CN103181904B - A kind of ertapenem sodium freeze-dried preparation and preparation method thereof - Google Patents
A kind of ertapenem sodium freeze-dried preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to lyophilized formulations of the ertapenem shown in a kind of formula 1 and preparation method thereof.Purity >=98.0% of ertapenem in the lyophilized formulations of ertapenem of the present invention, and be substantially devoid of the open loop catabolite shown in formula 2, character is more stable, is more conducive to storage and clinical practice.
<b>1</b>
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of ertapenem sodium freeze-dried preparation and preparation method thereof.
Background technology
Ertapenem (Ertapenemsodium; 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.
CN1481385A discloses the preparation method of the final formulation product of the sodium salt of the ertapenem carbon dioxide adduct shown in a kind of formula 3:
3
Obtained freeze-drying formulation products purity is about 95%, and total assorted content is 4.1 ~ 5.2%, and wherein, open loop content of degradation products is 2.3 ~ 2.7%, and total dimer content is 1.5 ~ 2.3%.
WO2009150630 discloses the pharmaceutical composition of the sodium salt of the ertapenem carbon dioxide adduct shown in a kind of contained 3, and product purity increases, and reaches 97%, and wherein, total dimer content is 1.35%, and open loop content of degradation products is 1.0%.
The structural formula of above-mentioned open loop catabolite and dimer is as follows:
(1) open loop catabolite, structural formula as shown in Equation 2:
2
(2) dimer, mainly contain following several, structural formula is as follows:
。
AnantVailaya etc. at JournalofChromatographyA, 1079 (2005) 80 – 91
exploitingpHmismatchinpreparativehigh-performanceliquidc hromatographicrecoveryofertapenemfrommotherliquorstreamsin also describe several impurity that may exist in ertapenem preparation process, these impurity are also likely brought in preparation by raw material:
(3) Pro-MABA, structural formula is as follows:
Pro-MABA
(4) oxazinones, structural formula is as follows:
Oxazinone
(5) p-aminobenzyl ertapenem, structural formula is as follows:
P-aminobenzyl ertapenem
(6) methanol addition compound product, structural formula is as follows:
Methanol addition compound product
(7) acetic acid addition compound product, structural formula is as follows:
Acetic acid addition compound product.
Because ertapenem is unstable compound, high impurity content is unfavorable for formulation products storage and uses, and is therefore still necessary to reduce the impurity content in formulation products further, improves product purity.
Summary of the invention
The present inventor finds through a large amount of experimental studies: the quality stability of ertapenem formulation products mainly catch up with state (1) relevant with (2) class impurity content, as first kind impurity content > 0.5% in ertapenem preparation compositions, and/or during Equations of The Second Kind content of impurities > 1.0%, by the quality stability of appreciable impact ertapenem formulation products.
Because ertapenem is unstable compound, very easily degrade in the preparation process of preparation.In order to reduce the impurity content in ertapenem formulation products, the present inventor has carried out a large amount of Optimization Work to ertapenem preparation process, finally have found a kind of preparation method of ertapenem sodium freeze-dried preparation, below corresponding Control of Impurities to appreciable impact content, thus obtain a kind of stay-in-grade ertapenem sodium freeze-dried preparation, ensure clinical efficacy and the drug safety of ertapenem preparation of sodium.
Therefore, one aspect of the present invention provides a kind of formula
1the lyophilized formulations of shown ertapenem,
1
Described lyophilized formulations is made up of following component dosing lyophilizing:
Component 1000 bottles of consumptions
Ertapenem crude drug (in ertapenem) 1160.0g
Sodium bicarbonate 203.0g
Sodium hydroxide regulates pH to be 6.8 ~ 8.0, is preferably 7.2 ~ 7.6, is more preferably 7.3 ~ 7.5,
Water for injection adds to 11000g
It is characterized in that, purity >=98.0% of ertapenem in described lyophilized formulations, and be substantially devoid of the open loop catabolite shown in formula 2,
2。
Wherein:
Open loop content of degradation products≤0.5% shown in described formula 2.
Described lyophilized formulations also can contain dimer impurity further, and described dimer is selected from: Dimer I, Dimer II, Dimer III, Dimer-H
2oa, Dimer-H
2one or more mixture in Ob, Dimer V.
Preferably, total content≤1.0% of described dimer.
Described lyophilized formulations also can contain Pro-MABA impurity, content≤0.3% further; He/Huo oxazinone, content≤0.1%.
Moisture≤2.0% in described lyophilized formulations.
Preferably, the invention provides the lyophilized formulations of the ertapenem shown in a kind of formula 1,
1
Described lyophilized formulations is made up of following component dosing lyophilizing:
Component 1000 bottles of consumptions
Ertapenem crude drug (in ertapenem) 1160.0g
Sodium bicarbonate 203.0g
Sodium hydroxide regulates pH to be 6.8 ~ 8.0, is preferably 7.2 ~ 7.6, is more preferably 7.3 ~ 7.5,
Water for injection adds to 11000g
It is characterized in that, ertapenem purity >=98.0% in described lyophilized formulations, open loop content of degradation products≤0.5%, total content≤1.0% of dimer, Pro-MABA content≤0.3% ， oxazinone content≤0.1%, moisture≤2.0%.
Ertapenem sodium freeze-dried preparation stability of the present invention significantly improves, and is mainly manifested in following several respects:
1. lyophilized formulations of the present invention selects water for injection or 0.9% sodium chloride injection to redissolve solvent as sample, 0.9% sodium chloride injection is as final diluent, it is stable that venoclysis liquid places 8 hours in room temperature, and stability is apparently higher than prior art gained ertapenem lyophilized formulations product;
2. ertapenem sodium freeze-dried preparation of the present invention adopts the lidocaine injection redissolution sample of 3.2ml2.0%, in 1 hour, every Testing index all meets the requirements, and lyophilized formulations of the present invention is more stable compared to the ertapenem lyophilized formulations product of prior art gained, its related substances is lower;
3. ertapenem sodium freeze-dried preparation sample of the present invention was through the long term test of 24 months, related substance increase about 2%, and the main impurity increased is open loop catabolite and dimer, and all other indexs have no significant change, and sample stability is good; Compare with prior art gained ertapenem formulation products with commercialized product " happy ten thousand it ", due to products obtained therefrom initial impurity of the present invention especially open loop catabolite and dimer content low, impurity increase is relatively slow, and character is more stable.
Therefore, ertapenem sodium freeze-dried preparation of the present invention more will be conducive to storage, and clinical application is safer.
The present invention additionally provides a kind of preparation method of described ertapenem sodium freeze-dried preparation on the other hand, comprises the steps:
(1) recipe quantity sodium bicarbonate is dissolved in partial syringe water;
At (2) 0 ~ 5 DEG C, in step (1) solution, add recipe quantity ertapenem crude drug, stirring and dissolving, then regulate pH for 6.8 ~ 8.0 with sodium hydroxide solution gained solution; Inject water to recipe quantity;
(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 ertapenem sodium freeze-dried preparation; Or the sterile solution that step (3) obtains is carried out lyophilization, obtain ertapenem sterile freeze-drying preparation.
Wherein:
Ertapenem crude drug purity (HPLC detection) >=98.5% in described step (2), preferably >=99.0%.
PH is preferably 7.2 ~ 7.6 in described step (2), within the scope of this, final lyophilized formulations 60 DEG C accelerate 5 days more stable; When pH is 7.3 ~ 7.5, final lyophilized formulations 60 DEG C accelerate 5 days the most stable; Concentration of sodium hydroxide solution used is selected from 0.5 ~ 5N, is preferably 1 ~ 3N.
In described step (3), activated carbon dosage is 0.05% ~ 0.2%, and within the scope of this, absorption 60min medicinal liquid content has no significant effect.Aseptic filtration is preferably the microporous filter membrane of 0.2 μm, 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 (2) in injection bottle, then carry out lyophilization, obtain ertapenem sodium freeze-dried preparation; Or by the sterile solution quantitative separating that obtains in (3) in injection bottle, then carry out lyophilization, obtain ertapenem sterile freeze-drying preparation.Described injection bottle is preferably the lyophilizing cillin bottle of neutral boron silica glass material.
Step before lyophilizing in step (2), (3) and step (4), be called the time before lyophilizing above-mentioned total time used, before described lyophilizing, the time should control within 6 hours (≤6 hours), within the scope of this, final lyophilized formulations 60 DEG C accelerate 5 days comparatively stable, preferably control within 5 hours (≤5 hours), more preferably control within 4 hours (≤4 hours).
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 about 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy is to about-25 ~-20 DEG C, and lyophilized machine chamber pressure maintains about 6 ~ 10 hours under about 20 ~ 30 handkerchiefs; Be cooled to-35 ~-30 DEG C again, lyophilized machine chamber pressure maintains about 10 ~ 20 hours under about 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy is to about-25 ~-20 DEG C, and lyophilized machine chamber pressure maintains about 6 ~ 10 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 10 handkerchiefs or power at low pressure.
Also the solution obtained in (2) can be carried out lyophilizing in batch, then gained powder be carried out subpackage, obtain ertapenem sodium freeze dry; Or the sterile solution obtained in (3) is carried out lyophilizing in batch, then gained powder is carried out aseptic subpackaged, obtain the aseptic freeze-dried powder preparation of ertapenem.
In the preparation method of ertapenem sodium freeze-dried preparation, the present inventor is by adjusting the addition sequence of each supplementary material in step (1) and (2), and regulate the trickle control of pH, the control of liquid preparation time with sodium hydroxide, and groping freeze-drying curve, successfully reduce the degraded of ertapenem in production process, improve the final quality of the pharmaceutical preparations of ertapenem.
The present invention also relates on the other hand ertapenem sodium freeze-dried preparation of the present invention for the preparation of the application in anti-infectives.
Accompanying drawing explanation
Fig. 1 is that the HPLC of the embodiment of the present invention 1 sample tests collection of illustrative plates, wherein:
Peak1 Wei oxazinone peak;
Peak2 is Pro-MABA peak;
Peak3 is open loop catabolite peak;
Peak4 is ertapenem peak;
Peak5 ~ 8 are dimer peak.
Detailed description of the invention
Following embodiment is only to illustrate in greater detail the present invention, instead of restriction the present invention.
The preparation of embodiment 1 ertapenem sodium freeze-dried preparation
Table 1 ertapenem sodium freeze-dried preparation prescription (1000 bottles of amounts, specification: 1g)
| Supplementary material title | Consumption (g) |
| Ertapenem (in ertapenem) | 1160.0g |
| Sodium bicarbonate | 203.0g |
| Sodium hydroxide | In right amount |
| Water for injection | Add to 11000g |
| By every bottle of 11g subpackage, make 1000 bottles altogether |
Preparation technology:
(1) sodium bicarbonate of recipe quantity is dissolved in 7000g water for injection, is cooled to 0 ~ 5 DEG C, for subsequent use;
At (2) 0 ~ 5 DEG C, by the ertapenem sodium raw materials (HPLC purity is 99.1%) of recipe quantity, slowly join in above-mentioned sodium bicarbonate solution, stirring and dissolving; Then slowly add 1N sodium hydroxide solution appropriate (about 1200g), regulate solution ph to 7.3 ~ 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
Sampling, carries out water content, HPLC purity test;
(5) tamponade, rolls aluminium-plastic cap, and inspection, labeling, obtains ertapenem finished dosage form.
Products obtained therefrom water content is 1.8%, HPLC purity 98.52%, and each impurity content is: total dimer 0.75%, open loop catabolite 0.45%, Pro-MABA0.26% ， oxazinone 0.03%.
Embodiment 2 ~ 12: the preparation (dosing pH investigates) of ertapenem sodium freeze-dried preparation
With reference to embodiment 1 formulation and technology, just change the dosing pH value in step (2), experimental result sees the following form:
Table 3 embodiment 2 ~ 12 experimental result
。
Experimental result shows, during drug solution preparing, pH value controls between 6.8 ~ 8.0, and it is metastable that final dried frozen aquatic products accelerates 5 days at 60 DEG C.Wherein, when medicinal liquid pH value is 7.2 ~ 7.6, sample is more stable; When medicinal liquid pH value is 7.3 ~ 7.5, sample is the most stable.
Embodiment 13 ~ 20: the preparation of the ertapenem sodium freeze-dried preparation investigation of time (before the lyophilizing)
With reference to embodiment 1 formulation and technology, just change step (2) and (3) liquid preparation time used, experimental result sees the following form:
Table 4 embodiment 13 ~ 20 experimental result
。
Experimental result shows, before lyophilizing, time controling is within 6 hours, and it is metastable that final dried frozen aquatic products accelerates 5 days at 60 DEG C.Wherein, before lyophilizing, time controling is within 5 hours, and sample is more stable; Liquid preparation time controls within 4 hours, and sample is the most stable.
Embodiment 21: the preparation of ertapenem sodium freeze-dried preparation
With reference to embodiment 1 formulation and technology, ertapenem sodium raw materials HPLC purity used just in step (2) changes into 98.5%, products obtained therefrom water content is 1.7%, HPLC purity 98.17%, each impurity content is: total dimer 0.98%, open loop degradation product 0.49%, Pro-MABA0.29% ， oxazinone 0.07%.
Embodiment 22: the preparation (with reference to the open method of prior art) of ertapenem sodium freeze-dried preparation
Prescription is with embodiment 1.
Preparation technology:
(1) sodium bicarbonate of recipe quantity is dissolved in 7000g water for injection, is cooled to 0 ~ 5 DEG C, for subsequent use;
At (2) 0 ~ 5 DEG C, by the ertapenem sodium raw materials (HPLC purity is 98.5%) of recipe quantity, slowly join in above-mentioned sodium bicarbonate solution, drip 10%(W/V simultaneously) sodium hydroxide solution, maintaining solution ph is 7.4 ~ 7.7, mends and injects water to 11000g, stir;
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);
(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, start lyophilizing program, freeze-drying curve is as follows:
Table 5 embodiment 22 freeze-drying curve
Sampling, carries out water content, HPLC purity test;
(5) tamponade, rolls aluminium-plastic cap, and inspection, labeling, obtains ertapenem finished dosage form.
Products obtained therefrom water content is 2.1%, HPLC purity 97%, and each impurity content is: total dimer 1.35%, open loop degradation product 1.0%, Pro-MABA0.45% ， oxazinone 0.20%.
Embodiment 23: the research of formulation soln compatibility stability
The stability of embodiment 1,21 and 22 gained ertapenem preparation of sodium different diluent in venoclysis and intramuscular injection two kinds of different routes of administration is investigated.
The compound method of venoclysis liquid is as follows:
Adopt the 1g this product in water for injection or 0.9% sodium chloride injection 10ml dissolving cillin bottle, fully jolt to dissolving, immediately the solution in cillin bottle is transferred in 50ml0.9% sodium chloride injection, detect in 8 hours after medicine dissolution.
The compound method of intramuscular injection is as follows:
Use 3.2ml1.0% lidocaine hydrochloride injection (not containing epinephrine) dissolves the 1g this product in cillin bottle, fully jolts and makes dissolving, detect in 2 hours after medicine dissolution.
Result of the test is in table 6 and 7.
Table 6 venoclysis liquid study on the stability result of the test
。
Shown by the detection data in table 6, lyophilized formulations of the present invention selects water for injection or 0.9% sodium chloride injection to redissolve solvent as sample, 0.9% sodium chloride injection is as final diluent, it is stable that venoclysis liquid places 8 hours in room temperature, and stability is apparently higher than prior art gained ertapenem lyophilized formulations product, clinical application is safer.
Table 7 intramuscular injection study on the stability result of the test
。
Shown by the detection data in table 7, lyophilized formulations of the present invention and prior art gained ertapenem formulation products adopt the lidocaine injection redissolution sample of 3.2ml2.0%, in 1 hour, every Testing index all meets the requirements, but lyophilized formulations of the present invention is more stable, its related substances is lower, and clinical application treatment is safer.
Embodiment 24: long-term stable experiment
Get the embodiment of the present invention 1,21 and 22 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 8.
Table 8 ertapenem lyophilized formulations long-term stable experiment result
Table 8-1
Table 8-2
。
Result of the test shows: ertapenem sodium freeze-dried preparation sample of the present invention through the long term test of 24 months, related substance increase about 2%, the main impurity increased is open loop catabolite and dimer, and all other indexs have no significant change, and sample stability is good; Compare with prior art gained ertapenem formulation products with commercialized product " happy ten thousand it ", due to products obtained therefrom initial impurity of the present invention especially open loop catabolite and dimer content low, impurity increase is relatively slow, and character is more stable, more be conducive to storing, clinical application is safer.
Claims (13)
1. the ertapenem sodium freeze-dried preparation shown in formula 1,
Described lyophilized formulations is made up of following component dosing lyophilizing:
It is characterized in that, purity >=98.0% of ertapenem in described lyophilized formulations, and open loop content of degradation products≤0.5% shown in formula 2,
The dimer of described lyophilized formulations also containing total content≤1%, described dimer is selected from: Dimer I, Dimer II, Dimer III, Dimer-H
2oa, Dimer-H
2one or more mixture in Ob, Dimer V,
2. lyophilized formulations as claimed in claim 1, is characterized in that, described sodium hydroxide regulates pH to be 7.2 ~ 7.6.
3. lyophilized formulations as claimed in claim 1, is characterized in that, described sodium hydroxide regulates pH to be 7.3 ~ 7.5.
4. the lyophilized formulations as described in as arbitrary in claim 1-3, is characterized in that, described lyophilized formulations also containing Pro-MABA impurity, content≤0.3%; He/Huo oxazinone impurity, content≤0.1%,
5. the lyophilized formulations as described in as arbitrary in claim 1-3, is characterized in that, described lyophilized formulations moisture≤2.0%.
6. the lyophilized formulations as described in as arbitrary in claim 1-3, it is characterized in that, ertapenem purity >=98.0% in described lyophilized formulations, open loop content of degradation products≤0.5%, total content≤1.0% of dimer, Pro-MABA content≤0.3% ， oxazinone content≤0.1%, moisture≤2.0%.
7. a preparation method for lyophilized formulations described in claim 1, comprises the steps:
(1) recipe quantity sodium bicarbonate is dissolved in partial syringe water;
At (2) 0 ~ 5 DEG C, in step (1) solution, add recipe quantity ertapenem crude drug, stirring and dissolving, then regulate pH for 6.8 ~ 8.0 with sodium hydroxide solution gained solution; Inject water to recipe quantity;
(3) optionally, by the process of step (2) gained solution with activated carbon, filter, then aseptic filtration, obtain sterile solution;
(4) by step (2) gained solution quantitative separating in injection bottle, carry out lyophilization, obtain ertapenem sodium freeze-dried preparation; Or sterile solution quantitative separating step (3) to be obtained is in injection bottle, carries out lyophilization, obtains ertapenem sterile freeze-drying preparation;
Described lyophilization 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-25 ~-20 DEG C, and lyophilized machine chamber pressure maintains 6 ~ 10 hours under 20 ~ 30 handkerchiefs; Be cooled to-35 ~-30 DEG C again, lyophilized machine chamber pressure maintains 10 ~ 20 hours under 20 ~ 30 handkerchiefs; Heating freeze dryer flaggy is to-25 ~-20 DEG C, and lyophilized machine chamber pressure maintains 6 ~ 10 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, injection bottle is taken out from freeze dryer.
8. preparation method as claimed in claim 7, is characterized in that, described step (2) sodium hydroxide solution regulates pH to be that sodium hydroxide solution regulates pH to be 7.2 ~ 7.6.
9. preparation method as claimed in claim 7, is characterized in that, described step (2) sodium hydroxide solution regulates pH to be that sodium hydroxide solution regulates pH to be 7.3 ~ 7.5.
10. the preparation method as described in as arbitrary in claim 7-9, is characterized in that, step before lyophilization in described step (2), (3) and step (4), above-mentioned steps total time used is≤6 hours.
11. preparation methoies as claimed in claim 10, is characterized in that, step before lyophilization in described step (2), (3) and step (4), above-mentioned steps total time used is≤5 hours.
12. preparation methoies as claimed in claim 10, is characterized in that, step before lyophilization in described step (2), (3) and step (4), above-mentioned steps total time used is≤4 hours.
The arbitrary described lyophilized formulations of 13. claim 1 ~ 6 is for the preparation of the application in anti-infectives.
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| A Comparison of the stability of ertapenem and meropenem in pharmaceutical preparations in solid state;Judyta Cielecka-Piontek等;《Journal of Pharmaceutical and Biomedical Analysis》;20070901(第46期);第52-57页 * |
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