CN1634152A - Raw material medicine of methylcantharidinimide and its preparation process - Google Patents
Raw material medicine of methylcantharidinimide and its preparation process Download PDFInfo
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- CN1634152A CN1634152A CNA2004100675893A CN200410067589A CN1634152A CN 1634152 A CN1634152 A CN 1634152A CN A2004100675893 A CNA2004100675893 A CN A2004100675893A CN 200410067589 A CN200410067589 A CN 200410067589A CN 1634152 A CN1634152 A CN 1634152A
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- methylcantharidimide
- cantharidin
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Abstract
The invention discloses a N-methylcantharidimide raw material medicament for tumor resistance, which is prepared through cantharis selection, disintegrating, cantharidin extraction, cantharidin degreasing, methylcantharidinimide synthesizing, N-methylcantharidimide refining, disinfecting, and packaging. The invention can be applied to the production of antineoplastics of various dose form, including tablet, capsule, granule, oral liquid, injection, fluid infusion and ointment.
Description
The present invention relates to a kind of raw material of Chinese medicine medicine, is a kind ofly to have better inhibiting direct killing cancerous cell detoxification synergic to tumor, and the antitumor specific drug of Chinese medicine west system is a kind of antineoplastic raw material medicine of methylcantharidinimiand.
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 objective of the invention is to overcome above-mentioned cantharis and the existing defective of cantharidin medicine, providing a kind of can take for a long time, safe and reliable antitumor drug clinical commonly used, it is the digestive tract reaction of antitumor drug as none both, does not also have the urinary system reaction due to the cantharidin.By cantharidin again after semi-synthetic, the synergic raw material medicine of methylcantharidinimiand of detoxification.
The present invention is through reasonably prescription and processing technique are prepared from by cantharis.
Raw material medicine of methylcantharidinimiand of the present invention is through selecting, pulverizing by cantharis; Cantharidin extracts, defat; N-methylcantharidimide is synthetic, refining, drying obtains raw material medicine of methylcantharidinimiand.Concrete grammar and preparation technology are as follows:
The present invention a kind ofly has better inhibiting direct killing cancerous cell to tumor, the raw material medicine of methylcantharidinimiand of the synergic Chinese medicine of detoxification west system.It is the medicament that is formed by following technical process by cantharis.
1. cantharis picks, pulverizes.
Place stainless steel disc to pick cantharis, remove foreign material, put into the rustless steel drip pan.Drip pan is placed on the baking car, pushes in the drying room, drying is 10 hours in the temperature about 50 ℃, exsiccant cantharis is put into high speed disintegrator pulverize, smashing fineness to 40 order.After flour bag to be stored up is filled, the worm powder is poured in the stainless steel cask.
2. cantharidin extracts.
The proportion that feeds intake is:
Cantharis powder: acetone: hydrochloric acid=1 (kg): 3 (kg): 5 (ml)
Acetone can dissolve most resins, fat and oils.Acetone can mix arbitrarily with water, as the dewatering and defatting agent of organizing organ pipe etc. of cantharis.Microorganism can not be lived in acetone, and the organ pipe of organizing of cantharis can be not corrupt in acetone dewatering and defatting process.Hydrochloric acid is added in a small amount of leaching solvent to improve its usefulness.
With 100 kilograms～400 kilograms in worm powder, 300 kilograms～1200 kilograms in acetone, hydrochloric acid drops into 500 for 500 milliliters～2000 milliliters and rises in 2000 liters of rustless steel extraction pot, opens steam and is 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 300 kilograms to 1200 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.
The proportion that feeds intake 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. N-methylcantharidimide is synthetic.
The proportion that feeds intake is:
Cantharidin elaboration (more than 95%): methyl amine water (AR) 25～30%=1: 1.04
In 1000 milliliters to 4000 milliliters there-necked flasks, add cantharidin, add methyl amine water again, heating makes its dissolving in the electric heating chuck, 75 ℃ to 85 ℃ back flow reaction 1 hour, pours out product and cooled off 4 hours crystallize in the time of 20 ℃.
In N-methylcantharidimide synthesis mother liquid suction reaction bulb.Stir, the heating of electric heating chuck, and open condensed water, reclaim methyl amine water.When kettle temperature reaches 90 ℃ of left and right sides, stop to reclaim.Connect the methyl amine water of recovery, synthetic reaction can be applied mechanically.Material is poured in the beaker, and stirred,, add a cover to room temperature with the Glass rod gap.Next day, dig pine, pour the 2# glass filter into and drain.This drains thing is the N-methylcantharidimide crude product.
5. N-methylcantharidimide is refining.
The proportion that feeds intake is:
Crude product: purified water=1: 12
The N-methylcantharidimide crude product is dropped into 1500 milliliters to 6000 ml flasks, add 3 times of amount purified water, open stirring, the heating of electricity consumption thermal jacket, temperature is controlled at below 80 ℃, treats that it dissolves fully, uses 2# vierics sucking filtration while hot, remove impurity, filtrate is carried out sucking filtration again cooling below 20 ℃ 3 hours, gets the N-methylcantharidimide crystallization, repeat above operation three times, promptly get the wet product of N-methylcantharidimide.But the mother solution successive is applied mechanically.
Refinement mother liquor adds flask for the first time, opens stirring, is heated to backflow with the electric heating spacer, distills out moisture content.Be distilled to when the mother solution amount remains 1/3rd left and right sides in the flask, material in the flask is poured in the flask, the gap is stirred to crystallize, adds a cover and spends the night.Next day, smash pine, pour the 2# glass filter into and filter.Gained reclaimed materials charging feedstock bag, weighing is the wet product of N-methylcantharidimide.
The wet product of N-methylcantharidimide are paved equably put into electric drying oven with forced convection on drip pan, temperature is controlled at below 50 ℃, and be 24 hours drying time.Promptly get the N-methylcantharidimide finished product.
The N-methylcantharidimide that crushes is put into blender, mix, incorporation time is 0.5 hour, mixes about a collection of general 500 grams.
For the formula proportion and the processing technique that further specify raw material medicine of methylcantharidinimiand of the present invention, embodiments of the invention are as follows:
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.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 300 kilograms to 1200 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.According to above-mentioned 3 to 5 technical process operation.Get 1.2 kilograms of N-methylcantharidimide finished products and close 1200 grams.
Antitumor N-methylcantharidimide sheet by above-mentioned prescription and preparation technology's gained has the following advantages and curative effect.
1. raw material medicine of methylcantharidinimiand of the present invention, the state of an illness has significant alleviation after tumour patient is taken, and alleviates patient's pain significantly, improves patient's sleep, increases patient's appetite.
2. the present invention is the derivant of cantharidin, aspect anticancer and the liter white two very big effect is being arranged all, but cancer cell specific induction of apoptosis, the activity of phosphoprotein phosphatase PP2A in the anticancer, blocking-up cancerous cell mitosis, destruction of cancer cells skeleton, improve immunologic function, strengthen the NK cytoactive.Can shorten the time that leukocyte is ripe in bone marrow, discharge again in early days, the later stage promotes the propagation of hematopoietic stem cell.
3. N-methylcantharidimide sheet absorption in vivo, distribution and excretory speed are very fast.Oral back is easy to reach effective blood drug level in body, mainly be distributed in gallbladder, liver, with cancerous cell certain affinity interaction is arranged.In 24 hours, most people discharge in the body from the urine excrement, do not have the savings phenomenon.
4. after the TACE operation, the tendency of deterioration of liver function often appears in the patient, and N-methylcantharidimide can prevent the infringement of TACE operation back liver function effectively, and the side effect that also can alleviate chemotherapeutics has positive meaning to liver function protecting.
5. N-methylcantharidimide has unique effect to treatment hepatocarcinoma.It can alleviate liver pain, liver tumor body is dwindled or suppresses the tumor bulk-growth.And have advantages such as evident in efficacy, safe and reliable, that toxicity is little.Be the oral Chinese medicine tablet of comparatively ideal treatment hepatocarcinoma, simultaneously pulmonary carcinoma, esophageal carcinoma, colon cancer and breast carcinoma also had curative effect preferably.
The preparation technology of antineoplastic N-methylcantharidimide of the present invention is reasonable, simple and practical, safe and effective, the finished product stable in properties, is easy to detect.Can be widely used in the production of the antineoplastic agent of multiple dosage forms such as tablet, capsule, granule, oral liquid, injection, infusion solutions and ointment.
Claims (3)
1. an antitumor specific drug that has better inhibiting direct killing cancerous cell, the synergic Chinese medicine of detoxification west to make to tumor is a kind of raw material medicine of methylcantharidinimiand of dirty tumor.It is characterized in that it is to pass to down the crude drug that technical process forms by cantharis.
A. cantharis is pulverized, picks.
Place stainless steel disc to pick cantharis, remove foreign material, put into the rustless steel drip pan.Drip pan is placed on the baking car, pushes in the drying room, drying is 10 hours in the temperature about 50 ℃, exsiccant cantharis is put into high speed disintegrator pulverize, smashing fineness to 40 order.After flour bag to be stored up is filled, the worm powder is poured in the stainless steel cask.
B. cantharidin extracts.
The proportion that feeds intake is:
Cantharis powder: acetone: hydrochloric acid=1 (kg): 3 (kg): 5 (ml)
With 100 kilograms～400 kilograms in worm powder, 300 kilograms～1200 kilograms in acetone, hydrochloric acid drops into 500 for 500 milliliters～2000 milliliters and rises in 2000 liters of rustless steel extraction pot, opens steam and is 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 300 kilograms to 1200 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.
The proportion that feeds intake 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. N-methylcantharidimide is synthetic.
The proportion that feeds intake is:
Cantharidin elaboration (more than 95%): methyl amine water (AR) 25～30%=1: 1.04
In 1000 milliliters to 4000 milliliters there-necked flasks, add cantharidin, add methyl amine water again, heating makes its dissolving in the electric heating chuck, 75 ℃ to 85 ℃ back flow reaction 1 hour, pours out product and cooled off 4 hours crystallize in the time of 20 ℃.
In N-methylcantharidimide synthesis mother liquid suction reaction bulb.Stir, the heating of electric heating chuck, and open condensed water, reclaim methyl amine water.When kettle temperature reaches 90 ℃ of left and right sides, stop to reclaim.Connect the methyl amine water of recovery, synthetic reaction can be applied mechanically.Material is poured in the beaker, and stirred,, add a cover to room temperature with the Glass rod gap.Next day, dig pine, pour the 2# glass filter into and drain.This drains thing is the N-methylcantharidimide crude product.
E. N-methylcantharidimide is refining.
The proportion that feeds intake is:
Crude product: purified water=1: 12
The N-methylcantharidimide crude product is dropped into 1500 milliliters to 6000 ml flasks, add 3 times of amount purified water, open stirring, the heating of electricity consumption thermal jacket, temperature is controlled at below 80 ℃, treats that it dissolves fully, uses 2# vierics sucking filtration while hot, remove impurity, filtrate is carried out sucking filtration again cooling below 20 ℃ 3 hours, gets the N-methylcantharidimide crystallization, repeat above operation three times, promptly get the wet product of N-methylcantharidimide.But the mother solution successive is applied mechanically.
Refinement mother liquor adds flask for the first time, opens stirring, is heated to backflow with the electric heating spacer, distills out moisture content.Be distilled to when the mother solution amount remains 1/3rd left and right sides in the flask, material in the flask is poured in the flask, the gap is stirred to crystallize, adds a cover and spends the night.Next day, smash pine, pour the 2# glass filter into and filter.Gained reclaimed materials charging feedstock bag, weighing is the wet product of N-methylcantharidimide.
The wet product of N-methylcantharidimide are paved equably put into electric drying oven with forced convection on drip pan, temperature is controlled at below 50 ℃, and be 24 hours drying time.Promptly get the N-methylcantharidimide finished product.
The N-methylcantharidimide that crushes is put into blender, mix, incorporation time is 0.5 hour, mixes about a collection of general 500 grams.
2. antineoplastic N-methylcantharidimide sheet according to claim 1 is characterized in that optimum formula and technology are as follows in above-mentioned prescription and the technology:
After cantharis selected, pulverizes, in cantharis 1 (kg): acetone 3 (kg): the ratio of hydrochloric acid 5 (ml).Take by weighing 200 kilograms of canthariss: 600 kilograms in acetone: hydrochloric acid drops in 1000 liters of rustless steel extraction pot for 1000 milliliters, through above-mentioned technical process operation, gets N-methylcantharidimide finished product 1200 grams.
3. the raw material medicine of methylcantharidinimiand of making according to the formula proportion described in claim 1 and 2 and processing technique can be applicable to the production of the antineoplastic agent of multiple dosage forms such as tablet, capsule, granule, oral liquid, injection, infusion solutions and ointment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100675893A CN1634152A (en) | 2004-10-28 | 2004-10-28 | Raw material medicine of methylcantharidinimide and its preparation process |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2004100675893A CN1634152A (en) | 2004-10-28 | 2004-10-28 | Raw material medicine of methylcantharidinimide and its preparation process |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796794A (en) * | 2012-08-31 | 2012-11-28 | 哈尔滨工业大学 | Preparation method of cantharis toxin |
| CN108003175A (en) * | 2018-01-09 | 2018-05-08 | 河南牧农生物科技有限公司 | A kind of extraction process of cantharidin |
| CN108553429A (en) * | 2018-05-02 | 2018-09-21 | 江苏四环生物制药有限公司 | A kind of anticancer methylcantharidinimitablet tablet and preparation method thereof |
-
2004
- 2004-10-28 CN CNA2004100675893A patent/CN1634152A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796794A (en) * | 2012-08-31 | 2012-11-28 | 哈尔滨工业大学 | Preparation method of cantharis toxin |
| CN108003175A (en) * | 2018-01-09 | 2018-05-08 | 河南牧农生物科技有限公司 | A kind of extraction process of cantharidin |
| CN108553429A (en) * | 2018-05-02 | 2018-09-21 | 江苏四环生物制药有限公司 | A kind of anticancer methylcantharidinimitablet tablet and preparation method thereof |
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