CN102579371A - Gemcitabine hydrochloride freeze-dried powder injection - Google Patents
Gemcitabine hydrochloride freeze-dried powder injection Download PDFInfo
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- CN102579371A CN102579371A CN2012100418884A CN201210041888A CN102579371A CN 102579371 A CN102579371 A CN 102579371A CN 2012100418884 A CN2012100418884 A CN 2012100418884A CN 201210041888 A CN201210041888 A CN 201210041888A CN 102579371 A CN102579371 A CN 102579371A
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- gemcitabine hydrochloride
- powder injection
- gemcitabine
- dried powder
- injection
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Abstract
The invention relates to a gemcitabine hydrochloride freeze-dried powder injection, and further relates to a preparation method of the gemcitabine hydrochloride freeze-dried powder injection, as well as application of the gemcitabine hydrochloride lyophilized powder injection in preparing medicines for treating non-small-cell carcinoma, pancreatic cancer and the like in middle and late stages.
Description
Technical field
The present invention relates to a kind of gemcitabine hydrochloride lyophilized powder injection and preparation method thereof, and the purposes in medicines such as preparation treatment middle and advanced stage nonsmall-cell lung cancer and cancer of pancreas.
Background technology
Primary bronchogenic carcinoma of lung is present one of global modal malignant tumor, has occupied first of the malignant tumor in the developed regions of developed country and developing country pulmonary carcinoma; See that from data in recent years pulmonary carcinoma is the highest malignant tumor of industrially developed country's mortality rate such as America and Europe, wherein almost the pulmonary carcinoma more than 80% is nonsmall-cell lung cancer.Had data to show, the lung cancer morbidity rate of big and medium-sized cities such as the Shanghai of China, Beijing has occupied first of the various malignant tumor.
The international cooperating research of tumor can be patient's behavior state, stadium and body weight as clear and definite prognosis factor.Specific prognosis factor can be predicted nonsmall-cell lung cancer patient's survival rate, and for early stage, behavior state was good, does not have remarkable weight loss, and the women when favourable prognosis factor comprised diagnosis.Age and histology's hypotype are very little to the influence of prognosis.
Gemcitabine hydrochloride is a CCSA, mainly acts on the DNA tumor cell of synthesis stage.Its process nucleoside kinase in cell changes into has active nucleoside diphosphate (dFdCDP) and NTP (dFdCTP).DFdCDP suppresses ribonucleotide reductase, thus the amount, the especially dCTP that have reduced the synthetic of DNA and repaired necessary Deoxydization nucleotide.DFdCTP can combine to get into DNA with the dCTP competition, causes and shelters chain termination, dna break, apoptosis.Gemcitabine hydrochloride single therapy nonsmall-cell lung cancer effective percentage be 12%～45% and cisplatin combined application effective percentage be 39.8%～71.5t%.
Because the gemcitabine hydrochloride less stable is prone to degraded, generation possibly cause the impurity of toxic and side effects.Existing known technology does not improve the suggestion of above defective yet.
CN200910032906 has instructed a kind of gemcitabine hydrochloride lyophilized powder injection; Improve the stability of gemcitabine hydrochloride lyophilized powder injection; Make its stability in preparation, transportation and storage process better; Compatibility solution can be placed the long period during clinical use, makes clinical use become convenient, and also having reduced greatly simultaneously increases the hidden danger of bringing for patient's drug safety because of impurity (related substance).
Summary of the invention
The object of the present invention is to provide a kind of gemcitabine hydrochloride lyophilized powder injection, it comprises gemcitabine hydrochloride, mannitol and sodium acetate, and wherein three's content ratio is 1: (1～3): 0.15, and preferred 1: 2.5: 0.15.
Another object of the present invention is to provide a kind of method for preparing above-mentioned gemcitabine hydrochloride lyophilized powder injection, this method comprises dissolving, standardize solution, bottling and lyophilizing.
Another object of the present invention is to provide the purposes of above-mentioned gemcitabine hydrochloride lyophilized powder injection in medicines such as preparation treatment middle and advanced stage nonsmall-cell lung cancer and cancer of pancreas.
On the basis of CN200910032906; The present invention has carried out further research screening to prescription, and finishing screen is selected a kind of new gemcitabine hydrochloride lyophilized powder injection, greatly improves the stability of gemcitabine hydrochloride lyophilized powder injection; Make its stability in preparation, transportation and storage process better; Compatibility solution can be placed the long period during clinical use, makes clinical use become convenient, has also reduced greatly to increase the hidden danger of bringing to patient's drug safety because of impurity simultaneously.
The specific embodiment
For detailed bright specifically the present invention, the spy provides following examples, but does not mean that any restriction of the present invention.
Embodiment 1
Prescription
Gemcitabine hydrochloride 228g
Mannitol 570g
Sodium acetate 34.2g
Water for injection adds to 6000ml
Process 1000 bottles altogether
Take by weighing mannitol and sodium acetate, add 80% amount water for injection, dissolve and stir; Add gemcitabine hydrochloride again, dissolve and stir, transfer pH to 2.7 with 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide solution; After the intermediate passed examination, add the injection water and be settled to full dose.Solution is delivered in the sterilizing room through peristaltic pump, and is extremely clear and bright through the filtering with microporous membrane of 0.22 μ m, and the loading amount fill of pressing every bottle of 6ml is in the 25ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot.Sabot is treated that the lyophilizing sample puts in the freeze drying box, close chamber door, circulating pump, compressor and plate low temperature valve are opened in start; Utilize conduction oil that products temperature is descended, to reach-30 ℃ of continued freezing when products temperature, when making products temperature reach-40 ℃ of left and right sides, and the closing plate low temperature valve; Open electrical heating and mix low temperature valve and be provided with automatically, kept this products temperature 3 hours, then open condenser valve, when the condenser valve temperature reaches-45 ℃; Open vacuum system, current box vacuum reach 20Pa when following, begin the sublimation drying that heats up, and last baking temperature is 30 ℃; Kept this temperature 3 hours, in close after the case vacuum does not have remarkable destruction before the valve, tamponade, outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.
Embodiment 2
Prescription
Gemcitabine hydrochloride 228g
Mannitol 228g
Sodium acetate 34.2g
Water for injection adds to 6000ml
Process 1000 bottles altogether
Take by weighing mannitol and sodium acetate, add 80% amount water for injection, dissolve and stir; Add gemcitabine hydrochloride again, dissolve and stir, transfer pH to 2.7 with 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide solution; After the intermediate passed examination, add the injection water and be settled to full dose.Solution is delivered in the sterilizing room through peristaltic pump, and is extremely clear and bright through the filtering with microporous membrane of 0.22 μ m, and the loading amount fill of pressing every bottle of 6ml is in the 25ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot.Sabot is treated that the lyophilizing sample puts in the freeze drying box, close chamber door, circulating pump, compressor and plate low temperature valve are opened in start; Utilize conduction oil that products temperature is descended, to reach-30 ℃ of continued freezing when products temperature, when making products temperature reach-40 ℃ of left and right sides, and the closing plate low temperature valve; Open electrical heating and mix low temperature valve and be provided with automatically, kept this products temperature 3 hours, then open condenser valve, when the condenser valve temperature reaches-45 ℃; Open vacuum system, current box vacuum reach 20Pa when following, begin the sublimation drying that heats up, and last baking temperature is 30 ℃; Kept this temperature 3 hours, in close after the case vacuum does not have remarkable destruction before the valve, tamponade, outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.
Embodiment 3
Prescription
Gemcitabine hydrochloride 228g
Mannitol 684g
Sodium acetate 34.2g
Water for injection adds to 6000ml
Process 1000 bottles altogether
Take by weighing mannitol and sodium acetate, add 80% amount water for injection, dissolve and stir; Add gemcitabine hydrochloride again, dissolve and stir, transfer pH to 2.7 with 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide solution; After the intermediate passed examination, add the injection water and be settled to full dose.Solution is delivered in the sterilizing room through peristaltic pump, and is extremely clear and bright through the filtering with microporous membrane of 0.22 μ m, and the loading amount fill of pressing every bottle of 6ml is in the 25ml cillin bottle, and part is butyl rubber bung beyond the Great Wall, sabot.Sabot is treated that the lyophilizing sample puts in the freeze drying box, close chamber door, circulating pump, compressor and plate low temperature valve are opened in start; Utilize conduction oil that products temperature is descended, to reach-30 ℃ of continued freezing when products temperature, when making products temperature reach-40 ℃ of left and right sides, and the closing plate low temperature valve; Open electrical heating and mix low temperature valve and be provided with automatically, kept this products temperature 3 hours, then open condenser valve, when the condenser valve temperature reaches-45 ℃; Open vacuum system, current box vacuum reach 20Pa when following, begin the sublimation drying that heats up, and last baking temperature is 30 ℃; Kept this temperature 3 hours, in close after the case vacuum does not have remarkable destruction before the valve, tamponade, outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.
Test Example 1 gemcitabine hydrochloride lyophilized powder injection determination of related substances
Measure according to HPLC (Chinese Pharmacopoeia 2005 version two ones)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler; Is mobile phase with acetic acid by buffer (get acetic acid by 3.85g, add water 800ml and make dissolving, add glacial acetic acid adjust pH to 5.7, add water to 1000ml)-methanol (90: 10), and the detection wavelength is 268nm.Each is an amount of to get gemcitabine hydrochloride reference substance and cytosine; The accurate title, decide; Be dissolved in water and dilute and process the solution that every 1ml contains gemcitabine 0.1mg, cytosine 0.1mg, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; Number of theoretical plate should be not less than 2000 by the gemcitabine hydrochloride peak, and the separating degree at gemcitabine hydrochloride peak and cytosine peak should be greater than 2.0.
It is an amount of to get the gemcitabine hydrochloride lyophilized powder injection content, and accurate the title decides, and adds mobile phase dissolving and dilution and processes the solution that contains gemcitabine 1mg among every 1ml approximately, as need testing solution; Precision is measured in right amount, processes the solution that contains 10 μ g among every 1ml with the mobile phase dilution, as contrast solution.Get contrast solution 20 μ l and inject chromatograph of liquid; Regulate detection sensitivity; Make the peak height of main constituent chromatographic peak be about 20%～30% of full scale; Precision is measured each 20 μ l of need testing solution and contrast solution again, injects chromatograph of liquid respectively, 3 times of chromatogram to the main constituent peak retention time of record test sample.As showing impurity peaks, measure each impurity peak area sum except that the adjuvant peak in the need testing solution chromatogram, calculate and promptly get gemcitabine hydrochloride lyophilized powder injection related substance percentage composition.
Result of the test is seen table 1.
Test Example 2 gemcitabine hydrochloride lyophilized powder injection assays
Measure according to HPLC (Chinese Pharmacopoeia 2005 version two ones)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler; Is mobile phase with acetic acid by buffer (get acetic acid by 3.85g, add water 800ml and make dissolving, add glacial acetic acid adjust pH to 5.7, add water to 1000ml)-methanol (90: 10), and the detection wavelength is 268nm.Each is an amount of to get gemcitabine hydrochloride reference substance and cytosine; The accurate title, decide; Be dissolved in water and dilute and process the solution that every 1ml contains gemcitabine 0.1mg, cytosine 0.1mg, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; Number of theoretical plate should be not less than 2000 by the gemcitabine hydrochloride peak, and the separating degree at gemcitabine hydrochloride peak and cytosine peak should be greater than 2.0.
Get the gemcitabine hydrochloride lyophilized powder injection content, mixing, precision takes by weighing in right amount, is dissolved in water and is diluted to the solution that contains gemcitabine 0.1mg among every 1ml approximately, and precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; Other the gemcitabine hydrochloride reference substance that is dried to constant weight of learning from else's experience 105 ℃ is an amount of, is dissolved in water and is diluted to the solution that contains gemcitabine 0.1mg among every 1ml approximately, measures with method,, promptly gets with calculated by peak area by external standard method.
Result of the test is seen table 1.
Table 1 gemcitabine hydrochloride lyophilized powder injection check result
| Embodiment | Content (%) | Related substance (%) |
| 1 | 99.89 | 0.18 |
| 2 | 99.87 | 0.20 |
| 3 | 99.85 | 0.22 |
Test Example 3 stability tests
At 25 ℃; Relative humidity is under 60 ± 5% the condition embodiment 1, embodiment 2 and embodiment 3 prepared gemcitabine hydrochloride preparation finished products to be placed 12 months; Issue standard WS1-(X-429)-2003Z with reference to office of national Bureau of Drugs Supervision, at quarterly intervals the content of the gemcitabine hydrochloride in the test sample and single maximum/total impurities content.Testing result is seen shown in the table 2.
Table 2 gemcitabine hydrochloride freeze-dried powder stability test result
Can find out that from result of the test gained preparation impurity content of the present invention is low, the stability performance is excellent, thereby promotes the storage period of medicine, can ensure the safety of medication simultaneously.
Claims (4)
1. gemcitabine hydrochloride lyophilized powder injection, it comprises gemcitabine hydrochloride, mannitol and sodium acetate, and wherein three's content ratio is 1: (1～3): 0.15.
2. 1: 2.5: 0.15 of being of gemcitabine lyophilized injectable powder according to claim 1, wherein said content ratio.
3. a method for preparing like any described gemcitabine lyophilized injectable powder of claim 1～2 comprises dissolving, standardize solution, bottling and lyophilizing.
4. like the purposes of any described gemcitabine lyophilized injectable powder of claim 1～2 in medicines such as preparation treatment middle and advanced stage nonsmall-cell lung cancer and cancer of pancreas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100418884A CN102579371A (en) | 2012-02-23 | 2012-02-23 | Gemcitabine hydrochloride freeze-dried powder injection |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012100418884A CN102579371A (en) | 2012-02-23 | 2012-02-23 | Gemcitabine hydrochloride freeze-dried powder injection |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060089328A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solutions |
| CN101564381A (en) * | 2009-06-05 | 2009-10-28 | 江苏奥赛康药业有限公司 | Gemcitabine hydrochloride lyophilized powder injection |
| CN102144981A (en) * | 2011-04-07 | 2011-08-10 | 海南锦瑞制药股份有限公司 | Gemcitabine hydrochloride lyophilized powder injection and preparation method thereof |
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2012
- 2012-02-23 CN CN2012100418884A patent/CN102579371A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060089328A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solutions |
| CN101564381A (en) * | 2009-06-05 | 2009-10-28 | 江苏奥赛康药业有限公司 | Gemcitabine hydrochloride lyophilized powder injection |
| CN102144981A (en) * | 2011-04-07 | 2011-08-10 | 海南锦瑞制药股份有限公司 | Gemcitabine hydrochloride lyophilized powder injection and preparation method thereof |
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Application publication date: 20120718 |