CN101143134A - Dexrazoxane freezing-dried powder injection and preparation method thereof - Google Patents
Dexrazoxane freezing-dried powder injection and preparation method thereof Download PDFInfo
- Publication number
- CN101143134A CN101143134A CNA200710133249XA CN200710133249A CN101143134A CN 101143134 A CN101143134 A CN 101143134A CN A200710133249X A CNA200710133249X A CN A200710133249XA CN 200710133249 A CN200710133249 A CN 200710133249A CN 101143134 A CN101143134 A CN 101143134A
- Authority
- CN
- China
- Prior art keywords
- dexrazoxane
- temperature
- preparation
- hydrochloric acid
- dried powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a dexrazoxane freeze-dried powder injection and the preparation method. The preparation is used for resisting the cardiac toxicity which is induced by the cumulate quantity of adriamycin. The dexrazoxane freeze-dried powder injection contains the active components of the dexrazoxane and hydrochloric acid, the weight proportion of which is 1 to 0.05 to 0.5, and the preferential proportion is 1 to 0.2 to 0.5. The preparation method is that the hydrochloric acid is put into an aseptic vessel; the water for injecting is added till 80 percent of the preparation quantity, and the temperature is reduced and kept at 2 to 6 DEG C; the dexrazoxane is added to be mixed, and the hydrochloric acid of 1.0mol/L is dripped slowly into the solution to be solved while mixing the solution; the water for injecting is added till the full quantity; active carbon of 0.3 percent is added for absorbing for thirty minutes, and then the solution is decarbonized; after the medium body content is mensurated as being eligible, the solution is filtered by a 0.22 micron-micropore filtering filer; the filtrate is filled into a 25ml cillin bottle according to the filling quantity of 10ml each bottle, and the bottles are partially plugged by buna plugs and filled onto a plate to be sent into a freeze-drying box; a temperature probe is inserted, and the box door is closed; the filtrate is warmed, sublimed and dried be stages; nitrogen is puffed; the plugs are pressed; the filtrate is taken out from the box for rolling the openings, detecting the quality and packaging and the preparation can be obtained.
Description
Technical field
The present invention relates to a kind of dexrazoxane freezing-dried powder injection and preparation method thereof, said preparation is used to resist the inductive cardiac toxicity of amycin cumulant, provides clinical under safety preferably, allow to use more heavy dose of amycin and more treatment course of treatment.
Background technology
Anthracycline antibiotics (antracycline antibiotics) is an antineoplastic agent commonly used clinically.Daunorubicin is the first generation, and amycin is the second filial generation, now manually semi-synthetic numerous congener such as epirubicin, 4 '-deoxidation amycin etc.Mitoxantrone then is the anthracycline compound of synthetic.Be mainly used in acute and chronic leukemia, malignant lymphoma clinically, also be used for the combined chemotherapy of gastric cancer, small cell lung cancer, ovarian cancer, breast carcinoma etc.But the side effect such as this class medicine such as amycin toxicity are big, nauseating except that producing, vomiting, bone marrow depression, also can cause relevant cardiac toxicity, this toxicity has limited its clinical practice.
Dexrazoxane is two lactim compounds, and 1970 synthetic by Creighton, is a kind of strong cell internal crosslinker.Herman EH in 1972 etc. are by finding that to the dog heart pharmacological testing that exsomatizes dexrazoxane has protective effect to heart; after having carried out the mammalian toxicity research of a series of different generas; carry out clinical trial; by in early days, at random, the contrast clinical research; statistics had the above cancer patient's (mainly being breast carcinoma, soft tissue sarcoma etc.) of 1500 examples to confirm that 90% can reduce and the inductive cardiac toxicity of dexrazoxane coupling amycin approximately in 1996, showed as left ventricular ejection time (LVET) prolongation and heart failure incidence rate and descended.Do not influence the anti-tumor activity of amycin.Do not increase new toxicity, the dexrazoxane that studies show that of pharmacokinetics does not change the distribution of amycin, paclitaxel, metabolism and drainage yet.Dexrazoxane can resist the inductive cardiac toxicity of amycin cumulant, provides clinical under safety preferably, allow to use more heavy dose of amycin and more treatment course of treatment.
Because the dexrazoxane poor stability is especially unstable under the solution state, need make lyophilized formulations, but how to guarantee that the stability in lyophilized formulations itself and the preparation process is the problem that a needs solves.External dexrazoxane lyophilized formulations pinkiness, the dexrazoxane lyophilized formulations that we adopt common lyophilizing preparation technology preparation is pinkiness also, and after measured, related substance significantly rises.Higher impurity (related substance) may bring potential toxic and side effects, thereby causes the hidden danger of clinical drug safety aspect.Therefore, how to prepare the better dexrazoxane lyophilized formulations of stability is the problem that people attempt to solve always.
Summary of the invention
The objective of the invention is provides a kind of dexrazoxane freezing-dried powder injection and preparation method thereof at above weak point, dexrazoxane freezing-dried powder injection by the present invention's preparation, do not need to add extra stabilizing agent, by the proper pH value of control medicinal liquid and precisely control process parameters guaranteed the stability of dexrazoxane freezing-dried powder injection, guarantee clinical drug safety.
Want to solve the stable problem of dexrazoxane freezing-dried powder injection, not only need rationally to set prescription,, more need precisely to control producing each stage process parameter at the unsettled a plurality of factors of dexrazoxane.The present invention is directed to the unsettled characteristics of dexrazoxane solution, in process for preparation, make stable acidity and cryogenic solution environmental earlier, add dexrazoxane again, guaranteed dexrazoxane stablizing from be formulated into the whole process of fill.Ensuing freeze-drying process, the present invention adopts distinctive low-temperature quick-freezing, sublimation drying stage by stage heats up, the freeze drying process of (10 ℃) parsing-desiccation under the lower temperature, the lyophilizing of gained dexrazoxane is shaped good, has obtained the good crystal formation of the more conventional lyophilizing crystallization of stability, and water content is low, favourable stable transportation and storage have thoroughly solved the stable problem of dexrazoxane freezing-dried powder injection.
A kind of dexrazoxane freezing-dried powder injection and preparation method thereof is to adopt following scheme to realize:
A kind of dexrazoxane freezing-dried powder injection contains active component dexrazoxane and hydrochloric acid, and the weight proportion of dexrazoxane and hydrochloric acid is 1: 0.06～0.5.
The weight proportion of described dexrazoxane and hydrochloric acid is preferably 1: 0.2～and 0.5.
Described dexrazoxane freezing-dried powder injection, the chemical name of dexrazoxane is: (s)-(+)-4, and 4 '-(1-methyl 1,2-ethanetetrayl)-two (2, the 6-piperazinedione), structural formula is:
Molecular formula is: C
11H
16N
4O
4Molecular weight is: 268.28.
The preparation method of described dexrazoxane freezing-dried powder injection, its preparation method is:
Get hydrochloric acid and put sterile chamber, add injection water to 80% amount of preparation, cooling and insulation are between 2～6 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add to the full amount of water for injection, add 0.3% activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ to make product temperature (being products temperature) decline, when the product temperature reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 4～6 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing;
The weight proportion of described dexrazoxane and hydrochloric acid is 1: 0.06～0.5.
The weight proportion of described dexrazoxane and hydrochloric acid is preferably 1: 0.2～and 0.5.
A kind of dexrazoxane freezing-dried powder injection of the present invention does not need to add extra stabilizing agent by this scheme, adjuvant still less have still less incompatibility and the clinical drug safety of Geng Gao.At the unsettled characteristics of dexrazoxane solution, in process for preparation, make stable acidity and cryogenic solution environmental earlier, add dexrazoxane again, guaranteed dexrazoxane stablizing from be formulated into the whole process of fill.Ensuing freeze-drying process, adopt distinctive low-temperature quick-freezing, sublimation drying stage by stage heats up, the freeze drying process of (10 ℃) parsing-desiccation under the lower temperature, the lyophilizing of gained dexrazoxane is shaped good, invariant color, obtained the good crystal formation of the more conventional lyophilizing crystallization of stability, water content is low, and favourable stable transportation and storage have thoroughly solved the stable problem of dexrazoxane freezing-dried powder injection.In a word, the present invention has improved the stability of dexrazoxane freezing-dried powder injection in preparation process greatly, and the dexrazoxane freezing-dried powder injection impurity (its related substances) of preparation gained is lower, and the quality stable homogeneous is stored and transport convenient.Preparation technology of the present invention is simple, convenient feasible, good reproducibility is easy to realize industrialized great production, and freeze-drying time is short, percent defective (variable color) is low, lamp inspection inspection rejects difficulty is low, saves manpower, short production cycle, lower percent defective and lower human cost, production cost is reduced significantly, can produce considerable economic and social benefit.
The specific embodiment
Further specify the present invention below by embodiment.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:
Prescription
Dexrazoxane 250g
Concentrated hydrochloric acid 37ml
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get concentrated hydrochloric acid and put sterile chamber, add the injection water to 80000ml, cooling and insulation are at 4 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add the injection water to 10000ml, added the 30g activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when the product temperature reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 5 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing promptly.
Embodiment 2:
Prescription
Dexrazoxane 250g
Concentrated hydrochloric acid 120ml
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get concentrated hydrochloric acid and put sterile chamber, add the injection water to 80000ml, cooling and insulation are at 2 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add the injection water to 10000ml, added the 30g activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when the product temperature reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 4 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing promptly.
Embodiment 3:
Prescription
Dexrazoxane 250g
Concentrated hydrochloric acid 310ml
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get concentrated hydrochloric acid and put sterile chamber, add the injection water to 80000ml, cooling and insulation are between 6 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add the injection water to 10000ml, added the 30g activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when the product temperature reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 6 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing promptly.
Embodiment 4:
Prescription
Dexrazoxane 250g
Concentrated hydrochloric acid 200ml
Water for injection adds to 10000ml
Make 1000 bottles altogether
Get concentrated hydrochloric acid and put sterile chamber, add the injection water to 80000ml, cooling and insulation are between 4 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add the injection water to 10000ml, added the 30g activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when sample reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 5 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing promptly.
Embodiment 5:
The dexrazoxane freezing-dried powder injection determination of related substances
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2005 version two ones)
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-0.01mol/L potassium dihydrogen phosphate (15: 85) is mobile phase; The detection wavelength is 208nm.Number of theoretical plate calculates by the dexrazoxane peak should be not less than 3000.
It is an amount of to get the dexrazoxane freezing-dried powder injection content, add mobile phase dissolving and dilution and make need testing solution and the contrast solution that contains 200 μ g and 3 μ g among every 1ml, according to the chromatographic condition under the assay item, get contrast solution 20 μ l and inject chromatograph of liquid, regulate detector sensitivity, its main constituent peak height is the 20-30% of full scale, and precision is measured need testing solution and each 20 μ l of contrast solution again, inject chromatograph of liquid respectively, the record chromatogram is to 3 times of the main peak retention time.If any impurity peaks, measure each impurity peak area summation except that the adjuvant peak in the chromatogram of need testing solution, calculate and promptly get dexrazoxane freezing-dried powder injection related substance percentage composition.
Embodiment 6:
The dexrazoxane freezing-dried powder injection assay
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2005 version two ones)
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-0.01mol/L potassium dihydrogen phosphate (15: 85) is mobile phase; The detection wavelength is 208nm.Number of theoretical plate calculates by the dexrazoxane peak should be not less than 3000.
Get the dexrazoxane freezing-dried powder injection content, mixing, precision takes by weighing in right amount (being equivalent to dexrazoxane 20mg), adds the mobile phase dissolving and is diluted to the solution that contains 20 μ g among every 1ml, shakes up, as need testing solution; It is an amount of that other gets the dexrazoxane reference substance, the accurate title, decide, add the mobile phase dissolving and be diluted to the solution that contains 20 μ g among every 1ml approximately, product solution in contrast, measure each 20 μ l of above-mentioned two kinds of solution respectively, inject chromatograph of liquid, the record chromatogram, with calculated by peak area, promptly get the content of dexrazoxane freezing-dried powder injection by external standard method.
Embodiment 7:
The dexrazoxane freezing-dried powder injection determination of water
Get the dexrazoxane freezing-dried powder injection content, measure according to aquametry (Chinese Pharmacopoeia 2005 version two ones).
Embodiment 8:
Get described dexrazoxane freezing-dried powder injection, by embodiment 5, embodiment 6, and embodiment 7 quicken to place under (40 ℃ ± 2 ℃, RH75% ± 5%) and long-term (25 ℃ ± 2 ℃, RH60% ± 10%) condition and carry out the stability test investigation, experimental result sees Table 1, table 2.
Table 1 injection dexrazoxane accelerated test is investigated the result
| Batch | Standing time (moon) | Character | Dissolving color and clarity | pH | Content (%) | Moisture (%) | Related substance (HPLC, %) |
| 1 | 0 1 2 3 6 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.34 3.36 3.38 3.35 3.35 | 101.4 101.8 101.4 101.2 101.6 | 1.75 1.83 1.82 1.85 1.91 | 0.94 0.91 0.86 0.82 1.11 |
| 2 | 0 1 2 3 6 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.39 3.36 3.37 3.36 3.36 | 100.4 100.1 100.2 100.2 100.3 | 2.13 2.11 2.25 2.31 2.24 | 0.99 0.96 0.83 0.83 1.27 |
| 3 | 0 1 2 3 6 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.42 3.34 3.36 3.35 3.36 | 99.44 99.62 99.41 99.56 99.70 | 1.98 2.01 2.14 2.08 2.09 | 1.13 0.98 0.93 0.87 1.22 |
Table 2 injection dexrazoxane long term test is investigated the result
| Batch | Standing time (moon) | Character | Dissolving color and clarity | pH | Content (%) | Moisture (%) | Related substance (HPLC, %) |
| 1 | 0 1 3 6 9 12 18 24 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.34 4.35 4.37 4.35 4.38 4.32 4.30 4.36 | 101.4 101.6 101.5 101.2 101.3 101.4 101.5 101.1 | 1.75 1.85 1.89 2.01 1.99 2.13 2.24 2.31 | 0.94 0.93 0.76 0.95 1.01 1.02 1.01 1.14 |
| 2 | 0 1 3 6 9 12 18 24 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.39 4.38 4.39 4.40 4.41 4.37 4.38 4.42 | 100.4 100.5 100.5 100.6 100.2 100.2 100.4 100.2 | 2.13 2.18 2.22 2.24 2.31 2.37 2.38 2.41 | 0.99 0.89 0.92 0.93 0.99 1.01 1.00 1.15 |
| 3 | 0 1 3 6 9 12 18 24 | Class color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and powdery type color loose block and loose bulk of powdery type color and powder | The faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of the faint yellow clarification of faint yellow clarification | 4.42 4.41 4.43 4.44 4.45 4.40 4.41 4.42 | 99.44 99.30 99.76 99.66 99.51 99.40 99.28 99.36 | 1.98 1.86 2.15 2.29 2.35 2.39 2.45 2.41 | 1.13 1.01 0.86 1.00 1.00 1.06 1.08 1.03 |
Result of the test shows, described dexrazoxane freezing-dried powder injection was placed 6 months through accelerated test (40 ℃ ± 2 ℃, RH75% ± 5%), kept sample 6 months through long term test (25 ℃ ± 2 ℃, RH60% ± 10%), every investigation index, relatively have no significant change before comprising the color of character, solution and clarity, acidity, content, related substance, moisture etc. and placing, steady quality is reliable.
Embodiment 9:
Get described dexrazoxane freezing-dried powder injection through Beijing Tumour Hospital, attached first hospital of Xi'an Communications University and Sichuan Tumor Hospiatal's clinical research, dexrazoxane freezing-dried powder injection and amycin coupling according to the technical solution of the present invention preparation can reduce by the inductive cardiac toxicity of amycin, show as left ventricular ejection fraction and prolong.Do not influence the anti-tumor activity of amycin, do not increase new toxicity yet.
Multicenter study shows, treating cardiac toxicity that breast carcinoma and malignant lymphoma cause by amycin according to the dexrazoxane freezing-dried powder injection of technical solution of the present invention preparation and amycin use in conjunction, to send out rate be 0%, and the cardiac toxicity that amycin treatment breast carcinoma and malignant lymphoma are caused by amycin is sent out rate and is 8.33%, two group obvious significant difference (P＜0.05) is relatively arranged.So the dexrazoxane freezing-dried powder injection according to the technical solution of the present invention preparation can obviously be protected the cardiac toxicity that is caused by amycin.
According to the dexrazoxane freezing-dried powder injection and the amycin use in conjunction of technical solution of the present invention preparation, the untoward reaction of the generation no obvious significant difference (P〉0.05) of comparing with the amycin group.
Claims (5)
1. a dexrazoxane freezing-dried powder injection is characterized in that containing active component dexrazoxane and hydrochloric acid, and the weight proportion of dexrazoxane and hydrochloric acid is 1: 0.06～0.5.
2. dexrazoxane freezing-dried powder injection according to claim 1, it is characterized in that the weight proportion of dexrazoxane and hydrochloric acid is preferably 1: 0.2～0.5.
3. dexrazoxane freezing-dried powder injection according to claim 1 is characterized in that the chemical name of described dexrazoxane is: (s)-(+)-4,4 '-(1-methyl 1,2-ethanetetrayl)-two (2, the 6-piperazinedione), structural formula is:
Molecular formula is: C
11H
16N
4O
4Molecular weight is: 268.28.
4. the preparation method of the described dexrazoxane freezing-dried powder injection of claim 1 is characterized in that its preparation method is:
Get hydrochloric acid and put sterile chamber, add injection water to 80% amount of preparation, cooling and insulation are between 2～6 ℃, add dexrazoxane, stir evenly, under agitation slowly drip 1.0mol/L hydrochloric acid to dissolving, add to the full amount of water for injection, add 0.3% activated carbon adsorption 30 minutes, take off charcoal, after mensuration intermediate content is qualified, with 0.22 μ m filtering with microporous membrane, filtrate is pressed the loading amount fill of every bottle of 10ml in the 25ml cillin bottle, part is the fourth rubber stopper beyond the Great Wall, and sabot is sent in the freeze drying box, insert temperature probe, close chamber door, open freeze dryer in advance, utilize conduction oil that flaggy is freezed, reach-40～-45 ℃ until the flaggy temperature, rapidly the dexrazoxane solution of fill in aseptic cillin bottle is sent into freeze dryer, close chamber door, and keep flaggy temperature-40～-45 ℃ that the product relaxing the bowels with purgatives of warm nature is fallen, when the product temperature reaches-40 ℃, stop board is cold, the open cold condenser, and utilization is simultaneously mixed cold continuation and was kept this product temperature 3 hours, when condenser temperature reaches-40 ℃, open vacuum system, insulation begins the distillation that heats up stage by stage after finishing, and the phase I distillation rises to the flaggy temperature-20 ℃ rapidly, therebetween with preceding case vacuum control between 15～20Pa, beginning second stage distillation rises to 0 ℃ with the flaggy temperature rapidly after 10 hours, therebetween with preceding case vacuum control between 15～20Pa, beginning phase III distillation after 10 hours, rapidly the flaggy temperature is risen to 20 ℃, therebetween with preceding case vacuum control between 10～15Pa, when the product temperature reach 10 ℃ the beginning parsing-desiccations, the flaggy temperature is controlled to be 10 ℃, vacuum is not controlled, and keeps this temperature 4～6 hours, after the case vacuum does not have after the obvious decline before valve in closing, inflated with nitrogen, tamponade, outlet rolls mouth, quality inspection, packing;
The weight proportion of described dexrazoxane and hydrochloric acid is 1: 0.06～0.5.
5. the preparation method of dexrazoxane freezing-dried powder injection according to claim 4, it is characterized in that the weight proportion of dexrazoxane and hydrochloric acid is preferably 1: 0.2～0.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710133249XA CN101143134A (en) | 2007-10-15 | 2007-10-15 | Dexrazoxane freezing-dried powder injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710133249XA CN101143134A (en) | 2007-10-15 | 2007-10-15 | Dexrazoxane freezing-dried powder injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101143134A true CN101143134A (en) | 2008-03-19 |
Family
ID=39205991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710133249XA Pending CN101143134A (en) | 2007-10-15 | 2007-10-15 | Dexrazoxane freezing-dried powder injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101143134A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103393609A (en) * | 2013-07-31 | 2013-11-20 | 江苏奥赛康药业股份有限公司 | Dexrazoxane-containing composition and preparation method thereof, and dexrazoxane freeze-drying preparation and redissolving solvent thereof |
| CN104173297A (en) * | 2013-05-27 | 2014-12-03 | 北京星昊医药股份有限公司 | Dexrazoxane freeze-dried powder injection and preparation method thereof |
| CN108226309A (en) * | 2016-12-13 | 2018-06-29 | 江苏奥赛康药业股份有限公司 | A kind of analysis method of dexrazoxane |
| CN108619153A (en) * | 2017-03-20 | 2018-10-09 | 江苏奥赛康药业股份有限公司 | Composition containing dexrazoxane and its lyophilized preparation |
| CN109497960A (en) * | 2012-07-10 | 2019-03-22 | 贝克顿迪金森法国两合公司 | Integrated injecting systems, integrated injection device and the method for monitoring injection event |
| CN114306251A (en) * | 2021-12-22 | 2022-04-12 | 乐普药业股份有限公司 | Freeze-dried preparation containing dexrazoxane and preparation method thereof |
| CN114983948A (en) * | 2022-06-14 | 2022-09-02 | 郑州市中心医院 | Pharmaceutical composition containing creatine phosphate sodium and preparation method thereof |
-
2007
- 2007-10-15 CN CNA200710133249XA patent/CN101143134A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109497960A (en) * | 2012-07-10 | 2019-03-22 | 贝克顿迪金森法国两合公司 | Integrated injecting systems, integrated injection device and the method for monitoring injection event |
| CN109497960B (en) * | 2012-07-10 | 2021-06-25 | 贝克顿迪金森法国两合公司 | Integrated injection system, integrated injection device and method of monitoring an injection event |
| US11172877B2 (en) | 2012-07-10 | 2021-11-16 | Becton Dickinson France S.A.S. | Integrated injection system and communication device |
| CN104173297A (en) * | 2013-05-27 | 2014-12-03 | 北京星昊医药股份有限公司 | Dexrazoxane freeze-dried powder injection and preparation method thereof |
| CN103393609A (en) * | 2013-07-31 | 2013-11-20 | 江苏奥赛康药业股份有限公司 | Dexrazoxane-containing composition and preparation method thereof, and dexrazoxane freeze-drying preparation and redissolving solvent thereof |
| CN108226309A (en) * | 2016-12-13 | 2018-06-29 | 江苏奥赛康药业股份有限公司 | A kind of analysis method of dexrazoxane |
| CN108226309B (en) * | 2016-12-13 | 2020-06-16 | 江苏奥赛康药业有限公司 | Analysis method of dexrazoxane |
| CN108619153A (en) * | 2017-03-20 | 2018-10-09 | 江苏奥赛康药业股份有限公司 | Composition containing dexrazoxane and its lyophilized preparation |
| CN114306251A (en) * | 2021-12-22 | 2022-04-12 | 乐普药业股份有限公司 | Freeze-dried preparation containing dexrazoxane and preparation method thereof |
| CN114306251B (en) * | 2021-12-22 | 2023-08-11 | 乐普药业股份有限公司 | Freeze-dried preparation containing dexrazoxane and preparation method thereof |
| CN114983948A (en) * | 2022-06-14 | 2022-09-02 | 郑州市中心医院 | Pharmaceutical composition containing creatine phosphate sodium and preparation method thereof |
| CN114983948B (en) * | 2022-06-14 | 2023-06-23 | 郑州市中心医院 | Pharmaceutical composition containing creatine phosphate sodium and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100396276C (en) | Compositions containing organic compounds | |
| CN101143134A (en) | Dexrazoxane freezing-dried powder injection and preparation method thereof | |
| CN101411710B (en) | Pemetrexed disodium freeze-dried injection and preparation method thereof | |
| CN102274195B (en) | Oxiracetam freeze-dried powder preparation and preparation method thereof | |
| CN108853032B (en) | A kind of injection fluorouracil composition freeze-drying pulvis | |
| CN100506213C (en) | Lansoprazole freeze-dried powder for injection and preparing method thereof | |
| CN102258531B (en) | Medicinal composition containing adenosine cyclophosphate and meglumine and preparation method thereof | |
| CN101584668A (en) | Bendamustine hydrochloride freeze-dried powder injection | |
| CN103251565A (en) | Voriconazole freeze-dried powder injection for injection and preparation method thereof | |
| CN101756897B (en) | Clindamycin hydrochloride injection and preparation method thereof | |
| CN101897666B (en) | Pazufloxacin mesilate injection preparation and detection method thereof | |
| CN102525963A (en) | Netilmicin sulfate lyophiled powder injection and preparation method thereof | |
| CN110812334A (en) | Voriconazole pharmaceutical composition for injection and preparation method thereof | |
| CN101940557B (en) | Method for preparing fat-soluble vitamin freeze-dried powder injection | |
| CN101904862B (en) | Water-soluble vitamin composition freeze-drying preparation for injection | |
| CN103040855B (en) | Pharmaceutical composition of fludarabine phosphate and preparation method thereof | |
| CN103265561A (en) | Azlocillin sodium compound, preparation method and medicine composition thereof | |
| CN104771369B (en) | A kind of Fludarabine phosphate freeze-dried powder injection | |
| CN100506212C (en) | Sodium-NCTD freeze-dried powder for injection and preparing method thereof | |
| CN102274185A (en) | Antitumor pH-sensitive liposome and freeze-dried powder injection thereof, and preparation methods thereof | |
| CN103980279A (en) | Methotrexate compound and methotrexate for injection | |
| CN100591330C (en) | Freezing-dried clofarabine powder injection and its preparation method | |
| CN101081211A (en) | Water indissoluble carbostyrile compound injection and method for preparing the same | |
| CN108992413B (en) | Pemetrexed disodium freeze-dried powder injection and preparation method thereof | |
| CN102813631B (en) | Method for preparing phentolamine mesilate freeze-drying powder injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080319 |