CN102772373B - A kind of injection vinorelbine tartrate injectable powder and preparation method thereof - Google Patents
A kind of injection vinorelbine tartrate injectable powder and preparation method thereof Download PDFInfo
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- CN102772373B CN102772373B CN201110120426.7A CN201110120426A CN102772373B CN 102772373 B CN102772373 B CN 102772373B CN 201110120426 A CN201110120426 A CN 201110120426A CN 102772373 B CN102772373 B CN 102772373B
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Abstract
The invention provides a kind of injection vinorelbine tartrate injectable powder, be made up of vinorelbine tartrate and filler, wherein filler is lactose, preferred α-lactose monohydrate.Wherein the weight percentage of each component is as follows: vinorelbine tartrate 14-25%, α-lactose monohydrate 75-86%.The present invention also provides a kind of method preparing described injection vinorelbine tartrate injectable powder.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to injection vinorelbine tartrate injectable powder and preparation method thereof.
Background technology
Vinorelbine, English vinorelbine by name, chemical name is 3 ', 4 '-two dehydrogenation-4 '-deoxidation-8 '-navelbine.
Vinorelbine is broad-spectrum anti-tumor medicine, the first-line treatment medicine of advanced Non-small cell lung (NSCLC), also for the treatment of metastatic breast cancer (mammary carcinoma), refractory non-Hodgkin's lymphoma, ovarian cancer and tumor of head and neck.List at present " national basic medical insurance Drug catalogue ".ASCO (American Society of Clinical Oncology) common recognition in 2006, vinorelbine+cisplatin is the preferred embodiments of current NSCLC adjuvant chemotherapy, is the first-selected chemotherapeutics of breast carcinoma clinical practice guideline recommendation Soaked mammary cancer after surgery in 2006.
Vinorelbine tartrate is developed by Pierre Fabre, and took the lead in 1989 in France's listing, dosage form is injection, is the aseptic aqueous solution of vinorelbine tartrate, without other additive any.
The domestic existing dosage form of current vinorelbine tartrate is injection, injection freeze-dried powder and capsule, and the filler that wherein freeze-dried powder uses is mannitol and tartaric acid.
Chinese patent application CN02152537.4, title: the pharmaceutical formulation of injection and preparation method.Be in dextran, mannitol, sodium chloride, sorbitol, citric acid at least one as filler.Chinese patent application CN03103644.9, title: injection vinorelbine injectable powder and preparation method.Using at least one in dextran, mannitol, sodium chloride, sorbitol, citric acid, glucose, hydrolyzed protein as filler.But in these 2 patent application documents, how all do not investigate the stability of the preparation obtained when doing filler with these materials.
Summary of the invention
In lyophilized formulations, purity is not limited only to the requirement of filler high, nontoxic, without antigen, is applicable to commercial production etc., also need to make obtained freeze-drying prods have good stability.The present inventor finds through long-term experiment, for vinorelbine tartrate injectable powder, adopt at least one in dextran disclosed in prior art, mannitol, sodium chloride, sorbitol, citric acid, glucose, hydrolyzed protein as filler, the product utilizing the prescription ratio of prior art disclosed in it and preparation method to obtain all fails to obtain gratifying stability.
And only have employing lactose, when particularly α-lactose monohydrate is as filler, everyway obtains gratifying effect.Not only obtain good stability, and formulation aesthetics is good, without subsiding, spraying the bad outward appearance such as bottle, atrophy, the obtained product heavy molten time is less than 30S.
For lactose, market exists the product of various ways, as α-lactose monohydrate, β-Lactis Anhydrous, α-Lactis Anhydrous, unformed lactose and β-lactose monohydrate, different crystal formations and solvation degree make them have different character.When preparing different pharmaceutical preparation as filler, not only can have an impact to production process, also can have an impact to the quality stability of preparation.
The invention provides a kind of injection vinorelbine tartrate injectable powder, be made up of vinorelbine tartrate and filler, wherein filler is lactose, preferred α-lactose monohydrate.
Wherein the weight percentage of each component is as follows:
Vinorelbine tartrate 14-25%
α-lactose monohydrate 75-86%.
The present invention also provides a kind of method preparing described injection vinorelbine tartrate injectable powder, and step is as follows:
1. lactose adds water for injection and is stirred to dissolving, is heated to 60 ± 5 DEG C,
2. take the activated carbon adsorption thermal source of lactose solution 0.25% (w/w), lactose solution filters through filter element de-carbon, is cooled to room temperature for subsequent use,
3. the vinorelbine tartrate taking recipe quantity adds the appropriate lactose solution cooled and is stirred to dissolving, injects and complements to full dose with water, and after stirring, sample thief carries out the project such as content, color and detects; Aseptic filtration,
4. the medicinal liquid of filtration is divided and be filled in cillin bottle, then by lyophilizing plug half tamponade on cillin bottle,
5. the sample after half tamponade is transferred to immediately the freeze drying box in freeze dryer, starts lyophilizing program.
Wherein step 1. in the concentration of lactose solution be 4-6g/100ml.
For Pharmaceutical composition, complicated mutual relation is there is, the wherein change of a kind of component, content or its specification, the even change of feed postition between its various ingredients contained, all may form impact to other components, and then affect the character of whole compositions.
In practice, inventor has found following problem:
1, vinorelbine tartrate is met light or heat and is all very easily degraded, should the working condition of first-selected terminal sterilization if therefore follow SFDA guideline in injection production process, but meets the sterilising conditions that F0 value is greater than 8, then can produce the thermal degradation products transfinited; According to high risk sterile filling technique, to packing and placing, conditional request is higher, and the effect duration of product can be limited very greatly; And cryodesiccated technique again after adopting sterile filling, greatly can improve the stability of product and the convenience etc. of transport.
2, lactose is the most frequently used a kind of adjuvant of pharmaceutical field, the present inventor finds in practice, adopt the lactose aqueous solution of 4-6g/100ml to prepare the freeze-dried preparation of vinorelbine tartrate, the formulation aesthetics of gained is good, without subsiding, spraying the bad outward appearance such as bottle, atrophy; The obtained product heavy molten time is less than 30S, and physics and chemistry has good stability.
Inventor has attempted again the multiple lactose such as α-lactose monohydrate, β-Lactis Anhydrous, α-Lactis Anhydrous, unformed lactose and β-lactose monohydrate, found that the freeze-dried products of several lactose is without obvious mass discrepancy, but in several lactose, the stability of α-lactose monohydrate is best, most therefore preferably is α-lactose monohydrate.
In embodiments, the invention provides and comprise 10mg to 20mg, the injection vinorelbine tartrate injectable powder of such as 10mg, 15mg and 20mg, this also stems from the experimental design that different size equal proportion is amplified, so not only be conducive to producing, more be conducive to the multiple choices of different patient, make the compliance of patient better.
Product prepared by the present invention can reach preferably outward appearance, the molten behavior of good weight and be better than the physics and chemistry stability of existing commercialized product.
Detailed description of the invention
Following examples illustrate of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1 (vinorelbine tartrate 14%, α-lactose monohydrate 86%)
1. taking α-lactose monohydrate adds after appropriate water for injection is stirred to dissolving, mends water for injection to enough; Lactose solution is heated to 60 ± 5 DEG C.
Take the active carbon of lactose solution 0.25% (w/w), get appropriate lactose solution and add after active carbon moistening, after stirring insulation 20min, then the active carbon adding second part of equivalent stirs insulation 20min, and absorption terminates.
Lactose solution filters through filter element de-carbon, is cooled to room temperature for subsequent use.
2. the vinorelbine tartrate taking recipe quantity adds the appropriate lactose solution cooled and is stirred to dissolving, complements to full dose, and after stirring, sample thief carries out the project such as content, color and detects; Aseptic filtration.
3. the medicinal liquid of filtration is divided in the cillin bottle being filled to washing and sterilizing, then by lyophilizing plug half tamponade of washing and sterilizing on cillin bottle.
4. the sample after half tamponade is transferred to immediately the freeze drying box in freeze dryer, starts lyophilizing program.
5. the sample of tamponade, through rolling aluminium lid, inspection, labeling and packaging, gets product.
Embodiment 2 (vinorelbine tartrate 20%, α-lactose monohydrate 80%)
1. taking α-lactose monohydrate adds after appropriate water for injection is stirred to dissolving, mends water for injection to enough; Lactose solution is heated to 60 ± 5 DEG C.
Take the active carbon of lactose solution 0.25% (w/w), get appropriate lactose solution and add after active carbon moistening, after stirring insulation 20min, then the active carbon adding second part of equivalent stirs insulation 20min, and absorption terminates.
Lactose solution filters through filter element de-carbon, is cooled to room temperature for subsequent use.
2. the vinorelbine tartrate taking recipe quantity adds the appropriate lactose solution cooled and is stirred to dissolving, complements to full dose, and after stirring, sample thief carries out the project such as content, color and detects; Aseptic filtration.
3. the medicinal liquid of filtration is divided in the cillin bottle being filled to washing and sterilizing, then by lyophilizing plug half tamponade of washing and sterilizing on cillin bottle.
4. the sample after half tamponade is transferred to immediately the freeze drying box in freeze dryer, starts lyophilizing program.
5. the sample of tamponade, through rolling aluminium lid, inspection, labeling and packaging, gets product.
Embodiment 3 (vinorelbine tartrate 25%, α-lactose monohydrate 75%)
1. taking α-lactose monohydrate adds after appropriate water for injection is stirred to dissolving, mends water for injection to enough; Lactose solution is heated to 60 ± 5 DEG C.
Take the active carbon of lactose solution 0.25% (w/w), get appropriate lactose solution and add after active carbon moistening, after stirring insulation 20min, then the active carbon adding second part of equivalent stirs insulation 20min, and absorption terminates.
Lactose solution filters through filter element de-carbon, is cooled to room temperature for subsequent use.
2. the vinorelbine tartrate taking recipe quantity adds the appropriate lactose solution cooled and is stirred to dissolving, complements to full dose, and after stirring, sample thief carries out the project such as content, color and detects; Aseptic filtration.
3. the medicinal liquid of filtration is divided in the cillin bottle being filled to washing and sterilizing, then by lyophilizing plug half tamponade of washing and sterilizing on cillin bottle.
4. the sample after half tamponade is transferred to immediately the freeze drying box in freeze dryer, starts lyophilizing program.
5. the sample of tamponade, through rolling aluminium lid, inspection, labeling and packaging, gets product.
Comparative example 1 utilizes filler disclosed in prior art to prepare vinorelbine freeze-dried powder
Respectively with A: mannitol and tartaric acid, B: dextran and sodium chloride, C: sorbitol, D: citric acid and glucose, do filler, prepares injection vinorelbine tartrate injectable powder according to the consumption of embodiment 1 Chinese medicine and filler and preparation technology.Products obtained therefrom is denoted as A, B, C, D respectively.
Comparative example 2 utilizes difference and sterilization process of the present invention to prepare Vinorelbine injection
Adopt terminal sterilization 115 DEG C/30min, terminal sterilization 121 DEG C/8min and sterile filling technique respectively, with the prescription of embodiment 1, do not add filler lactose, prepare vinorelbine tartrate injection.Products obtained therefrom is denoted as E, F and G respectively.
Comparative example 3 utilizes the lactose solution being different from concentration of the present invention to prepare vinorelbine freeze-dried powder
When lactose solution concentration is higher than 6g/100ml, during as 8g/100ml, there is the bad phenomenon such as crack in the outward appearance of freeze-drying prods.
Embodiment 4 product physical property compares
Visible, utilize the prescription that disclosed in α-lactose monohydrate of the present invention and prior art prepared by filler all can obtain gratifying physical property.
But the lyophilized formulations that also non-appearance meets the demands necessarily has satisfactory stability and safety, for this reason, the present inventor has carried out again following test.
Embodiment 5 (stability test 1)
Sample embodiment prepared and commercialized product (filler is mannitol and tartaric acid) put into 40 DEG C of calorstats and adjustable lighting box (4500Lx ± 500Lx), sample detection after 10 days.Result is as follows:
Visible, when doing filler with mannitol and tartaric acid, dextran and sodium chloride, sorbitol, citric acid and glucose, the related substance of products obtained therefrom (A, B, C and D) all has increase under illumination and hot conditions, and especially Photodegradation Products is all greater than 5%; And the Photodegradation Products of the vinorelbine tartrate aqueous solution (G) of aseptic processing fill is even beyond 10%; The stability of these products all far below the embodiment of the present invention 1,2 and 3 obtain the stability of product.
Embodiment 6 (stability test 2)
The product (E, F) of comparative example 2 is compared with the product of embodiment 1.
Result shows that vinorelbine tartrate injection is all higher through product (E and F) its thermal degradation products of terminal sterilization.Content for impurity limits, and pharmacopoeia of each country is difference slightly, and wherein Chinese Pharmacopoeia specifies that single impurity is less than 0.3%, and Photodegradation Products is less than 0.8%, and total impurities is less than 1.5%.The single impurity level of visible E and F has exceeded the limit of standards of pharmacopoeia, and total impurities is close to the limit of standards of pharmacopoeia, and its stability is much smaller than the stability of freeze-drying prods.
Embodiment 7 safety testing
(1) hemolytic test
The preparation of 2% rabbit erythrocyte suspension: new zealand rabbit heart extracting blood 10ml, put in beaker to stir with bamboo let and remove fibrin, then getting equivalent moves in 2 10ml graduated centrifuge tubes, respectively add normal saline 5ml, centrifugal 15min (1500rpm) after mixing, remove supernatant, then add normal saline cyclic washing 2 times as stated above, to the aobvious redness of supernatant liquid.Become the suspension of 2% (V/V) for subsequent use gained erythrocyte normal saline dilution.
Operating procedure: get 7, test tube, 1-5 pipe adds injection vinorelbine tartrate normal saline dilution liquid 0.1,0.2,0.3,0.4 and 0.5ml respectively, and No. 6 pipes are negative control pipe, and No. 7 pipes are positive control pipe.According to the form below arrangement adds 2% red blood cell suspension, 0.9% sodium chloride injection or sterilized water for injection, need testing solution successively.Each pipe is shaken up gently, to put in thermostatted water incubator 37 ± 0.5 DEG C of insulations 3 hours immediately.After adding need testing solution, 15min, 30min, 45min, 1h, 2h, 3h observe the haemolysis situation of each pipe.Result is charged in corresponding form.
Hemolysis in vitro test application of sample table
Observation index and result judge: when negative control pipe (managing for No. 6) occurs with condensing without haemolysis, when positive control pipe (No. 7 pipes) has haemolysis to occur, if the solution in test sample pipe, in 3 hours, haemolysis and cohesion does not occur, then test sample can inject use; If the solution in test sample pipe, in 3 hours, haemolysis and (or) cohesion occurs, then test sample should not inject use.
Result: at once occur haemolysis after positive control pipe (No. 7 pipes) adds sterilized water for injection; After all the other each pipes add corresponding solution, during 15min, erythrocyte starts to sink, and along with the prolongation of time, the erythrocyte of sinking increases gradually, and during 3h, a large amount of erythrocyte is sunken at the bottom of pipe; Along with the prolongation of time, supernatant increases gradually, and the supernatant of layering is achromatism and clarity.Except No. 7 pipes, all the other each pipes visible red cell after jolting evenly scatters, and proves without red blood cell condensation.
(2) vascular stimulation test
Visual morphological check result:
Injection Vinorelbine monotartrate intravenously administrable 1 time, after administration all there is not any abnormal response in 96h new zealand rabbit left and right ear.Contain the ear-edge tissue of blood vessel when all animals are drawn materials in injection site proximal part 1.5cm to 3cm place clip, visible vessels lines is clear, has no draw materials the position congestion of blood vessel and peripheral tissue edema.
Histopathologic examination's result:
Administration side: rabbit ear edge venous structures is clear, endothelium and blood vessel wall complete, acidophilia's material of Endovascular visible red cell and the red dye of homogenizing, but without thrombosis; Tissues surrounding vascular has no hemorrhage, edema and cell infiltration.
Control sides: rabbit ear edge venous structures is clear, endothelium and blood vessel wall complete, acidophilia's material of Endovascular visible red cell and a small amount of red dye of homogenizing, but without thrombosis, tissues surrounding vascular has no hemorrhage, edema and cell infiltration.
(3) hypersensitive test
Lumbar injection injection Vinorelbine monotartrate next day that this test adopting Cavia porcellus, high, medium and low dosage is respectively 0.2,0.1,0.05mg/ only, administration volume be 0.5ml/ only, totally three sensitization; The 10th day intravenous injection this product solution after last sensitization, high, medium and low dosage is respectively 0.4,0.2,0.1mg/ only, administration volume is 1ml/, excite, there is not any symptoms of allergic in result animal, shows: injection Vinorelbine monotartrate to Cavia porcellus without active whole body sensitization.
Injection Vinorelbine monotartrate group Hypersensitive tests result
Note :-indicate without anaphylaxis ,+indicate anaphylaxis ,+number represent response strength.
Claims (1)
1. an injection vinorelbine tartrate injectable powder, is made up of vinorelbine tartrate and filler, and it is characterized in that filler is α-lactose monohydrate, wherein the weight percentage of each component is as follows:
Vinorelbine tartrate 14-25%
α-lactose monohydrate 75-86%,
Described injection vinorelbine tartrate injectable powder prepares in accordance with the following methods, and described method step is as follows:
1. α-lactose monohydrate adds water for injection and is stirred to dissolving, lactose solution is heated to 60 ± 5 DEG C,
2. take the activated carbon adsorption thermal source of α-lactose monohydrate solution 0.25% (w/w), α-lactose monohydrate solution filters through filter element de-carbon, is cooled to room temperature for subsequent use,
3. the vinorelbine tartrate taking recipe quantity adds the α-lactose monohydrate solution stirring of appropriate cooling to dissolving, and complements to full dose, and after stirring, sample thief carries out content, color project detects; Aseptic filtration,
4. the medicinal liquid of filtration is divided and be filled in cillin bottle, then by lyophilizing plug half tamponade on cillin bottle,
5. the sample after half tamponade is transferred to immediately the freeze drying box in freeze dryer, starts lyophilizing program, wherein step 1. in the concentration of α-lactose monohydrate solution be 4-6g/100ml.
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| CN101534821A (en) * | 2006-12-29 | 2009-09-16 | 皮埃尔法布雷医药公司 | Freeze-dried injectable pharmaceutical combination of semisynthetic vinca alkaloids and carbohydrate stable at room temperature |
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| CN1437942A (en) * | 2003-02-08 | 2003-08-27 | 杭州华卫制药技术开发有限公司 | Vinorebin powder injection and preparation method |
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Effective date of registration: 20211215 Address after: No. 226, Huanghe Avenue, hi tech Zone, Shijiazhuang City, Hebei Province 050035 Patentee after: Jushi biopharmaceutical Co.,Ltd. Address before: No. 226 the Yellow River Avenue, Shijiazhuang, Hebei Province, Hebei Patentee before: CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co.,Ltd. |