Injection vinorelbine injectable powder and preparation methodTechnical field
What the present invention relates to a kind ofly uses about injection for intravenous, contain vinorelbine and be active ingredient, be used for the treatment of nonsmall-cell lung cancer, breast carcinoma, ovarian cancer, lymphadenomatous a kind of novel formulation, be powder ampoule agent for injection, its preparation comprises injection freeze-dried products and Injectable sterile packing goods.
Technical background
At present, cancer is the high a kind of disease of mortality rate in the world, become the arch enemy of man, many in the world countries all drop into a large amount of financial resources, the research work that material resources are carried out anticancer, especially develop the specific drug aspect that some control cancer, certain progress having been arranged, but failed a substantial breakthrough so far, mainly is that drug effect is not enough.
Vinorelbine is the alkaloid that extracts in the apocynaceae plant Herba Catharanthi Rosei (Catharanthus roseus or Vinca rosea), through the semi-synthetic new alkaloids that makes of chemistry, be a kind of medicine that is used for the treatment of nonsmall-cell lung cancer (NSCLC), breast carcinoma, ovarian cancer, lymphoma etc.
Vinorelbine, English name: Vinorelbine, another name NVB, vinorelbine.The preparation that has used clinically has only injection, and specification is every 10mg, 50mg, and solvent is an aqueous solution.Trade name have navelbine (NAVELBINE, NVB), Gai Nuo etc.The Vinorelbine monotartrate injection went on the market in France first in 1989, at present in 18 country's listings such as Colombia, Argentina, Czech, Slovakia, Italy, Peru, Vietnam, Mexico, China, Lebanon, Bulgaria, Malta, Portugal, Canada, Luxembourg, the U.S., Germany, China in 1993 through the health ministry approval of import, homemade medicine in 1999 the listing.
Its bitartrate of the present clinical practice of vinorelbine.Be white or off-white color crystalline powder, have and draw moistly, meet light or easily flavescence of heat, soluble in water, dissolving, molten in the ethanol part omitted, almost insoluble in chloroform in acetone, its aqueous solution is colourless or light yellow transparent liquid.
Vinorelbine is a special medicine of cycle, and it is to combine with tubulin that its anticancer pharmacology mechanism mainly acts on, and therefore makes cell microtubule in the mitosis process form obstacle.G capable of blocking during concentration＞12nM2-M the phase.Except to the splitted microtubule effect of silk sometimes, the aixs cylinder microtubule also there is affinity, therefore can cause neurotoxicity, but want light than vincristine (VCR).
The existing clinically more document announcement of vinorelbine injection, it is used for the treatment of nonsmall-cell lung cancer list medicine application effective percentage is 14%～33%; With cisplatin combined application effective percentage be 36%～52%.Breast cancer treatment also there is preferably the curative effect effective percentage between 35%～52%; With amycin use in conjunction curative effect further raising is arranged, vinorelbine also all has suitable curative effect to ovarian cancer, lymphoma.
Summary of the invention
The vinorelbine injectable powder and the preparation method that the object of the present invention is to provide a kind of a kind of injection for intravenous that with the vinorelbine is principal agent is made to use.This injection vinorelbine injectable powder, it includes with vinorelbine as principal agent, is mixed with the medicinal filler of 0-10 part part by weight at the most and makes powderous preparations in 1 part of principal agent, and wherein water content is in 12%.
Described medicinal filler is at least a composition in dextran, mannitol, sodium chloride, sorbitol, citric acid, glucose, the hydrolyzed protein, in 1 part of principal agent, be mixed with the medicinal filler of 0.5-1.2 part by weight, and the water content of powderous preparations is in 6%.
Described vinorelbine principal agent is that single salt or the two salt compound that makes reacted in a kind of acid of at least a vinorelbine free alkali or vinorelbine and tartaric acid, citric acid, maleic acid, lactic acid, malic acid, phosphoric acid, sulphuric acid, hydrochloric acid, carbonic acid.
The preparation method of described injection vinorelbine injectable powder, it is under aseptic condition, select for use vinorelbine as principal agent, earlier with at least a dissolution with solvents in water for injection, acetone, the ethanol, and add in proportion or do not add medicinal filler and produce vinorelbine solution through 0-0.3% medical active carbon decoloring, behind the reuse 0.22-0.45 μ m filtering with microporous membrane, carry out dehydrate and make aseptic powderous preparations.
Described vinorelbine solution is with 0.1% medical active carbon decoloring, and reuse 0.22 μ m filtering with microporous membrane carries out dehydrate again and makes aseptic powderous preparations.
The method that described dehydrate adopts includes at least a in direct lyophilization, lyophilizing powder packing method, spray drying method, hygroscopic desiccation method, micro-wave drying method, the hypobaric drying method, and makes water content in the aseptic powderous preparations of making in 12%.
The described direct lyophilization of dry employing of taking off, it is that vinorelbine solution is filtered, decolours through medicinal carbon, again through 0.22 μ m filtering with microporous membrane, make sterile solution, sterile solution is sub-packed in the cillin bottle, through lyophilization, roll the cap seal mouth, packing makes injection vinorelbine powderous preparations.
Described dehydrate adopts hypobaric drying method, it is that vinorelbine solution is filtered, decolours through medicinal carbon, again through 0.22 μ m filtering with microporous membrane, make sterile solution, sterile solution is sub-packed in the cillin bottle, drying under reduced pressure rolls the cap seal mouth, and packing makes injection vinorelbine injectable powder.
Described dehydrate adopts freeze-dried powder packing method, it is that vinorelbine solution is filtered, decolours through medicinal carbon, again through 0.22 μ m filtering with microporous membrane, make sterile solution, sterile solution is positioned in the deep bid aseptic freeze-dried, pulverizes, weight fraction is loaded in the cillin bottle in accordance with regulations, roll the cap seal mouth, packing makes injection vinorelbine injectable powder.
Described dehydrate adopts spray drying method, it is that vinorelbine solution is filtered, decolours through medicinal carbon, again through 0.22 μ m filtering with microporous membrane, make sterile solution, adopt spray-drying installation fast spraying drying, weight fraction is loaded in the cillin bottle in accordance with regulations, rolls the cap seal mouth, and packing makes injection vinorelbine injectable powder.
The consumption of described solvent gets final product with the dissolving of enough principal agents and filler, can suitably increase quantity of solvent according to the volume of lyophilized solid thing, and the quantity of solvent that preparation commonly used is every bottle can be at 1～5ml.
The content of principal agent can prepare 1mg～800mg/ bottle usually in vinorelbine, but the clinical specification recommended amounts of using is 10mg, 30mg, 50mg.
In the injection preparation method of vinorelbine, make injectable powder after can adopting different seasonings with the vinorelbine dehydrate.Moisture content is controlled at (percentage by weight) below 12% in the preparation, can obtain than stable formulation.Suitability for industrialized production moisture content should be controlled at below 5%.
Preparation of the present invention is identical with injection in the clinical scope of application.When using clinically, injectable powder (after 2～5ml), must be dissolved in about 125ml normal saline (15～20 minutes) vein input in the short time with a small amount of physiological saline solution earlier, a large amount of normal saline flushing veins that instil then reduce this medicine to the venous zest.Clinical administration dosage 25～30mg/m2, weekly, continuous 4～6 times is a course of treatment.
The present invention compared with prior art has the processing technology advanced person, and product stability is good, and effective active components is difficult for decomposing, and reduces curative effect, minimizing toxic and side effects that drug storage phase catabolite improves product especially.Keeping in Dark Place below 4 ℃, effect duration can reach more than 3 years, and-20 ℃ of lucifuge cold preservations can obtain longer effect duration.This Product transport is convenient, and product appearance is attractive in appearance, helps large-scale promotion application clinically.
The present invention will be described in detail below in conjunction with subordinate list: injectable powder preparation method of the present invention, mainly comprise the preparation of vinorelbine pharmaceutical solutions, filtration, decolouring and 0.22 μ m filtering with microporous membrane through medicinal carbon, make sterile solution, sterile solution is passed through seasoning, as lyophilization or drying under reduced pressure packing method dehydration powder process, and roll the cap seal mouth, packing forms.
Embodiment 1, take by weighing Vinorelbine monotartrate 13.85g (being equivalent to vinorelbine 10g), with mannitol 10g, add sterilized water for injection 2000ml, stirring makes its dissolving, measure the pH value 3.0～4.5 of solution, add medicinal carbon, filter, the filtrate reuse is equipped with 0.22 μ m nuclepore membrane filter and filters, and fill is in sterilized cillin bottle.At-30～-40 ℃ of pre-freezes 2～3 hours ,-36～-20 ℃ of 9 hours sublimation dryings, 30 ℃ again after dry 25～30 hours, add a cover, roll mouth, it is principal agent that packing promptly is able to vinorelbine, mannitol is the injectable powder of filler.
Embodiment 2, prepare with lyophilization packing method, in the toilet, take by weighing Vinorelbine monotartrate 41.55g (being equivalent to vinorelbine 30g), dextran 1 4g, sorbitol 6g place sterilized container together, add sterilized water for injection 2000ml, stir and make its dissolving, and the adding medicinal carbon filters, the filtrate reuse is equipped with 0.22 μ m microporous filter membrane steriliser and filters, and makes sterile solution.Sterile solution is placed in the deep bid aseptic freeze-dried, pulverized, measure lyophilized powder vinorelbine content, be loaded in the cillin bottle by vinorelbine conversion weight fraction, roll the cap seal mouth, packing promptly makes.
Embodiment 3, and drying under reduced pressure packing method takes by weighing Vinorelbine monotartrate 27.7g (vinorelbine 20g) in the toilet, Dextran-20 g places sterilized container, adds sterilized water for injection 2000ml, stirs to make its dissolving, add medicinal carbon, filter, the filtrate reuse is equipped with 0.22 μ m microporous filter membrane steriliser and filters, make sterile solution, sterile solution is positioned in the deep bid drying under reduced pressure, pulverize, weight fraction is loaded in the sterilized cillin bottle in accordance with regulations, rolls the cap seal mouth, and packing promptly.
The prescription of vinorelbine injectable powder of the present invention will be represented with following subordinate list:
| The prescription sequence number | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | ??9 | ??10 | ??11 | ??12 |
| Vinorelbine (mg) | ??10 | ??10 | ??20 | ??20 | ??30 | ??30 | ??10 | ??10 | ??20 | ??20 | ??30 | ??30 |
| Dextran (mg) | ??10 | ??20 | ??10 | ??20 | ??10 | ??20 | ??- | ??- | ??- | ??- | ??- | ??- |
| Mannitol (mg) | ??- | ??- | ??- | ??- | ??- | ??- | ??10 | ??20 | ??10 | ??20 | ??10 | ??20 |
| Water for injection (ml) | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 |
The above-mentioned vinorelbine of the present invention can be a kind of free alkali, also can be that single salt or the two salt compound that makes reacted in a kind of a kind of acid with tartaric acid, citric acid, maleic acid, phosphoric acid, sulphuric acid, hydrochloric acid, carbonic acid.This single salt or two salt compound are as the vinorelbine principal agent, and it is to be mixed with the above-mentioned acid of different molar concentrations by vinorelbine, and after the dissolving, with ether it is separated out in acetone soln, filters, and drying under reduced pressure forms.As: 1, the preparation of single vinorelbine tartrate, take by weighing 1.0g (1.29mmol) vinorelbine and tartaric acid 0.16g (1.25mmol) and under 25 ℃ of conditions, add the 70ml acetone solution, add an amount of ether, filter, drying under reduced pressure is promptly.2, the preparation of Vinorelbine monotartrate takes by weighing 1.0g (1.29mmol) vinorelbine and tartaric acid 0.38g (2.5mmol) adds the 70ml acetone solution under 25 ℃ of conditions, adds an amount of ether, filters, and drying under reduced pressure promptly.