
CN1198162A discloses ertapenem stable form as shown in Equation 2 first,
The preparation method of 2 compound of formula disclosed in the patent is, by 1 compound of formula and carbon dioxide source (such as sodium carbonate
Or sodium bicarbonate) mixing, and the mixture is dissolved, 2 compound of formula can usually be made.But its disclosed composition is with liquid
Existing for form, 2 compound of formula cannot be present in composition with fixed proportion.
CN1481385A discloses the final system of a kind of 2 compound of formula or its pharmaceutical salt, hydrate or solvate
The preparation method of agent product, the final preparation are freeze-dried powder.Its method is mentioned in the patent specification provides carbon mould
The alkali metal salt (such as mono-sodium salt) of alkene is converted into the high conversion of 2 compound of formula, but does not refer to above-mentioned high turn in the patent
Rate is how many.
The structural identification data and detection method of 2 compound of formula are not disclosed in above-mentioned 2 documents.
To sum up, in ertapenem final preparation disclosed in the prior art, with no specific disclosure of 2 compound of formula or its can medicine
Salt, hydrate or solvate are in proportion wherein.Since 2 compound of formula is the stable form of ertapenem,
Proportion determines the stability of final preparation in the final formulation, therefore, needs to ertapenem final preparation
Preparation process study, improve the ratio of 2 compound of final preparation Chinese style or its pharmaceutical salt, hydrate or solvate
Example, to improve the stability of ertapenem final preparation.
Summary of the invention
The present inventor has conducted extensive research ertapenem preparation prescription technique, and having finally found one kind can be improved
The method of the conversion ratio of 2 compound of final preparation Chinese style, obtained 2 compound of final preparation Chinese style or its pharmaceutical salt, water
It closes object or solvate proportion is up to 80% or more, substantially increase the stability of ertapenem final preparation.
Therefore, one aspect of the present invention provides a kind of solid pharmaceutical composition, it is characterised in that: it contains shown in formula 1
Ertapenem and 2 compound represented of formula or its sodium salt, hydrate or solvate and pharmaceutically acceptable auxiliary material,
Wherein:
2 compound represented of formula or its pharmaceutically acceptable salt, hydrate or solvate, account for its with shown in formula 1
The percentage of the total amount of ertapenem is not less than 80% preferably not lower than 85%, is more preferably not less than 90%.
The 2 compound represented sodium salt of formula is selected from following set of:
Above-mentioned formula 2-a is referred to as carbaminate to 2-g compound represented sodium salt.
Another aspect of the present invention provides a kind of preparation method of pharmaceutical composition as described above, which is characterized in that packet
Include following steps:
(1) it prepares sodium bicarbonate ethanol water: the sodium bicarbonate of recipe quantity is dissolved into 5~10% ethanol water
In, it is 2-12% that sodium bicarbonate concentration, which is made, and the sodium bicarbonate ethanol water of preferably 3-7% (w/w) is cooled to -5~0
DEG C, it is spare；
At a temperature of (2) -5~0 DEG C, the ertapenem sodium raw materials of recipe quantity are slowly added into and account for total dosage 40~70%
In the sodium bicarbonate ethanol water of step (1), stirring is slowly added to the sodium bicarbonate ethyl alcohol of surplus (30~60%) immediately
Optionally appropriate sodium hydroxide solution can be added dropwise in aqueous solution, to maintain pH value of reaction system between 7.0~8.0；
(3) optionally, step (2) acquired solution is handled with active carbon, filters, then be sterile filtered, obtains sterile solution；
(4) step (2) acquired solution is freeze-dried, obtains solid pharmaceutical composition of the invention；Or by step (3)
Obtained sterile solution is freeze-dried, and sterile solid pharmaceutical composition of the invention is obtained.
Wherein:
The total dosage of sodium bicarbonate and the molar ratio of ertapenem sodium raw materials are 3~1.5:1 in the step (2), preferably
2.5~2:1.
The initial content of sodium bicarbonate ethanol water preferably accounts for the 45~60% of total dosage in step (2)；Hydroxide
Sodium solution concentration (w/w) is 1-10%, preferably 2-5%；Reaction system pH is preferably kept at 7.3~7.7, more preferably 7.4
~7.6.
Activated carbon dosage is 0.05%~0.2% (w/w) in the step (3), within this range, adsorbs 60min medical fluid
Content has no significant effect.Be sterile filtered the preferably miillpore filter of 0.22um, and it is micro- that the miillpore filter is selected from polyvinylidene fluoride
One or both of hole filter membrane and polyethersulfone millipore filter.
Step (4) is preferred are as follows: by solution quantitative separating obtained in step (2) in injection bottle, it is dry then to carry out freezing
It is dry, obtain solid pharmaceutical composition of the invention；Or by sterile solution quantitative separating obtained in step (3) in injection bottle, so
After be freeze-dried, obtain sterile solid pharmaceutical composition of the invention.The injection bottle is preferably neutral boron silica glass
The freeze-drying cillin bottle of material.
The freeze-drying, in general, it is desirable that bottle about -45~-40 DEG C homogeneous heat treatment about 3~5 hours, then tie up
This temperature is held, lyophilized machine cavity chamber pressure maintains about 2~4 hours under 20~30 pas；Freeze dryer plate layer is heated to about -30
~-25 DEG C, lyophilized machine cavity chamber pressure maintains about 26~40 hours under about 20~30 pas；Heat freeze dryer plate layer temperature extremely
About 0 DEG C, and maintained about 4~8 hours in about 20~30 pas；It is warming up to 20 DEG C again, and is maintained about 10~15 hours in about 10 pas；So
After be warming up to 40 DEG C, and maintained about 8~12 hours in about 10 pas；Then freeze dryer plate layer is cooled down to room temperature.From freeze dryer
Before taking-up, bottle is fully sealed under the partial vacuum of about 20~30 pas or lower pressure.It is true in the part of≤10 pa pressure
Under sky, injection bottle tamponade is taken out from freeze dryer.
Solution obtained in (2) can also be lyophilized in batch, then be dispensed gained powder, obtain of the invention consolidate
State pharmaceutical composition；Or sterile solution obtained in (3) is lyophilized in batch, it is then that the progress of gained powder is aseptic subpackaged,
Obtain sterile solid pharmaceutical composition of the invention.
Another aspect of the present invention further relates to solid pharmaceutical composition of the present invention in being used to prepare anti-infectives
Using.
Compound 2 or its pharmaceutical salt in ertapenem solid pharmaceutical composition provided by the invention, hydrate or
Solvate proportion is up to 80% or more, and through 24 months long term tests, related substance increased seldom, and sample stability is good
It is good；Compared with commercialized product " happy ten thousand it ", impurity increase is relatively less, and property is more stable, is more advantageous to storage, clinical application is more
Safety.
Specific embodiment
Embodiment below, which is only that, is described in more detail the present invention, rather than limits the present invention.
Carbaminate detection method of content:
Instrument: 600 type nuclear magnetic resonance spectrometer of Bruker Advance
Solvent: D2O
Detection method: test sample is carried out1H-13C heteronuclear multiple-bond correlation 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 | Dosage (g) |
| Ertapenem | 1046g |
| Sodium bicarbonate | 353g |
| Ethyl alcohol | 350g |
| Sodium hydroxide | In right amount |
| Water for injection | Add to 11000g |
| It is dispensed by every bottle of 11g, 1000 bottles is made altogether |
Preparation process:
(1) it prepares 5% ethanol water: 350g ethyl alcohol being added in 6650g water for injection, is sufficiently mixed, place,
It is spare；The sodium bicarbonate of recipe quantity is dissolved in above-mentioned ethanol water, is cooled to -5~0 DEG C, sodium bicarbonate ethanol water is made
Solution for standby.
(2) the sodium bicarbonate ethanol water of total amount 50% is weighed, it is at -5~0 DEG C, the ertapenem of recipe quantity is former
Material (HPLC purity is 99.1%), is slowly added into above-mentioned solution, stirs, the carbon of surplus (i.e. total amount 50%) is added dropwise immediately
Sour hydrogen sodium ethanol water, then adjust with 2% (w/w) sodium hydroxide solution and maintain solution ph to 7.5, it stirs evenly, mends
11000g is injected water to, is stirred evenly；Time used is 1 hour.
Following steps carry out under hundred grades of clean environments:
(3) medical fluid is through 0.22 μm of miillpore filter (filter core) aseptic filtration of two-stage；Time used is 0.5 hour.
(4) clean using 20ml, sterile control freeze-drying cillin bottle dispenses medical fluid, and theoretical loading amount is 11g/ bottles, and half tamponade,
Sample after half tamponade is immediately transferred to the freeze dryer of drying box to -5 DEG C has been pre-chilled, the time used is 2 hours；Starting freeze-drying
Program, freeze-drying curve are as follows:
2 embodiment of table, 1 freeze-drying curve
(5) aluminium-plastic cap is rolled in tamponade, examines, labeling is to get solid pharmaceutical composition of the invention.
Take finished product sample D2O dissolution is configured to 200mg/mL solution, carries out carbaminate content detection, amino first
The ratio of hydrochlorate and ertapenem is 95:5.
Embodiment 2~9: the preparation (reaction system pH investigation) of ertapenem solid pharmaceutical composition
Referring to the formulation and technology of embodiment 1, only changes the step in (2) and matches liquid pH value, experimental result see the table below:
The experimental result of 3 embodiment 2~9 of table
| Embodiment | Medical fluid 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 |
The experimental results showed that pH value control is between 7.0~8.0 when drug solution preparing, carbaminate in final dried frozen aquatic products
Content is 80% or more；When medical fluid pH value is 7.3~7.7, carbamic acid salt content is 85% or more；Medical fluid pH value be 7.4~
When 7.6, carbamic acid salt content is 90% or more；When medical fluid pH value is 7.5, carbamic acid salt content is up to 95% (see implementation
Example 1).
Embodiment 10~14: the preparation (investigation of sodium bicarbonate dosage) of ertapenem solid pharmaceutical composition
Referring to the formulation and technology of embodiment 1, the dosage of sodium bicarbonate in (1) is only changed the step, experimental result see the table below:
The experimental result of 4 embodiment 10~14 of table
The experimental results showed that sodium bicarbonate and ertapenem molar ratio be between 1.5~3, amino in final dried frozen aquatic products
Formate content is 80% or more；When molar ratio is between 1.8~2.5, carbamic acid salt content is 85% or more；Molar ratio exists
When between 2.2~2.0, carbamic acid salt content is in 90% or more (see embodiment 1,12).
Embodiment 15: (sodium bicarbonate ethanol water initial content is examined for the preparation of ertapenem solid pharmaceutical composition
It examines)
Referring to the formulation and technology of embodiment 1, the initial content of sodium bicarbonate ethanol water in (2) is only changed the step,
Experimental result see the table below:
5 embodiment of table, 15~21 experimental result
The experimental results showed that in step (2) sodium bicarbonate ethanol water initial content total dosage 40~70% it
Between, carbamic acid salt content is 80% or more in final dried frozen aquatic products；When dosage is between the 45~60% of total dosage, carbamic acid
Salt content is 85% or more；When dosage is between the 50~55% of total dosage, carbamic acid salt content is 90% or more (see implementation
Example 1,18).
Embodiment 22: long-term stable experiment
Take the embodiment of the present invention 1,2,6 and 7 samples, simulation listing packaging, at 25 ± 2 DEG C of temperature, relative humidity 60% ±
Avoid light place under the conditions of 10% is detected in 0,3,6,9,12,18,24 the end of month sampling, by stability high spot reviews project
And measuring method is detected, and keeping sample under this condition by imitative product happy ten thousand is separately taken, and is sampled in same time point, is investigated related object
Matter situation of change, the results are shown in Table 6.
6 ertapenem solid pharmaceutical composition long-term stable experiment result of table
Table 6-1
Table 6-2
Table 6-3
Test result shows: ertapenem solid pharmaceutical composition of the invention, related through 24 months long term tests
Substance increases seldom, and sample stability is good；Compared with commercialized product " happy ten thousand it ", impurity increase is relatively less, and property is more steady
It is fixed, it is more advantageous to storage, clinical application is safer.
Claims (9)
1. a kind of solid pharmaceutical composition, it is characterised in that: it contains chemical combination shown in ertapenem shown in formula 1 and formula 2
Object or its sodium salt, hydrate or solvate and pharmaceutically acceptable auxiliary material,
2. pharmaceutical composition as described in claim 1, it is characterised in that: 2 compound represented of formula or its is pharmaceutically acceptable
Salt, hydrate or solvate account for itself and the total amount of ertapenem shown in formula 1 weight percent be not less than 80%,
Preferably not lower than 85%, more preferably it is not less than 90%.
3. pharmaceutical composition as claimed in claim 1 or 2, it is characterised in that: the sodium salt of 2 compound represented of formula is selected from
The group of the composition of compound shown in the following Expression 2-a to formula 2-g:
4. a kind of preparation method of pharmaceutical composition as claimed in claim 1 or 2, characterized by the following steps:
(1) it prepares sodium bicarbonate ethanol water: the sodium bicarbonate of recipe quantity is dissolved into 5~10% ethanol water,
It is 2-12% that sodium bicarbonate concentration, which is made, and the sodium bicarbonate ethanol water of preferably 3-7% (w/w) is cooled to -5~0 DEG C,
It is spare；
At a temperature of (2) -5~0 DEG C, the carbon of the step of ertapenem sodium raw materials of recipe quantity are slowly added into initial content (1)
In sour hydrogen sodium ethanol water, which is 40~70 (w/w) % of total dosage, and stirring is slowly added to surplus immediately
Sodium bicarbonate ethanol water appropriate sodium hydroxide solution optionally is added dropwise, to maintain pH value of reaction system 7.0~8.0
Between；
(3) optionally, step (2) acquired solution is handled with active carbon, filters, then be sterile filtered, obtains sterile solution；
(4) step (2) acquired solution is freeze-dried, obtains solid pharmaceutical composition；Or step (3) is obtained sterile molten
Liquid is freeze-dried, and sterile solid pharmaceutical composition is obtained.
5. the preparation method of pharmaceutical composition as claimed in claim 4, it is characterised in that: sodium bicarbonate in the step (2)
Total dosage and the molar ratio of ertapenem sodium raw materials are 1.5~3:1, preferably 2.5~2:1.
6. the preparation method of pharmaceutical composition as claimed in claim 4, it is characterised in that: sodium bicarbonate ethyl alcohol in step (2)
The initial content of aqueous solution is 45~60 (w/w) % of total dosage.
7. the preparation method of pharmaceutical composition as claimed in claim 4, it is characterised in that: reaction system pH is tieed up in step (2)
It holds 7.3~7.7, preferably 7.4~7.6.
8. the preparation method of pharmaceutical composition as claimed in claim 4, it is characterised in that: step (4) is that will obtain in step (2)
The solution arrived, or then sterile solution quantitative separating obtained in step (3) is freeze-dried in injection bottle；
The freezing dry process are as follows: injection bottle -45~-40 DEG C homogeneous heat treatment 3~5 hours, then maintain this temperature, it is low
Pressure freeze dryer chamber pressure maintains 2~4 hours under 20~30 pas；Freeze dryer plate layer is heated to -30~-25 DEG C, lyophilized
Machine cavity chamber pressure maintains 26~40 hours under 20~30 pas；Freeze dryer plate layer temperature is heated to 0 DEG C, and is maintained in 20~30 pas
4~8 hours；It is warming up to 20 DEG C again, and is maintained 10~15 hours in 10 pas；40 DEG C are then heated to, and maintains 8~12 in 10 pas
Hour；Then freeze dryer plate layer is cooled down to room temperature；Under the partial vacuum of≤10 pa pressure, by injection bottle tamponade, from freeze-drying
It is taken out in machine.
9. what the described in any item pharmaceutical compositions of claim 1-3 or the described in any item methods of claim 4-8 obtained consolidates
State pharmaceutical composition is preparing the application in anti-infectives.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810683783.6A CN109134469B (en) | 2013-12-31 | 2013-12-31 | Ertapenem sodium pharmaceutical composition and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 Division CN104739780A (en) | 2013-12-31 | 2013-12-31 | Ertapenem disodium pharmaceutical composition and preparation method thereof |
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| CN109134469A true CN109134469A (en) | 2019-01-04 |
| CN109134469B CN109134469B (en) | 2021-10-26 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1481385A (en) * | 2000-10-27 | 2004-03-10 | Process for formulation of antibiotic compounds | |
| 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 |
-
2013
- 2013-12-31 CN CN201810683783.6A patent/CN109134469B/en active Active
- 2013-12-31 CN CN201310750967.7A patent/CN104739780A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1481385A (en) * | 2000-10-27 | 2004-03-10 | Process for formulation of antibiotic compounds | |
| 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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| CN104739780A (en) | 2015-07-01 |
| CN109134469B (en) | 2021-10-26 |
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