CN101229167B - Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines - Google Patents
Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines Download PDFInfo
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- CN101229167B CN101229167B CN2008100469199A CN200810046919A CN101229167B CN 101229167 B CN101229167 B CN 101229167B CN 2008100469199 A CN2008100469199 A CN 2008100469199A CN 200810046919 A CN200810046919 A CN 200810046919A CN 101229167 B CN101229167 B CN 101229167B
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Abstract
The invention provides a preparation method of medical left folinic acid sodium and an application in preparation of tumor treatment medicine, relating to a preparation method of the medical left folinic acid sodium in tumor treatment medicine preparation. Two preparation methods of the medical left folinic acid sodium are that: firstly, the left folinic acid sodium of prescription dosage are weighed, water for injection is added to prepare a suspension solution, sodium hydroxide solution (or sodium carbonate, sodium bicarbonate solution) is added, the suspension solution is stirred for total dissolution, and then at least one supplement containing mannitol, dextran, glucose, sodium chloride or protein hydrolysate is added; the injecting agents comprise the dried powder injection and the directly prepared liquid formulation. Secondly, the left folinic acid sodium of prescription dosage are weighed, water for injection is added, and at least one supplement containing mannitol, dextran, glucose, sodium chloride or protein hydrolysate are added and stirred for total dissolution to prepare the solution; the injecting agents comprise the dried powder and the directly prepared liquid formulation. The left folinic acid sodium is applied in preparing medicine of tumor treatment.
Description
Technical field
The present invention relates to a kind of preparation method that is used to prepare the medicine sodium levofolinate of medicine for treating tumor thing.
Background technology
Calcium levofolinate is the laevoisomer of calcium folinate, calcium levofolinate is at first succeeded in developing by U.S.'s Hui Shi drug company, at first went on the market in 1994 in Britain, be mainly used in anti-anemia and the detoxifcation antagonist in tumor pharmacother, now comprising the listing of 10 several countries such as Italy, Canada, Japan, South Africa, Finland, Iceland, its preparation has tablet, aqueous injection and lyophilized injection, and recorded by " European Pharmacopoeia ", external clinical practice has fully confirmed the safety and effectiveness of this medicine.
Another form of folinic acid is the dl body, i.e. dl-LV, and the dl body can not utilize in vivo, just in order to postpone LV metabolism in vivo, it is retained for a long time, and reduces L body metabolic pathway in vivo, and weakens the effect of L body.L-leucovorin does not need can be participated in the reaction that utilizes folate to originate as one carbon unit by the dihydrofolate reductase reduction, and l-leucovorin can pass through cell membrane actively or passively, l-leucovorin basic role is identical with folic acid, but effect is better than folic acid, just can work because folic acid becomes folinic acid earlier in liver and bone marrow, and this product is the activity form of folinic acid.
The active component of calcium folinate is a folinic acid, and calcium ion does not have pharmacological action, and activity is not had help.The calcium salt water solublity is less, is difficult for making the preparation of high concentration, is restricted on usage and dosage; The clinical research data report is arranged, and 5-FU merges in the calcium folinate therapeutic process, has 50% the tube for transfusion clogging has taken place; On the other hand, calcium ion concentration too high in the blood plasma may cause unnecessary side effect, thereby calcium folinate usually needs slow instillation.Sodium folinate injection went on the market in Britain in 2000, and its active component is the same with calcium folinate, is all folinic acid.But sodium salt good water-solubility and biocompatibility make it to become the succedaneum of calcium folinate.
At present both at home and abroad listing has, and calcium folinate, calcium levofolinate and leucovorin sodium do not use the report of sodium levofolinate.
Summary of the invention
The objective of the invention is at above-mentioned present situation, aim to provide a kind of preparation method and the application in preparation medicine for treating tumor thing of medicine sodium levofolinate.
The implementation of the object of the invention is, the preparation method of medicine sodium levofolinate takes by weighing at least a adjuvant in mannitol, dextran, glucose, sodium chloride, the hydrolyzed protein, adds in the water for injection to dissolve, add 0.3% active carbon and boiled 20 minutes, filter carbon removal; Keep filling under nitrogen (or not filling nitrogen) state, add water for injection, stir adding sodium levofolinate down at mixer, make dissolving fully, the control pH value adds 0.05% active carbon again between 7.0-8.0, stirred 15 minutes, and filtered carbon removal, mix with the adjuvant that takes off charcoal, to clarification,, add water for injection through the 0.8u filtering with microporous membrane to aequum again through the 0.22u filtering with microporous membrane, stir, mixing is measured intermediate content, and is aseptic and fill packing or aseptic subpackaged after drying under the nitrogen.Sodium levofolinate is counted 25-250mg with folinic acid in every injection, and the weight proportion of sodium levofolinate and adjuvant is 1: 0.1-1: 20.
The application of medicine sodium levofolinate in preparation medicine for treating tumor thing, sodium levofolinate is used to prepare the medicine for the treatment of tumor.
Sodium levofolinate of the present invention has solved that calcium ion does not have pharmacological action in the calcium folinate, the easily unnecessary side effect that the tube for transfusion clogging takes place and bring, it is made up of a large amount of sodium ion that exist, that have good water-solubility in effective levo form and the body, make treatment more effectively, use safer, it is prepared into injectable powder and injection, has rapid, the rapid-action characteristics of effect.
The specific embodiment
The preparation method of medicine sodium levofolinate of the present invention has two kinds:
One of method, take by weighing the l-leucovorin of recipe quantity, add water for injection and make suspension, hydro-oxidation sodium solution (or sodium carbonate, sodium bicarbonate solution) stir make molten entirely, add at least a adjuvant that contains mannitol, dextran, glucose, sodium chloride, hydrolyzed protein, injection medicament comprises injectable powder after super-dry and the liquor of directly producing.
Method two, take by weighing the sodium levofolinate of recipe quantity, add water for injection, add at least a adjuvant that contains mannitol, dextran, glucose, sodium chloride, hydrolyzed protein again, stirring makes the complete molten solution of making, and injection medicament comprises injectable powder after super-dry and the liquor of directly producing.
The applicant has made pharmacodynamics test to folinic acid:
Folinic acid has obtained the confirmation of testing by strengthening the biochemical action of the inhibition of adenylic acid synzyme (TS) being regulated 5-FU continuously; The synergism of folinic acid and 5-FU drug combination realizes in the in vitro tests that comprises human various tumor cell lines that folinic acid isomer (6S and 6R) has obtained dose-effect relationship to the antitumor enhanced activity of 5-FU at the HCT-8 cell.The growth of 1nM (l)-folinic acid sustenticular cell, and (d)-isomer do not support.After cell was handled 24 hours with (l)-folinic acid, the increase along with the concentration of (l)-folinic acid can reduce 50% of 5-FU inhibition concentration.But (d)-folinic acid of 200umM is to the not influence of cell toxicant of 5-FU.
Suffering from the synergism that can observe medicine on the mice of colon cancer, but suffer from leukemia or late period CD8F1 breast carcinoma mice on do not observe.Further test shows that the folinic acid (180mg/kg/ days, 1-8 days) of high dose is converted into 5, and 10-methylene H4PteGlu accumulates in the mice EMT6 breast cancer cell, rather than bone marrow.The folinic acid administration is 2 hours before 5-FU (30mg/kg/ days, the 1-5 days) medication, compares with the single medicine of 5-FU, can obviously suppress tumor growth.The use of folinic acid does not have to increase the toxicity to the host.
The applicant has done pharmacological toxicology research to sodium levofolinate:
Get 6 of healthy guinea pigs, continuous 3 lumbar injection sodium levofolinate 1.25mg/ only are divided into it two groups then, 3 every group, from vena femoralis injection sodium levofolinate 2.5mg/ are only injecting back 14 days for the first time for first group; Second group in from vena femoralis injection sodium levofolinate 2.5mg/ only injecting for the first time back 21 days, the reaction that produces in the 15min after the observation administration.Reactions such as perpendicular hair, dyspnea, sneeze, retch, cough all do not appear in 6 Cavia porcelluss as a result, do not have phenomenons such as tic, collapse or death yet.
Rabbit injection 0.1-0.5ml (2.5mg/ml) does not produce haemolysis and cohesion to erythrocyte in 4h.Injection 2.5mg/ml l-leucovorin sodium solution 1ml in the rabbit bilateral quadriceps femoris muscle, establishing sodium chloride injection is matched group.Behind the administration 48h, pathological changes such as hyperemia, degeneration, necrosis all do not appear in 4 quadriceps femoris of 2 rabbit of perusal medicine group.Histopathological examination shows: the matched group organizational structure is normal, and muscle fiber is not seen morphological changes such as degeneration, necrosis, does not also see morphological changes such as inflammation between muscle in the matter.As seen a small amount of chronic inflammation cellular infiltration.Medicine group organizational structure is normal, and muscle fiber is not seen morphological changes such as degeneration, necrosis.Between muscle in the matter visible part chronic inflammation cell be kitchen range shape and strip and soak into.
Rabbit auricular vein injection 2.5mg/kg, the result shows, nonirritant.
By above evidence, leucovorin sodium and anti-tumor medicine have synergism, no cytotoxicity, injection nonirritant.It is an adjuvant therapy medicaments of tumor safely and effectively.
Enumerate specific embodiments of the invention below, but the invention is not restricted to these embodiment:
Example 1, l-leucovorin sodium freeze-dried powder injection
1 (specification: every contains sodium levofolinate in folinic acid 50mg) of prescription takes by weighing 25g lyophilizing skeleton agent mannitol and adds in the water for injection of 125ml and dissolve, and adds 0.3% active carbon and boils 20 minutes, filters carbon removal; Take by weighing the 50g l-leucovorin and add in 60 ℃ the 400m water for injection and make suspension, Dropwise 5 %NaOH stirs and makes dissolving, and mix with the mannitol that takes off charcoal, the control pH value adds 0.05% active carbon again between 7.0-8.0, stirred 15 minutes, filter carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, put cold, add water for injection to 600ml, stir mixing.Measure intermediate content, aseptic subpackaged in 1000 cillin bottles, determine the about 0.6ml of loading amount according to the intermediate measurement result for every bottle, the false add plug, send the freeze dryer lyophilization, cover tight plug, roll aluminium lid, the packing of labelling.
Write out a prescription for 2 (specification: every contains sodium levofolinate in folinic acid 100mg), with prescription 1, different is, taking by weighing 50g lyophilizing skeleton agent mannitol adds in the water for injection of 250ml and dissolves, taking by weighing the 100g l-leucovorin adds in 60 ℃ the 800m water for injection and makes suspension, put coldly, add water for injection, determine the about 1.2ml of loading amount according to the intermediate measurement result for every bottle to 1200ml.
Write out a prescription for 3 (specification: every contains sodium levofolinate in folinic acid 150mg), with prescription 1, different is, taking by weighing 75g lyophilizing skeleton agent mannitol adds in the water for injection of 375ml and dissolves, taking by weighing the 178g l-leucovorin adds in 60 ℃ the 1200m water for injection and makes suspension, put coldly, add water for injection, determine the about 1.8ml of loading amount according to the intermediate measurement result for every bottle to 1800ml.
Example 2, l-leucovorin sodium freeze-dried powder injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), prescription 1 with example 1, different is, taking by weighing 25g lyophilizing skeleton agent mannitol adds in the water for injection of 125ml and dissolves, taking by weighing the 53g sodium levofolinate adds in 60 ℃ the 400ml water for injection and makes solution, put coldly, add water for injection, determine the about 0.6ml of loading amount according to the intermediate measurement result for every bottle to 600ml.
Write out a prescription for 2 (specification: every contains sodium levofolinate in folinic acid 100mg), prescription 1 with example 1, different is, taking by weighing 50g lyophilizing skeleton agent mannitol adds in the water for injection of 250ml and dissolves, taking by weighing the 106g sodium levofolinate adds in 60 ℃ the 800ml water for injection and makes solution, put coldly, add water for injection, determine the about 1.2ml of loading amount according to the intermediate measurement result for every bottle to 1200ml.
Write out a prescription for 3 (specification: every contains sodium levofolinate in folinic acid 150mg), prescription 1 with example 1, different is, taking by weighing 75g lyophilizing skeleton agent mannitol adds in the water for injection of 375ml and dissolves, taking by weighing the 159g l-leucovorin adds in 60 ℃ the 1200ml water for injection and makes suspension, put coldly, add water for injection, determine the about 1.8ml of loading amount according to the intermediate measurement result for every bottle to 1800ml.
Example 3, l-leucovorin sodium freeze-dried powder injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), with the prescription 1 of example 1, different is to take by weighing the 5g dextran and replace mannitol.
Example 4, sodium levofolinate small-volume injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), under aseptic condition, with 400ml water for injection and nitrogen perfusion washing mixer, stir and add the 50g l-leucovorin down, get suspension, add 5% sodium hydroxide solution 85ml, make folinic acid be dissolved as salt fully, the control pH value is between 7.0-8.0, add 0.05% active carbon again, stirred 15 minutes, and filtered carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, add water for injection to 2000ml, stir mixing.Measure intermediate content, aseptic and fill and be sub-packed in 1000 bottles sealing under the nitrogen.
Write out a prescription for 2 (specification: every contains sodium levofolinate in folinic acid 100mg), with prescription 1, different is, with 800ml water for injection and nitrogen perfusion washing mixer, stir adding 100g l-leucovorin down, add 5% sodium hydroxide solution 170ml, add water for injection to 2000ml.
Write out a prescription for 3 (specification: every contains sodium levofolinate in folinic acid 150mg), with prescription 1, different is, with 1200ml water for injection and nitrogen perfusion washing mixer, stir adding 150g l-leucovorin down, add 5% sodium hydroxide solution 255ml, add water for injection to 2000ml.
Example 5, sodium levofolinate small-volume injection:
Prescription 1:(specification: every contains sodium levofolinate in folinic acid 50mg)
Under aseptic condition,, keep filling the water for injection that adds 400ml under the nitrogen state with water for injection and nitrogen perfusion washing mixer, stir adding 53g sodium levofolinate down, make dissolving fully, the control pH value is between 7.0-8.0, add 0.05% active carbon again, stirred 15 minutes, and filtered carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, add water for injection to 2000ml, stir mixing.Measure intermediate content, aseptic and fill and be sub-packed in 1000 bottles sealing under the nitrogen.
2 (specification: every contains sodium levofolinate in folinic acid 100mg) of prescription, with prescription 1, different is, keeps filling the water for injection that adds 800ml the nitrogen state under, stirs adding 106g sodium levofolinate down, adds water for injection to 2000ml.
3 (specification: every contains sodium levofolinate in folinic acid 150mg) of prescription, with prescription 1, different is, keeps filling the water for injection that adds 1200ml the nitrogen state under, stirs adding 159g sodium levofolinate down, adds water for injection to 2000ml
Example 6, sodium levofolinate bulk capacity injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), under aseptic condition, with water for injection and nitrogen perfusion washing mixer, the water for injection that adds 50000ml under the nitrogen state is filled in maintenance, stirs to add the 50g l-leucovorin down, gets suspension, add 5% sodium hydroxide solution 85ml, make folinic acid be dissolved as salt fully, the control pH value adds 900g sodium chloride between 7.0-8.0, add 0.05% active carbon again, stirred 15 minutes, and filtered carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, add water for injection to 100000ml, stir mixing.Measure intermediate content, aseptic and fill and be sub-packed in 1000 bottles or the bag sealing under the nitrogen.
Write out a prescription for 2 (specification: every contains sodium levofolinate in folinic acid 100mg), with prescription 1, different is that adding 100g sodium levofolinate adds 5% sodium hydroxide solution 170ml under stirring, and adds 900g sodium chloride.
Write out a prescription for 3 (specification: every contains sodium levofolinate in folinic acid 150mg), with prescription 1, different is that adding 150g sodium levofolinate adds 5% sodium hydroxide solution 255ml under stirring, and adds 900g sodium chloride.
Example 7, sodium levofolinate bulk capacity injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), under aseptic condition, with water for injection and nitrogen perfusion washing mixer, keep filling the water for injection that adds 50000ml under the nitrogen state, stir and add the 53g sodium levofolinate down, leucovorin sodium is dissolved fully, and the control pH value adds 900g sodium chloride between 7.0-8.0, add 0.05% active carbon again, stirred 15 minutes, and filtered carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, add water for injection to 100000ml, stir mixing.Measure intermediate content, aseptic and fill and be sub-packed in 1000 bottles or the bag sealing under the nitrogen.
Annotate: also available glucose replaces sodium chloride, or adds antioxidant.
Write out a prescription for 2 (specification: every contains sodium levofolinate in folinic acid 100mg), with prescription 1, different is that adding 106g sodium levofolinate adds 900g sodium chloride under stirring.
Write out a prescription for 3 (specification: every contains sodium levofolinate in folinic acid 150mg), with prescription 1, different is that adding 159g sodium levofolinate adds 900g sodium chloride under stirring.
Example 8, sodium levofolinate bulk capacity injection
Write out a prescription for 1 (specification: every contains sodium levofolinate in folinic acid 50mg), under aseptic condition, with water for injection and nitrogen perfusion washing mixer, keep filling the water for injection that adds 50000ml under the nitrogen state, stir and add the 53g sodium levofolinate down, leucovorin sodium is dissolved fully, and the control pH value adds 4500g sodium chloride between 7.0-8.0, add 0.05% active carbon again, stirred 15 minutes, and filtered carbon removal, filtrate is through the extremely clarification of 0.8u filtering with microporous membrane, again through the 0.22u filtering with microporous membrane, add water for injection to 500000ml, stir mixing.Measure intermediate content, aseptic and fill and be sub-packed in 1000 bottles or the bag sealing under the nitrogen.
The preparation of example 9, sodium levofolinate,
Take by weighing l-leucovorin 100g, join in the 400ml absolute methanol, gradation adds sodium hydroxide 30g, adds molecular sieve 40g, room temperature stirs 1h down, sucking filtration, and the filtering molecular sieve adds 400ml acetone in the filtrate, abundant mix homogeneously, sucking filtration, the filter cake oven dry gets the 95g sodium levofolinate.
Claims (2)
1. the preparation method of medicine sodium levofolinate is characterized in that taking by weighing at least a adjuvant in mannitol, dextran, glucose, sodium chloride, the hydrolyzed protein, adds in the water for injection to dissolve, and adds 0.3% active carbon and boils 20 minutes, filters carbon removal; Keep filling nitrogen or not filling under the nitrogen state, add water for injection at mixer, stir and add sodium levofolinate down, make dissolving fully, the control pH value adds 0.05% active carbon again between 7.0-8.0, stirred 15 minutes, filter carbon removal, mix, through the extremely clarification of 0.8u filtering with microporous membrane with the adjuvant that takes off charcoal, again through the 0.22u filtering with microporous membrane, add water for injection to aequum, stir mixing, measure intermediate content, aseptic and fill packing or aseptic subpackaged after drying under the nitrogen, sodium levofolinate is counted 25-250mg with folinic acid in every injection, and the weight proportion of sodium levofolinate and adjuvant is 1: 0.1-1: 20.
2. the application of the described medicine sodium levofolinate of claim 1 in preparation medicine for treating tumor thing is characterized in that sodium levofolinate is used to prepare the medicine for the treatment of tumor.
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Families Citing this family (4)
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| CN101862333B (en) * | 2009-04-20 | 2013-07-24 | 天津药物研究院 | Stable sodium levofolinate oral preparation and preparation method thereof |
| CN102125558A (en) * | 2011-01-10 | 2011-07-20 | 齐建新 | Compound sodium levofolinate fluorouracil antineoplastic medicament |
| CN102743331A (en) * | 2011-04-18 | 2012-10-24 | 邹巧根 | Disinfection preparation containing levorotatory folinic acid sodium |
| CN112472673A (en) * | 2020-12-07 | 2021-03-12 | 南京海纳医药科技股份有限公司 | Freeze dried levofolinic acid powder for injection and its production process |
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