CN1586500A - Disodium cantharidinate injection for treating tumor and its preparing method - Google Patents
Disodium cantharidinate injection for treating tumor and its preparing method Download PDFInfo
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- CN1586500A CN1586500A CNA2004100529384A CN200410052938A CN1586500A CN 1586500 A CN1586500 A CN 1586500A CN A2004100529384 A CNA2004100529384 A CN A2004100529384A CN 200410052938 A CN200410052938 A CN 200410052938A CN 1586500 A CN1586500 A CN 1586500A
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- disodium cantharidinate
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- cantharidin
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Abstract
The disodium cantharidinate injection for treating tumor is prepared through crushing blistere beetle, extracting cantharidin, defatting cantharidin, synthesizing disodium cantharidinate, refining disodium cantharidinate, forming disodium cantharidinate injection, packing and sterilizing. As one kind of wide spectrum antitumor medicine, the present invention is suitable for treating primary liver cancer, lung cancer, oesophagus cancer and other cancers, and may be used in treating hepatitis, liver cirrhosis, etc.
Description
The present invention relates to a kind of intravenous drip type injection, is a kind of injection agent in a new generation's treatment tumor that great role is all arranged aspect anticancer and the liter white two, is a kind of disodium cantharidinate injection for the treatment of tumor.
Before more than 2,000 years, the Chinese medicine of China is just brought into use cantharis treatment tumor.This property of medicine acrid in the mouth is cold, and is poisonous, but the counteracting toxic substances phagedenoma, and the removing blood stasis eliminating stagnation is to act on significantly attacking by class Chinese medicine.But toxic and side effects is very big, takes oral cavity, back, pharyngeal mucosa hyperemia, nausea and vomiting, loss of appetite, diarrhoea, dysurea, frequent micturition, hematuria etc.And can not grasp the dosage of medicine, be difficult to clinically use.The active ingredient of Mylabris treatment tumor is a cantharidin.Though the cantharidin taking convenience that extracts through science, and pharmaceutical quantities also is easy to grasp, toxic and side effects is still very big, and the effective dose of cantharidin and toxicity dose are very approaching.
The natural resources of cantharis is very deficient, 10 tons of China's annual production less thaies.Wild cantharis mainly is grown in the South China Tropical humid region, and based on the food leguminous plant, the conservation of natural environment of life requires very high.Natural environment polluted in recent years, and the output of wild cantharis is reduced significantly, and the artificial cultivation cantharis does not also have successful experience.
The objective of the invention is to overcome above-mentioned cantharis and the existing defective of cantharidin medicine, provide a kind of and can make full use of the cantharis resource, the medicine of the clinical treatment tumour that energy is long-term, safety clothes are used, it is the digestive tract reaction of antitumor drug as none both, the urinary system reaction of not having cantharidin again and being caused.By cantharidin again after semi-synthetic, the synergic disodium cantharidinate injection of detoxification.
The present invention is through reasonably prescription and processing technique are prepared from by cantharis.
Disodium cantharidinate injection of the present invention be synthetic by cantharis pulverizing, cantharidin extraction, cantharidin defat, disodium cantharidinate, disodium cantharidinate is refining, the disodium cantharidinate injection is synthetic and embedding, sterilization, obtains the disodium cantharidinate injection.Concrete grammar and preparation technology are as follows:
1. cantharis is pulverized.
Cantharis is picked, remove foreign material, put into then on the rustless steel drip pan, drying is 10 hours in the temperature of about 50 ℃ in drying room, and exsiccant cantharis is put into high speed disintegrator smashing fineness to 40 order.
2. cantharidin extracts.
Formula proportion is:
Cantharis powder: acetone: hydrochloric acid=1 (kg): 2～5 (kg): 3～7 (ml)
With 200 kilograms in cantharis powder, 400 kilograms to 1000 kilograms in acetone, hydrochloric acid drops into 500 for 600 milliliters to 1400 milliliters and rises in 2000 liters of rustless steel extraction pot, opens steam and is warming up to 30 ℃ to 40 ℃, and insulation was soaked 24 hours, and preceding 10 hours every stirring in 2 hours 5 minutes.With corrosion resisting centrifugal pump leachate in the extraction pot is evacuated in the basin.Repeat above operation, soak with 400 kilograms to 1000 kilograms acetone insulations respectively and extract three times.Last leachate is evacuated in the recover and concentrates, and applies mechanically as extract next time.Open vacuum, leachate in the basin is evacuated in the recover, open Steam Heating, concentrate, when liquid temperature boiling point rises to 78 ℃, stop heating, emit concentrated solution, contain in the stainless steel cask, at room temperature natural crystallize is more than 12 hours.After leachate is drained, take out the worm slag, centralized collection is handled.
3. cantharidin defat.
Formula proportion is:
Cantharidin crude product: cleaning mixture=1: 2.8
Cleaning mixture proportioning: petroleum ether (bp:60～90 ℃): ethanol (95%)=1: 1
With crystallize completely concentrated solution be the buchner funnel of filter material in order to silk, decompress filter is to doing.Crystal after draining is moved in the stainless steel disc, add the cleaning mixture that 0.5 times of petroleum ether and ethanol are made into, stir, basin is placed in the water-bath heats again, stir and be warming up to 30 ℃ with stainless steel knife.Be the buchner funnel of filter material in order to silk while hot, drain the back and drain with 0.2 times of cleaning mixture post rinse.And then repeat above operation three times, the crystallization of leukasmus Cantharidin, and this be contained in the porcelain dish dry, promptly get the cantharidin elaboration.
4. disodium cantharidinate is synthetic.
Formula proportion is:
Cantharidin elaboration (more than 95%): 40% sodium hydroxide solution: distilled water=1: 1.4: 8
In 1000 milliliters to 4000 milliliters there-necked flasks, add cantharidin, add 40% sodium hydroxide solution and distilled water again by above-mentioned formula proportion, heating made its dissolving in the electric heating chuck, 75 ℃ to 85 ℃ back flow reaction 1 to 2 hour.Distill out moisture content, be distilled to when the mother solution amount remains 1/3rd left and right sides in the flask, pour out product and cooled off 4 hours in the time of 20 ℃, the gap is stirred to crystallize, gets the disodium cantharidinate crude product.
5. disodium cantharidinate is refining.
Formula proportion is:
Disodium cantharidinate crude product: purified water: active carbon=1: 8: 0.01
The disodium cantharidinate crude product is dropped into 1500 milliliters to 6000 ml flasks, add 8 times of amount purified water, add 1% left and right sides active carbon again.Distill out moisture content, cooling crystallization promptly gets the disodium cantharidinate finished product.
6. the disodium cantharidinate injection is synthetic.
Formula proportion is: per ten thousand consumptions of per 500 consumptions of every content of supplementary material
Disodium cantharidinate 0.1mg 50mg 1g
Sodium sulfite 2mg～6mg 1000mg～3000mg 20g～60g
EDTA 0.2mg 100mg 2g
Propylene glycol 0.2ml～0.6ml 100ml～200ml 21～61
Water for injection is an amount of an amount of
Get 100ml～300ml propylene glycol, add an amount of water for injection, during 50 ℃～60 ℃ of agitating heating, add 1000mg～3000mg sodium sulfite solution and 100mgEDTA according to the above ratio, regulate pH value about 7.0, add disodium cantharidinate finished product 50mg again, stir and make dissolving, add injection water volume to 1000ml, adding needle-use activated carbon stirs, coarse filtration detects intermediate after taking off charcoal, and qualified back fine straining leads to N to clear and bright
2Embedding, 100 ℃ of flowing steam sterilizations 30 minutes promptly get the disodium cantharidinate injection that the present invention treats tumor.
Prescription of the present invention and technology are reasonable, practical, the disodium cantharidinate finished product stable in properties of above-mentioned 1 to 5 preparation, and safety is good, is easy to detect.Can be applicable to the production of the antitumor drug of multiple dosage forms such as injection, transfusion, capsule, tablet.
The disodium cantharidinate injection of the treatment tumor by above-mentioned prescription and preparation technology's gained has the following advantages and curative effect.
1. the present invention treats the disodium cantharidinate injection intravenous drip of tumor.1 time on the one, each 2 to 10ml, dilutes the back in right amount with 0.9% sodium chloride or 5% to 10% glucose injection and instils.
2. injection of the present invention has the effect of obvious alleviation cancer pain after the tumour patient intravenous drip, improve the clinical symptoms of tumour patient, improves patient's quality of life.
3. the present invention is the derivant of cantharidin, aspect anticancer and the liter white two very big effect being arranged all, cancerous cell is had directly kill and inhibitory action; Stimulate medulla hematopoietic system, the elevating blood leukocyte.
4. after the intravenous drip of this injection, most of medicine is discharged from urine.Significantly improve body's immunological function; With put, chemotherapy combined uses and to heighten the effect of a treatment; Before the surgical oncology art, postoperative uses, but the after treatment effect.
5. disodium cantharidinate is the broad-spectrum anti-tumor medicine, is applicable to the treatment of kinds of tumors such as primary hepatocarcinoma, pulmonary carcinoma, esophageal carcinoma, nasopharyngeal carcinoma, malignant lymphoma, bladder cancer, gynecologic malignant tumor, also can be used for hepatitis, liver cirrhosis and hepatitis b virus carrier.
The disodium cantharidinate injection that the present invention treats tumor is the injection according to the processing technique preparation process gained of above-mentioned cantharis.Embodiments of the invention are as follows:
After cantharis selected, pulverizes, in the cantharis powder: acetone: hydrochloric acid=1 (kg): 3 (kg): 5 (ml) ratio, take by weighing in 200 kilograms in cantharis powder, 600 kilograms in acetone, 1000 liters of rustless steel extraction pot of 1000 milliliters of inputs of hydrochloric acid, open steam and be warming up to 30 ℃ to 40 ℃, insulation was soaked 24 hours, and preceding 10 hours every stirring in 2 hours 5 minutes.With corrosion resisting centrifugal pump leachate in the extraction pot is evacuated in the basin.Repeat above operation, soak with 600 kilograms of acetone insulations respectively and extract three times.Last leachate is evacuated in the recover and concentrates, and applies mechanically as extract next time.Open vacuum, leachate in the basin is evacuated in the recover, open Steam Heating, concentrate, when liquid temperature boiling point rises to 78 ℃, stop heating, emit concentrated solution, contain in the stainless steel cask, at room temperature natural crystallize is more than 12 hours.After leachate is drained, take out the worm slag, centralized collection is handled.Processing technique preparation process according to above-mentioned 3 to 5.Get 1.2 kilograms of disodium cantharidinate finished products.
The disodium cantharidinate injection is synthetic.
Formula proportion is: per ten thousand consumptions of per 500 consumptions of every content of supplementary material
Disodium cantharidinate 0.1mg 50mg 1g
Sodium sulfite 3mg 1500mg 30g
EDTA 0.2mg 100mg 2g
Propylene glycol 0.6ml 300ml 61
Water for injection is an amount of an amount of
Get the 300ml propylene glycol, add an amount of water for injection, during 50 ℃～60 ℃ of agitating heating, add 1500mg sodium sulfite solution and 100mgEDTA according to the above ratio, regulate pH value about 7.0, add disodium cantharidinate finished product 50mg again, stir and make dissolving, add injection water volume to 1000ml, adding needle-use activated carbon stirs, coarse filtration detects intermediate after taking off charcoal, and qualified back fine straining leads to N to clear and bright
2Embedding, 100 ℃ of flowing steam sterilizations 30 minutes promptly get the disodium cantharidinate injection that the present invention treats tumor.1000ml can be made into 500 of the injections of 2ml specification, and every disodium cantharidinate injection contains disodium cantharidinate 0.1mg.
Claims (3)
1. the injection agent in a new generation's treatment tumor that great role is all arranged aspect anticancer and the liter white two is a kind of disodium cantharidinate injection for the treatment of tumor.It is characterized in that it is the medicament that is prepared from by following processing technique by cantharis.
A. cantharis is pulverized.
Cantharis is picked, remove foreign material, put into then on the rustless steel drip pan, drying is 10 hours in the temperature of about 50 ℃ in drying room, and exsiccant cantharis is put into high speed disintegrator smashing fineness to 40 order.
B. cantharidin extracts.
Formula proportion is:
Cantharis powder: acetone: hydrochloric acid=1 (kg): 2～5 (kg): 3～7 (ml)
With 200 kilograms in cantharis powder, 400 kilograms to 1000 kilograms in acetone, hydrochloric acid drops into 500 for 600 milliliters to 1400 milliliters and rises in 2000 liters of rustless steel extraction pot, opens steam and is warming up to 30 ℃ to 40 ℃, and insulation was soaked 24 hours, and preceding 10 hours every stirring in 2 hours 5 minutes.With corrosion resisting centrifugal pump leachate in the extraction pot is evacuated in the basin.Repeat above operation, soak with 400 kilograms to 1000 kilograms acetone insulations respectively and extract three times.Last leachate is evacuated in the recover and concentrates, and applies mechanically as extract next time.Open vacuum, leachate in the basin is evacuated in the recover, open Steam Heating, concentrate, when liquid temperature boiling point rises to 78 ℃, stop heating, emit concentrated solution, contain in the stainless steel cask, at room temperature natural crystallize is more than 12 hours.After leachate is drained, take out the worm slag, centralized collection is handled.
C. cantharidin defat.
Formula proportion is:
Cantharidin crude product: cleaning mixture=1: 2.8
Cleaning mixture proportioning: petroleum ether (bp:60～90 ℃): ethanol (95%)=1: 1
With crystallize completely concentrated solution be the buchner funnel of filter material in order to silk, decompress filter is to doing.Crystal after draining is moved in the stainless steel disc, add the cleaning mixture that 0.5 times of petroleum ether and ethanol are made into, stir, basin is placed in the water-bath heats again, stir and be warming up to 30 ℃ with stainless steel knife.Be the buchner funnel of filter material in order to silk while hot, drain the back and drain with 0.2 times of cleaning mixture post rinse.And then repeat above operation three times, the crystallization of leukasmus Cantharidin, and this be contained in the porcelain dish dry, promptly get the cantharidin elaboration.
D. disodium cantharidinate is synthetic.
Formula proportion is:
Cantharidin elaboration (more than 95%): 40% sodium hydroxide solution: distilled water=1: 1.4: 8
In 1000 milliliters to 4000 milliliters there-necked flasks, add cantharidin, add 40% sodium hydroxide solution and distilled water again by above-mentioned formula proportion, heating made its dissolving in the electric heating chuck, 75 ℃ to 85 ℃ back flow reaction 1 to 2 hour.Distill out moisture content, be distilled to when the mother solution amount remains 1/3rd left and right sides in the flask, pour out product and cooled off 4 hours in the time of 20 ℃, the gap is stirred to crystallize, gets the disodium cantharidinate crude product.
E. disodium cantharidinate is refining.
Formula proportion is:
Disodium cantharidinate crude product: purified water: active carbon=1: 8: 0.01
The disodium cantharidinate crude product is dropped into 1500 milliliters to 6000 ml flasks, add 8 times of amount purified water, add 1% left and right sides active carbon again.Distill out moisture content, cooling crystallization promptly gets the disodium cantharidinate finished product.
F. the disodium cantharidinate injection is synthetic.
Formula proportion is: per ten thousand consumptions of per 500 consumptions of every content of supplementary material
Disodium cantharidinate 0.1mg 50mg 1g
Sodium sulfite 2mg～6mg 1000mg～3000mg 20g～60g
EDTA 0.2mg 100mg 2g
Propylene glycol 0.2ml～0.6ml 100ml～300ml 2l～6l
Water for injection is an amount of an amount of
Get 100ml～300ml propylene glycol, add an amount of water for injection, during 50 ℃～60 ℃ of agitating heating, add 1000mg～3000mg sodium sulfite solution and 100mgEDTA according to the above ratio, regulate pH value about 7.0, add disodium cantharidinate finished product 50mg again, stir and make dissolving, add injection water volume to 1000ml, adding needle-use activated carbon stirs, coarse filtration detects intermediate after taking off charcoal, and qualified back fine straining leads to N to clear and bright
2Embedding, 100 ℃ of flowing steam sterilizations 30 minutes promptly get the disodium cantharidinate injection that the present invention treats tumor.
2. according to the disodium cantharidinate finished product of the described treatment tumor of the A to E in the claim 1, it is characterized in that optimum formula and preparation technology are as follows among above-mentioned prescription and the preparation technology:
After cantharis selected, pulverizes, in cantharis powder 1 (kg): acetone 3 (kg): the ratio of hydrochloric acid 5 (ml), take by weighing 200 kilograms in cantharis powder, 600 kilograms in acetone, 1000 milliliters of hydrochloric acid, drop in 1000 liters of rustless steel extraction pot, through the processing technique preparation process of above-mentioned B to E, get 1.2 kilograms of disodium cantharidinate finished products.
Prescription of the present invention and technology are reasonable, practical, the disodium cantharidinate finished product stable in properties of above-mentioned A to E preparation, and safety is good, is easy to detect.Can be applicable to the production of the antitumor drug of multiple dosage forms such as injection, transfusion, capsule, tablet.
3. the disodium cantharidinate injection according to the described treatment tumor of the F in the claim 1 is characterized in that the optimum formula ratio of disodium cantharidinate injection is:
Per ten thousand consumptions of per 500 consumptions of every content of supplementary material
Disodium cantharidinate 0.1mg 50mg 1g
Sodium sulfite 3mg 1500mg 30g
EDTA 0.2mg 100mg 2g
Propylene glycol 0.6ml 300ml 6l
Water for injection is an amount of an amount of
Get the 300ml propylene glycol, add an amount of water for injection, during 50 ℃～60 ℃ of agitating heating, add 1500mg sodium sulfite solution and 100mgEDTA according to the above ratio, regulate pH value about 7.0, add disodium cantharidinate finished product 50mg again, stir and make dissolving, add injection water volume to 1000ml, adding needle-use activated carbon stirs, coarse filtration detects intermediate after taking off charcoal, and qualified back fine straining leads to N to clear and bright
2Embedding, 100 ℃ of flowing steam sterilizations 30 minutes promptly get the disodium cantharidinate injection that the present invention treats tumor.1000ml can be made into 500 of the injections of 2ml specification, and every disodium cantharidinate injection contains disodium cantharidinate 0.1mg.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2004100529384A CN1586500A (en) | 2004-07-19 | 2004-07-19 | Disodium cantharidinate injection for treating tumor and its preparing method |
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| CNA2004100529384A CN1586500A (en) | 2004-07-19 | 2004-07-19 | Disodium cantharidinate injection for treating tumor and its preparing method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100386089C (en) * | 2006-03-02 | 2008-05-07 | 上海慈瑞医药科技有限公司 | Compound lentinan preparation and its preparing method |
| EP2309853A1 (en) * | 2008-08-01 | 2011-04-20 | Lixte Biotechnology, Inc. | Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase |
| CN101633661B (en) * | 2007-02-13 | 2011-06-01 | 北京世纪博康医药科技有限公司 | Process for preparing sodium cantharidinate |
| CN102146086A (en) * | 2011-04-12 | 2011-08-10 | 贵州金桥药业有限公司 | Preparation method of sodium cantharidate |
| US11931354B2 (en) | 2013-04-09 | 2024-03-19 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
-
2004
- 2004-07-19 CN CNA2004100529384A patent/CN1586500A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100386089C (en) * | 2006-03-02 | 2008-05-07 | 上海慈瑞医药科技有限公司 | Compound lentinan preparation and its preparing method |
| CN101633661B (en) * | 2007-02-13 | 2011-06-01 | 北京世纪博康医药科技有限公司 | Process for preparing sodium cantharidinate |
| EP2309853A1 (en) * | 2008-08-01 | 2011-04-20 | Lixte Biotechnology, Inc. | Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase |
| EP2309853A4 (en) * | 2008-08-01 | 2012-04-25 | Lixte Biotechnology Inc | Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase |
| CN102146086A (en) * | 2011-04-12 | 2011-08-10 | 贵州金桥药业有限公司 | Preparation method of sodium cantharidate |
| CN102146086B (en) * | 2011-04-12 | 2012-03-07 | 贵州金桥药业有限公司 | Preparation method of sodium cantharidate |
| US11931354B2 (en) | 2013-04-09 | 2024-03-19 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
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