CN104739828B - 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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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- ZXNAQFZBWUNWJM-HRXMHBOMSA-M ertapenem sodium Chemical compound [Na+].O=C([C@H]1[NH2+]C[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C([O-])=O)=O)[C@H](O)C)NC1=CC=CC(C([O-])=O)=C1 ZXNAQFZBWUNWJM-HRXMHBOMSA-M 0.000 title claims description 19
- 229960002818 ertapenem sodium Drugs 0.000 title claims description 19
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims abstract description 34
- 229960002770 ertapenem Drugs 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 22
- 239000002994 raw material Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 8
- 239000008174 sterile solution Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000002924 anti-infective effect Effects 0.000 claims description 2
- 229960005475 antiinfective agent Drugs 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000012423 maintenance Methods 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 description 12
- 208000015181 infectious disease Diseases 0.000 description 10
- 239000003814 drug Substances 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000857 drug effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- -1 1- ethoxy Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000032376 Lung infection Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 ensure that the treatment validity of ertapenem final preparation less than 70%.
Description
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 entitled：
(1R, 5S, 6S, 8R, 2S*, 4S*) -2- [2- [3- carboxyl-phenyl carbamoyl]-pyrrolidinyl -4- is thio] -
6- (1- ethoxy) -1- beta-methyl carbapenem -3- formic acid mono-sodium salt is United States Merck company and Astrazeneca AB's joint development
New-type wide-spectrum carbapenem antibiotic, to include gram positive bacteria and Negative aerobe and anaerobic bacteria all have it is good anti-
Bacterium activity.
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 of alkene（Such as mono-sodium salt）It 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.The present inventor has found under study for action, final in ertapenem
Contain a certain proportion of 2 compound of formula in preparation, although ensure that the stability of final preparation, also will affect the anti-of preparation
Bacterium activity.Therefore, it needs to compound 2 in ertapenem final preparation or its pharmaceutical salt, hydrate or solvent
The ratio of compound is studied, to improve ertapenem final preparation on the basis of guaranteeing certain preparation stability
Treat validity.
Summary of the invention
The present inventor by numerous studies, find 2 compound of ertapenem final preparation Chinese style or its pharmaceutical salt,
Hydrate or solvate proportion can be improved lower than 70% under the premise of meeting ertapenem final preparation stability
The therapeutic activity of 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 20-70%, preferably 30-65%, more preferably 40-60%.
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. first by part recipe quantity（Initial content）Ertapenem sodium raw materials be added in 0-5 DEG C of water for injection,
Stirring and dissolving；
2. at 0-5 DEG C, the sodium bicarbonate of recipe quantity, stirring and dissolving are added into step 1. acquired solution；
3. at 0-5 DEG C, the ertapenem sodium raw materials of remaining recipe quantity, stirring and dissolving are added into step 2. acquired solution；
4. by step, 3. acquired solution adjusts pH value to 6.8-8.0 with sodium hydroxide solution；
5. optionally, 4. acquired solution is handled with active carbon by step, filters, then be sterile filtered, obtain sterile solution；
6. by step, 4. acquired solution is freeze-dried, and obtains solid pharmaceutical composition of the invention；Or 5. step is obtained
To sterile solution be freeze-dried, obtain sterile solid pharmaceutical composition of the invention.
Wherein：
The step 1. in ertapenem sodium raw materials and step 2. in the molar ratio of sodium bicarbonate be preferably 1:0.5-2, more
Preferably 1:0.8-1.5.
The step 1. in initial content ertapenem sodium raw materials be recipe quantity 30-70%, preferably 40-60%, more
Preferably 45-55%.
The pH value of the step 4. is preferably 7.2~7.6, and more preferably 7.3~7.5.
Step be 6. by step 4. obtained in solution, or by step 5. obtained in sterile solution quantitative separating in injection
Agent bottle, is then freeze-dried；
The freezing dry process is：Injection bottle -45~-40 DEG C homogeneous heat treatment 3~5 hours, then maintain this temperature
Degree, lyophilized machine cavity chamber pressure maintain 2~4 hours under 10~30 pas；Freeze dryer plate layer is heated to -30~-20 DEG C, low pressure
Freeze dryer chamber pressure maintains 26~40 hours under 10~30 pas；Freeze dryer plate layer temperature is heated to 0 DEG C, and in 10~30 pas
It maintains 4~8 hours；It is warming up to 20 DEG C again, and in 10 pas and following maintains 10~15 hours；40 DEG C are then heated to, and 10
Pa and it is following maintain 8~12 hours；Then freeze dryer plate layer is cooled down to room temperature；Under the partial vacuum of≤10 pa pressure, it will infuse
Agent bottle tamponade is penetrated, is taken out from freeze dryer.
Ertapenem solid pharmaceutical composition provided by the invention has good stability, and treated effect and cure rate
Height, treatment time is short, reduces treatment cost, improves patient compliance.
Another aspect of the present invention further relates to solid pharmaceutical composition of the present invention in being used to prepare anti-infectives
Using.
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：Bruker Advance600 type nuclear magnetic resonance spectrometer
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 | 185g |
| 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. recipe quantity sodium bicarbonate is dissolved in 1L water for injection, it is cooled to 0-5 DEG C, it is spare；
2. the ertapenem sodium raw materials of 50% recipe quantity are added in 0-5 DEG C of water for injection 7L, stirring and dissolving；
3. at 0-5 DEG C, the sodium bicarbonate solution of step 1. is added into step 2. acquired solution；
4. at 0-5 DEG C, the ertapenem sodium raw materials of remaining 50% recipe quantity being slowly added into step 3. acquired solution, are stirred
Mix dissolution；
5. by step, 4. solution adjusts pH value to 7.4-7.6 with 1N sodium hydroxide solution, benefit injects water to 11000g,
It stirs evenly.
Following steps carry out under hundred grades of clean environments：
6. medical fluid is through 0.22 μm of miillpore filter of two-stage（Filter core）Aseptic filtration.
7. clean using 20ml, sterile control freeze-drying cillin bottle dispenses medical fluid, 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；Starting freeze-drying program, freeze-drying curve is such as
Under：
2 embodiment of table, 1 freeze-drying curve
7. aluminium-plastic cap is rolled in tamponade, examine, 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 55:45.
Embodiment 2~6:The preparation of ertapenem solid pharmaceutical composition（Sodium bicarbonate dosage is investigated）
Referring to the formulation and technology of embodiment 1, only change the step（1）The dosage of middle sodium bicarbonate, experimental result see the table below：
The experimental result of 3 embodiment 2~6 of table
The experimental results showed that sodium bicarbonate and ertapenem molar ratio be between 0.5~2.0, ammonia in final dried frozen aquatic products
The proportional region of base formates and ertapenem is 20:80~70:30.
Embodiment 7~13：The preparation of ertapenem solid pharmaceutical composition（Ertapenem sodium raw materials initial charge is examined
It examines）
Referring to 1 formulation and technology of embodiment, the initial charge of ertapenem sodium raw materials in 2., experiment knot are only changed the step
Fruit see the table below：
4 embodiment of table, 7~13 experimental result
The experimental results showed that step 2. in ertapenem sodium raw materials initial charge between 30~70%, it is final to be lyophilized
The proportional region of carbaminate and ertapenem is 20 in product:80~70:30.
Embodiment 14：Accelerated stability test
The embodiment of the present invention 1,2,4,5,7,8,11,12 and 13 samples are taken, simulation listing is packed, at 30 DEG C ± 2 DEG C of temperature,
Avoid light place under conditions of relative humidity 65% ± 5%, respectively at 0,1,2,3,6 the end of month, sampling is detected, by stability emphasis
Investigation project and measuring method are detected, and the results are shown in Table 5.
5 ertapenem solid pharmaceutical composition accelerated stability test result of table
Table 5-1
Table 5-2
Table 5-3
Test result shows：In ertapenem solid pharmaceutical composition of the invention, carbaminate ratio >=20%
When, through 6 months accelerated tests, indices still conformed to the quality standard drafted, and sample stability is preferable；With in composition
The increase of carbaminate ratio, sample stability have increased trend；When the ratio of carbaminate in composition exists<30%
When, sample stability changes greatly；When the ratio of carbaminate in 30%≤composition is ≤65%, sample stability variation
Opposite to reduce, when the ratio of 40%≤carbaminate≤60%, sample stability variation is smaller, almost unchanged.
Embodiment 15：Effect experiment
1, mouse systemic infection model
Test drug：Embodiment 1,2,4,5,7,8,11,12 and 13 gained samples.
Test method：Staphylococcus aureus（Clinical isolation）37 DEG C of Liquid Culture 18h are taken, by bacterium solution after culture
Thallus is collected in centrifugation, is then made appropriate dilution with sterile saline, is carried out than turbid, to determine the concentration of bacterium solution.Again with 5% stomach
Membranogen solution is diluted to 2 times every milliliter of practical infection concentration, abdominal cavity infection mouse, 0.5ml/ mouse.And 60 minutes after infection
It was administered twice with 6 hours, the sum of dosage is to test whole dosages, embodiment 1,2,4,5,7,8,11,12 and 13 twice
Gained sample is configured to 6 drug concentrations respectively, and the agent between drug concentration is away from being 1：0.7, administration route is gastric infusion.
Every group of 10 mouse.It after administration, is observed continuously 7 days, using the 7th day result as final statistical result.It is united with Bliss method
Meter, which is learned, to be calculated, and calculates embodiment to each ED for trying bacterium50.Test result：It is shown in Table 6.
2, mouse lung infection model
Test drug：Embodiment 1,2,4,5,7,8,11,12 and 13 gained samples.
Test method：Take pneumococcus（Clinical separation strain）2.0×107CFU/ml bacterium solution, collunarium are inoculated with 0.1ml/ mouse, sense
Dye is oral to give embodiment 1,2,4,5,7,8,11,12 and 13 gained samples after 24 hours, divides 2 times dosing interval 12 hours, agent
Amount is 25mg/kg, and every group of 8 mouse separately set blank control group（It is not administered after infection）.In 24 hours execution mouse are administered, take
Lung weighing, dilution measures each group viable count after being homogenized.
Test result：It is shown in Table 6.
3, mouse leg muscle infection model
Test drug：Embodiment 1,2,4,5,7,8,11,12 and 13 gained samples.
Test method：Take pneumococcus（Clinical separation strain）7.5×105CFU/ml bacterium solution, leg muscle inject 0.1ml/
Infecting mouse, points 2 times dosing interval 6 hours after infection 2 hours, 1,2,4,5,7,8,11,12 and of subcutaneous administration 5mg/kg
13 gained samples, every group of 8 mouse take leg muscle when administration and after administration 24 hours, weigh, measure after being homogenized
Each group viable count.Separately set blank control group（It is not administered after infection）.In 24 hours execution mouse are administered, leg muscle is taken to weigh,
Dilution measures each group viable count after being homogenized.
Test result：It is shown in Table 6.
The test result of 6 embodiment 15 of table
*:The p compared with control group<0.05;**:The p compared with control group<0.01
Test result shows：Ertapenem solid pharmaceutical composition of the invention has stronger anti-general infection, lung
Infection and lower limb infection ability；With the increase of carbaminate ratio in pharmaceutical composition, sample drug effect has the tendency that decrease；
When carbaminate ratio in pharmaceutical composition≤70%, drug effect is stronger；When carbaminate ratio is 30 in pharmaceutical composition
When~65%, pharmacodynamic change is relatively small；When carbaminate ratio is 40~60% in pharmaceutical composition, pharmacodynamic change is opposite
It is smaller, it is almost unchanged.
To sum up, in ertapenem solid pharmaceutical composition of the invention, when carbaminate ratio is in 20-70%,
With good stability and drug effect；When carbaminate ratio is in 30-65%, stability and drug effect are preferable, and change opposite
It is smaller；When carbaminate ratio is in 40-60%, stability and drug effect are also preferable, and variation is relatively smaller, almost without change
Change.
Claims (10)
1. a kind of solid pharmaceutical composition, it is characterised in that：Contain 2 compound represented of ertapenem shown in formula 1 and formula
Or its pharmaceutically acceptable salt or hydrate and pharmaceutically acceptable auxiliary material,
1
2
Wherein, 2 compound represented of formula or its pharmaceutically acceptable salt or hydrate account for itself and ertapenem shown in formula 1
Total amount weight percent be 30-65%.
2. pharmaceutical composition as described in claim 1, it is characterised in that：2 compound represented of formula or its is pharmaceutically acceptable
Salt or hydrate to account for the weight percent of itself and the total amount of ertapenem shown in formula 1 be 40-60%.
3. pharmaceutical composition as claimed in claim 1 or 2, it is characterised in that：2 compound represented of formula pharmaceutically may be used
The salt of receiving is sodium salt, the group selected from 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 any one of claims 1-3, it is characterised in that：Including as follows
Step：
1. the ertapenem sodium raw materials of i.e. initial content are added to 0-5 DEG C of note by the ertapenem sodium raw materials of part recipe quantity
It penetrates in water, stirring and dissolving, the ertapenem sodium raw materials of the initial content are 30-70 (w/w) % of recipe quantity；
2. at 0-5 DEG C, the sodium bicarbonate of recipe quantity is added into step 1. acquired solution, stirring and dissolving, the step is 1. middle to be located
The ertapenem sodium raw materials just measured and step 2. in the molar ratio of sodium bicarbonate be 1:0.8-1.5；
3. at 0-5 DEG C, the ertapenem sodium raw materials of remaining recipe quantity, stirring and dissolving are added into step 2. acquired solution；
4. by step, 3. acquired solution adjusts pH value to 6.8-8.0 with sodium hydroxide solution；
5. optionally, 4. acquired solution is handled with active carbon by step, filters, then be sterile filtered, obtain sterile solution；
6. by step, 4. acquired solution is freeze-dried, and obtains solid pharmaceutical composition；Or the sterile solution for 5. obtaining step
It is freeze-dried, obtains sterile solid pharmaceutical composition.
5. preparation method as claimed in claim 4, it is characterised in that：The step 1. in initial content ertapenem it is former
Material is the 40-60 of recipe quantity（w/w）%.
6. the preparation method of pharmaceutical composition as claimed in claim 5, it is characterised in that：The step 1. in initial content
Ertapenem sodium raw materials are the 45-55 of recipe quantity（w/w）%.
7. the preparation method as described in claim 4-6 is any, it is characterised in that：The pH value of the step 4. is 7.2 ~ 7.6.
8. preparation method as claimed in claim 7, it is characterised in that：The pH value of the step 4. is 7.3 ~ 7.5.
9. preparation method as claimed in claim 8, it is characterised in that：Step be 6. by step 4. obtained in solution, or will
Step 5. obtained in sterile solution quantitative separating in injection bottle, be then freeze-dried；
The freezing dry process is：Injection bottle -45 ~ -40 DEG C homogeneous heat treatment 3 ~ 5 hours, then maintain this temperature, low pressure
Freeze dryer chamber pressure maintains 2 ~ 4 hours under 10 ~ 30 pas；Freeze dryer plate layer is heated to -30 ~ -20 DEG C, lyophilized machine cavity room
Pressure maintains 26 ~ 40 hours under 10 ~ 30 pas；Freeze dryer plate layer temperature is heated to 0 DEG C, and is maintained 4 ~ 8 hours in 10 ~ 30 pas；
It is warming up to 20 DEG C again, and is maintained 10 ~ 15 hours below 10 pas；40 DEG C are then heated to, and maintenance 8 ~ 12 is small below 10 pas
When；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 dryer
Middle taking-up.
10. what the described in any item pharmaceutical compositions of claim 1-3 or the described in any item methods of claim 4-9 obtained consolidates
State pharmaceutical composition is preparing the application in anti-infectives.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310751547.0A CN104739828B (en) | 2013-12-31 | 2013-12-31 | A kind of ertapenem sodium pharmaceutical composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310751547.0A CN104739828B (en) | 2013-12-31 | 2013-12-31 | A kind of ertapenem sodium pharmaceutical composition and preparation method thereof |
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