CN102133201B - Faropenem sodium freeze-dried powder injection - Google Patents
Faropenem sodium freeze-dried powder injection Download PDFInfo
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- CN102133201B CN102133201B CN 201110070330 CN201110070330A CN102133201B CN 102133201 B CN102133201 B CN 102133201B CN 201110070330 CN201110070330 CN 201110070330 CN 201110070330 A CN201110070330 A CN 201110070330A CN 102133201 B CN102133201 B CN 102133201B
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Abstract
The invention relates to a Faropenem sodium freeze-dried powder injection, which comprises only one composition: Faropenem sodium. Preferably, injection water is added into Faropenem sodium powder with the particle size of 75 to 100mum to be prepared into Faropenem sodium solution with concentration of 5-20 percent for drying, thus obtaining a finished product. The Faropenem sodium freeze-dried powder injection is simple and feasible in preparation process, beneficial to operation, and suitable for needs for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of faropenem sodium freeze-dried powder injection, belong to technical field of medicine.
Background technology
Faropenem is the penems antibiotics of Japanese Suntory company exploitation, belongs to the atypia beta-lactam antibiotic, in 1986, in Japan, obtains the compound patent, and the patent No. is JP61,207387.Nineteen ninety and 1992 Japanese Yamanouchi drugmaker and U.S. Wyeth-Ayerst company obtain respectively the clinical licence of these product, jointly carry out clinical research, and in 1997 at first in Japan's listing, commodity are called Farom.
Each base polymer existed in beta-lactam antibiotic is the anaphylactogen that causes type Ⅰ hypersensitivity reaction, control the content of polymer in product, to reduce the anaphylactoid fundamental way of this type of antibiotic, especially the content of controlling polymer in injection seems even more important, the lactams structure is easy to hydrolysis simultaneously, to, by the Faropenem sodium drug administration by injection, must control polymer and generate and suppress hydrolysis, thereby meet the stability requirement of faropenem sodium injection.
Chinese patent CN1236814C discloses a kind of faropenem pharmaceutical composition that contains glutathion, and wherein compositions comprises the preparation method of tablet, capsule, granule and sterilized powder.This invention main advantage is to use glutathion as antioxidant, increases the stability of medicine; But the antioxidant glutathion has been added in this invention, there is no at present the injection rank, Product Safety is difficult to ensure.
Chinese patent CN1843354A discloses a kind of medicinal composition for injections that contains faropenem, contains one or more in antioxidant, metal chelating agent, antibacterial, PH regulator or adsorbent, and preparation adopts terminal sterilization.The faropenem preparation that this patent relates to is not investigated the stability of injection, same method preparation method faropenem injection, its aqueous solution high temperature sterilize degraded is violent, and in accelerating and keeping sample for a long time process, related substance and polymer obviously increase, solution changes color.
Chinese patent CN100536843C discloses a kind of pharmaceutical composition that contains faropenem or its acceptable salt or its hydrate, wherein contain antioxidant and aminoacid or dipeptides, also contain in addition one or more in stabilizing agent, antibacterial, PH regulator, preparation adopts terminal sterilization or filters the lyophilizing degerming; This invention is not still investigated polymer, the stability of injection is not investigated, and the content of polymer increases obviously in storage process, and stability of solution is poor, has added multiple additives simultaneously, and safety is difficult to ensure.
Chinese patent CN101904822A discloses a kind of faropenem sodium freeze-dried powder injection and preparation method thereof, has added antioxidant in preparation, adopts filtration sterilization.In this invention, mention for the Injectable sterile preparation, more stable while in organon faropenem molecule, containing 2.5 water of crystallization, now moisture content of raw material is in 15% left and right, and moisture is large, and the medicated powder mobility is bad, and in aseptic subpackaged process, loading amount is difficult to control; And the water content that raw material is larger is used for the agent of direct packaging aseptic powder needle for injection, preparation stability is difficult to ensure, so Faropenem sodium is unfavorable for being prepared into the injectable sterile powder preparation; But prepare lyophilized injectable powder, production cycle is long, Faropenem sodium is poor stability in aqueous solution, same degraded, in addition, after lyophilizing, Faropenem sodium or can lose part or all of water of crystallization in product, or have free water and do not remove, be difficult to guarantee that in final products, Faropenem sodium just in time contains 2.5 water of crystallization, both of these case, all reduced the stability of principal agent.
In sum, aspect the polymer generation of controlling the Faropenem sodium ejection preparation and inhibition hydrolysis, all there is certain limitation in prior art, and Chinese patent CN1843354A, CN100536843C and CN101904822A all fail to guarantee the problem that the faropenem sodium injection is degraded with the waterishlogging life in preparation process; Although Chinese patent CN1236814C adopts aseptic subpackaged technology, has added antioxidant, safety is difficult to ensure.
Summary of the invention
In view of the deficiencies in the prior art, the shortcoming that the object of the invention is to exist by the Faropenem sodium ejection preparation to the prior art report is studied, look for another way, a kind of faropenem sodium freeze-dried powder injection is provided, especially provide a kind of by lyophilizing after the Faropenem sodium wiring solution-forming, do not added the faropenem sodium freeze-dried powder injection of any additives simultaneously.Lyophilized injectable powder of the present invention shows through long-term storage and accelerated test, constant product quality.
The object of the present invention is achieved like this: a kind of faropenem sodium freeze-dried powder injection is characterized in that: Faropenem sodium, as unique composition, consist of.
Purpose of the present invention can also realize like this: the Faropenem sodium powder that is 75 ~ 100 μ m by particle diameter adds water for injection, is made into the solution that the faropenem na concn is 5 ~ 20%, lyophilizing.
The faropenem sodium freeze-dried powder injection the present invention relates to, its freeze-drying process specifically comprises the following steps:
1) the quick-freezing stage: before the faropenem sodium solution is put into, flaggy cools to-45 ℃, can freeze fast after making product put into freeze dryer, and insulation 2h, the decomposition and the oxidation that while reducing the Faropenem sodium solution state, occur;
2) the pre-freeze stage: after the quick-freezing stage finishes, flaggy is warmed up to-12 ℃, and insulation 2h makes the product eutectic point of rising again, and then flaggy is cooled to-40 ℃, insulation 3h;
3) sublimation drying: after the pre-freeze stage finishes, flaggy is warmed up to gradually 20 ℃ in 8 ~ 12h, and the line that makes to distil disappeared in this stage;
4) parsing-desiccation: after sublimation drying finishes, flaggy is warmed up to 35 ℃, and insulation 8h, fully volatilize moisture.
Lyophilizing is poured noble gas (as nitrogen) tamponade after finishing, and rolls lid, and packing gets product.
Compared with prior art, the faropenem sodium powder injection the present invention relates to has following advantage and significant progressive: (1) preparation stability is high.From the table 1 of specific embodiment, find out, the stability of faropenem sodium freeze-dried powder injection prepared by the present invention and prior art are without significant difference, and even some index is better than the preparation of prior art report.(2) overcome prior art prejudice.Prior art generally believes when preparing faropenem sodium freeze-dried powder injection need to add the lyophilizing proppant, yet the inventor is surprised to find that through overtesting, by not containing the direct lyophilizing of faropenem sodium solution of any additives, can obtain good looking appearance, steady quality, the higher Faropenem sodium freeze-dried powder of safety.Experiment showed, in faropenem sodium freeze-dried powder injection of the present invention and prior art that to add the freeze-dried powder effect obtained after antioxidant suitable and safer.(3) preparation technology's simple possible, be beneficial to operation, is applicable to the needs of industrialized great production.
The specific embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is further described, but protection scope of the present invention is not limited to these embodiment.
embodiment 1
Faropenem sodium 5g
Water for injection 100ml
The Faropenem sodium powder 5g that the particle diameter that takes the micronization acquisition is 75 ~ 100 μ m, add water for injection 100ml, stirs it is dissolved fully, and every 4ml fill is in the 10ml cillin bottle.The freeze dryer flaggy cools to-45 ℃, and fill is put into freeze dryer by cillin bottle after finishing, insulation 2h.The flaggy temperature is warmed up to-12 ℃, after insulation 2h, flaggy is cooled to-40 ℃, continue insulation 3h.Flaggy is warmed up in 8 ~ 12h to 20 ℃; After 35 ℃ of insulation 8h, pour the nitrogen tamponade, take out and roll lid pack and get final product.
the comparative example 1
Faropenem sodium 50g
Mannitol 100g
Sodium sulfite 2g
Sodium hydroxide (0.05mol/L) is appropriate
Water for injection 2000ml
The method provided according to patent CN101904822A embodiment 1, get supplementary material in above-mentioned prescription and prepare and get final product.
the comparative example 2
Faropenem sodium 50g
Mannitol 45g
Glutamic acid 2.0g
Cysteine 3.0g
Citric acid is appropriate
Water for injection 2000ml
The method provided according to patent CN100536843C embodiment 10, get supplementary material in above-mentioned prescription and prepare and get final product.
embodiment 2
[assay] according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.
chromatographic condition and system suitabilitywith octadecylsilane chemically bonded silica, it is filler; Acetonitrile-phosphate buffer (the 4.8g potassium dihydrogen phosphate adds 5.4g dipotassium hydrogen phosphate → 1000ml)-10% TBAH aqueous solution (15: 85: 2) of take is mobile phase, and the detection wavelength is 306nm; Theoretical cam curve is calculated and is not less than 2000 by the faropenem peak.
algoscopyget this product appropriate (approximately being equivalent to faropenem 200mg), put in the 100ml measuring bottle, adding mobile phase dissolves and is diluted to scale, shake up, filter, precision measures subsequent filtrate 5ml and puts in the 50ml measuring bottle, add mobile phase and be diluted to scale, shake up as need testing solution, precision measures 20 μ l injection liquid chromatographies, records chromatogram.Separately follow the example of the faropenem reference substance appropriate, accurately weighed, add mobile phase and dissolve and dilute and make every 1ml approximately containing the solution of faropenem 200 μ g, be measured in the same method.Press external standard method with C in the calculated by peak area test sample
12h
14nO
5the content of S.
related substanceget this product (approximately being equivalent to faropenem 50mg) accurately weighed, put in the 100ml measuring bottle, add the mutual-assistance of flowing and dissolve and be diluted to scale, shake up, filter, get subsequent filtrate as need testing solution; Precision measures 0.5ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up solution in contrast.According to the chromatographic condition under the assay item, get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, the peak height that makes main composition chromatographic peak is full scale 10%～25%, precision measures contrast solution and each 20 μ l of need testing solution again, difference injection liquid chromatography, record chromatogram to 2 times of main composition peak retention time, in the need testing solution chromatogram if any impurity peaks, single impurity peak area must not be greater than contrast solution main peak area (0.5%), 2 times (1.0%) each impurity peak area and that must not be greater than contrast solution main peak area.
[faropenem polymer] according to molecular exclusion chromatography (two appendix V H of Chinese Pharmacopoeia version in 2010), measure.
chromatographic condition and system suitabilitywith sephadex G-10(40 ~ 120 μ m) be filler, column internal diameter 1.0 ~ 1.5cm, post height 30 ~ 40cm.0.01mol/L phosphate buffer (get disodium hydrogen phosphate 2.19g and sodium dihydrogen phosphate 0.54g, add water 1000ml and dissolve) with pH7.0 is mobile phase A; Take 0.01% sodium dodecyl sulfate solution as Mobile phase B; Flow velocity is 1ml per minute; The detection wavelength is 254nm.Take mobile phase A as mobile phase, get the blue dextran 2000 solution 100 μ l injection liquid chromatographies of 2mg/ml, theoretical cam curve is calculated and is not less than 700 by blue dextran 2000 peaks, and tailing factor should be between 0.75 ~ 1.5.Separately take Mobile phase B as mobile phase, and precision measures contrast solution 100 μ l, continuous sample introduction 5 times, and the relative standard deviation of peak area should be not more than 5.0%.
the preparation of contrast solutionfollow the example of faropenem reference substance appropriate (approximately being equivalent to faropenem 20mg), accurately weighed, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, shake up.
algoscopyget this product appropriate (approximately being equivalent to faropenem 50mg), accurately weighed, put in the 100ml measuring bottle, add water and make to dissolve and be diluted to scale, shake up, precision measures 100 μ l, the injection liquid chromatography, the mobile phase A of take is measured as mobile phase, records chromatogram; Another precision measures contrast solution 100 μ l, and the injection liquid chromatography, take Mobile phase B as mobile phase, is measured in the same method.With calculated by peak area, contain the faropenem polymer in faropenem, mistake 2.0% not by external standard method.
moistureget this product, measure according to aquametry (two appendix VIII M first method A of Chinese Pharmacopoeia version in 2005), moisture content should be less than 5.0%.
Embodiment 1 and comparative example's 1,2 gained samples are placed in to 40 ℃, carry out accelerated test under the environment of RH75%, investigated respectively at sampling in the 0th, 3,6 months, investigate index and include the indexs such as related substance, content, polymer, visible foreign matters, concrete outcome sees the following form 1.
Table 1 faropenem sodium freeze dry study on the stability result
By upper table 1, can find out, the indexs such as the sample related substance prepared by the present invention, polymer are suitable with prior art, part index number is better than off-the-shelf item, but present technique has reduced the application of the adjuvants such as antioxidant, improve the safety of injection Faropenem sodium clinical practice, and changed the prejudice of prior art.
Claims (2)
1.
faropenem sodium is the purposes in preparing freeze-dried powder as unique composition, it is characterized in that, the step of freeze drying in this freeze-dried powder preparation process comprises:
the quick-freezing stage: first make flaggy cool to-45 ℃, then put into the Faropenem sodium aqueous solution for injection, insulation 2h;
the pre-freeze stage: after the quick-freezing stage finishes, flaggy is warmed up to-12 ℃, and insulation 2h, then be cooled to flaggy-40 ℃, insulation 3h;
sublimation drying: after the pre-freeze stage finishes, flaggy is warmed up to gradually 20 ℃ in 8～12h, and the line that makes to distil disappeared in this stage;
parsing-desiccation: after sublimation drying finishes, flaggy is warmed up to 35 ℃, and insulation 8h, fully volatilize moisture;
wherein, preparation method faropenem aqueous solution for injection isthe Faropenem sodium powder that is 75 ~ 100 μ m by particle diameter adds water for injection, the faropenem sodium solution that to be made into concentration be 5 ~ 20%.
2.
a kind of Faropenem sodium as the preparation method of the freeze-dried powder of unique composition, is characterized in that, comprises the following steps:
a) the Faropenem sodium powder is joined in water for injection and dissolves,the faropenem sodium solution that to be made into concentration be 5 ~ 20%
;
b) solution lyophilization a) by step, lyophilizing is poured nitrogen after finishing, and tamponade, roll lid, and packing gets product; Described lyophilization step comprises:
the quick-freezing stage: first make flaggy cool to-45 ℃, then put into the faropenem sodium solution, insulation 2h;
the pre-freeze stage: after the quick-freezing stage finishes, flaggy is warmed up to-12 ℃, and insulation 2h, then be cooled to flaggy-40 ℃, insulation 3h;
sublimation drying: after the pre-freeze stage finishes, flaggy is warmed up to gradually 20 ℃ in 8～12h, and the line that makes to distil disappeared in this stage;
parsing-desiccation: after sublimation drying finishes, flaggy is warmed up to 35 ℃, and insulation 8h, fully volatilize moisture;
wherein, step a) particle diameter of Faropenem sodium powder used be 75～100 μ m.
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| CN 201110070330 CN102133201B (en) | 2011-03-23 | 2011-03-23 | Faropenem sodium freeze-dried powder injection |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011394A (en) * | 2006-05-10 | 2007-08-08 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for injection containing faropenem |
| CN101033233A (en) * | 2006-03-07 | 2007-09-12 | 江苏正大天晴药业股份有限公司 | Faropenem sodium crystallization and preparation method thereof |
| CN101904822B (en) * | 2009-06-04 | 2011-11-09 | 鲁南制药集团股份有限公司 | Faropenem sodium freeze-drying powder and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101033233A (en) * | 2006-03-07 | 2007-09-12 | 江苏正大天晴药业股份有限公司 | Faropenem sodium crystallization and preparation method thereof |
| CN101011394A (en) * | 2006-05-10 | 2007-08-08 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for injection containing faropenem |
| CN101904822B (en) * | 2009-06-04 | 2011-11-09 | 鲁南制药集团股份有限公司 | Faropenem sodium freeze-drying powder and preparation method thereof |
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Effective date of registration: 20221124 Address after: 273400 Shandong city of Linyi province Feixian County North Ring Road No. 1 Patentee after: LUNAN NEW TIME BIO-TECH Co.,Ltd. Address before: 273400 Shandong city of Linyi province Feixian County North Ring Road No. 1 Patentee before: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. |
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