CN110256453A - A kind of preparation method of tetraodotoxin carboxylate - Google Patents

A kind of preparation method of tetraodotoxin carboxylate Download PDF

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Publication number
CN110256453A
CN110256453A CN201910613924.1A CN201910613924A CN110256453A CN 110256453 A CN110256453 A CN 110256453A CN 201910613924 A CN201910613924 A CN 201910613924A CN 110256453 A CN110256453 A CN 110256453A
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tetraodotoxin
fatty acid
preparation
carboxylate
saturated fatty
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赵继红
李伟
徐开俊
张宏业
姚峰
赵琦
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Jiangsu Huagui Pharmaceutical Co Ltd
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Jiangsu Huagui Pharmaceutical Co Ltd
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Priority to PCT/CN2019/113167 priority patent/WO2021003890A1/en
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
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    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Abstract

The present invention provides a kind of preparation method of tetraodotoxin carboxylate, and the method includes the following steps: the new compound that tetraodotoxin is dissolved in Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride, is generated after chemically reacting.The present invention has the following technical effect that one, and tetraodotoxin acidic aqueous solution is directly dissolved in the Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride of single component, obstructed Over emulsfication agent transition, method simplicity by the present invention.Two, tetraodotoxin carboxylate of the invention is the new compound of generation by tetraodotoxin and Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride after chemically reacting.Three, tetraodotoxin carboxylate of the invention does not have the high toxicity of tetraodotoxin, has absolute safety to human body when for oral preparation.Four, tetraodotoxin carboxylate of the invention can be used for being combined into compound preparation with other medicines, or be used in combination only as individual medicine material.

Description

A kind of preparation method of tetraodotoxin carboxylate
Technical field
The present invention relates to a kind of preparation methods of tetraodotoxin carboxylate, belong to field of medicaments.Tetraodotoxin of the invention Carboxylate is that tetraodotoxin is dissolved in Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride, is generated after chemically reacting New compound.This new compound does not have the toxicity of tetraodotoxin, can be used for amplifying the curative effect of concomitant medication, inhibits altogether With the dependence, tolerance and side effect of drug.High toxicity when taking orally the present invention overcomes tetraodotoxin is pacified for tetraodotoxin Full application opened up a new way.
Background technique
1909, Japanese scholars Tian Yuanliang is pure to extract a kind of crude product toxin from blowfish ovaries, was named as tetraodotoxin (Tetrodotoxin), abbreviation TTX.Nineteen fifty, the horizontal tail of Japanese Scientists shake the crystalloid substance that tetraodotoxin has been made, concurrently Now it is that a kind of toxicity is high, the small non-protein toxin of relative molecular mass, and structure is cage type ortho acid esters.It is opened from the fifties Begin, domestic and foreign scholars think that always tetraodotoxin has blocking effect for nerve cell sodium-ion channel, and think this resistance The disconnected transmitting blocked to pain signal, thereby produces the analgesic effect of tetraodotoxin.
Early eighties, Cai Zhiji, Huang Zhiqiang, Pan Xinfu et al. test the analgesic effect of tetraodotoxin using mouse.He Test include " hot plate adds sufficient test ", " acetic acid twisting test ", " root of the tail electro photoluminescence test " etc..The consistent table of experimental result Bright, single tetraodotoxin aqueous solution does not have analgesic effect to mouse, blocks sodium channel to generate analgesic activity to be negated Judgement.(such as Cai Zhiji, Huang Zhiqiang, Pan Xinfu " pharmacological research of domestic tetraodotoxin is made a summary ", Hebei aquatic science and technology, 1983, 1:1-3)
Since simple tetraodotoxin aqueous solution does not have apparent analgesic effect, domestic many scholars are according to experimental result, discovery Tetraodotoxin and one opioids of morphine are used in combination, the analgesic effect of concomitant medication can be amplified, inhibits the resistance to of concomitant medication By property.(Nanjing University Xu Ying, " Effect study of tetraodotoxin and morphine use in conjunction " Jiangsu clinical medicine such as rigid is miscellaneous recklessly The will fifth phase in 2001) (" tetraodotoxin and morphine join after the such as red by China Medicine University Xu Kaijun, Jiangsu Jing Jia medicine Zhao Share the influence of medicine Syndrome of Morphine Dependent and analgesia tolerance effect " Chinese Journal of Drug Dependence .2011,20-5.)
Inventors believe that tetraodotoxin fails the main reason for becoming new drug so far, not only due to tetraodotoxin individually makes It with no significant curative effect, while also residing in it and belonging to hypertoxicity alkaloid, virulence is equivalent to 1250 times of potassium cyanide, thus restricts The clinical application of tetraodotoxin.And think, only reduce or eliminate the high toxicity of tetraodotoxin, at the same retain it with it is other When drug shares, the advantage for the de-addiction synergy having can just make tetraodotoxin obtain extensive clinical application.
The deficiencies in the prior art
Nearly ten years, many experts attempt the form by changing tetraodotoxin, improve safety system of the tetraodotoxin in clinic Number.In September, 2004, Huang cause strong etc. to have invented patent " preparation method of tetraodotoxin oil phase formulation " (ZL 2004I10080577.7).Tetraodotoxin oil phase formulation has been made using oil-in-water, Water-In-Oil technology in the patent.
The present inventor has found although above-mentioned patent changes tetraodotoxin form present in drug by verifying, but There is no the structures for changing tetraodotoxin, and tetraodotoxin is only made to become the particle suspension by oil package in grease, obtain Be a kind of tetraodotoxin emulsion.
Summary of the invention
In order to solve technical problem of the existing technology, the present invention provides a kind of preparation sides of tetraodotoxin carboxylate Method.
Technical scheme is as follows:
A kind of preparation method of tetraodotoxin carboxylate, the tetraodotoxin carboxylate is that tetraodotoxin is dissolved in unsaturated lipid Fatty acid glyceride or saturated fatty acid glyceride, the new compound generated after chemically reacting.
The tetraodotoxin is the tetraodotoxin extracted from filefish internal organ.The sterling that can be purity >=99%, can also To be the crude product of purity≤98%.
The tetraodotoxin in Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride can dissolved amount be 1- 1500 μ g/ml, for dissolved amount such as more than 255 μ g/ml, tetraodotoxin is in saturation state.
The Unsaturatcd fatty acid glycerides refer to the single component Unsaturatcd fatty acid glycerides of purity >=98%, packet Include various oleins or glyceryl linoleate or glyceryl linolenate etc..
The saturated fatty acid glyceride refers to the single component saturated fatty acid glyceride of purity >=98%, including each Kind glyceryl laurate ester or tristerin or tripalmitin etc..
The Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride can be one of which, be also possible to two kinds Or more, it can be extracted from animals and plants, it can also be artificial synthesized.
The tetraodotoxin carboxylate preparation method, comprising: take the single component unsaturated fatty acid of purity >=98% sweet The single component saturated fatty acid glyceride of grease or purity >=98%, sets in beaker, heating water bath, and 50-80 DEG C of constant temperature, magnetic force Stirring, then tetraodotoxin acidic aqueous solution is instilled wherein, it after 24 hours continuously stir, stands, obtains tetraodotoxin esterification Object.
The volume ratio of the tetraodotoxin aqueous solution and Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride is 1 : 20 or more.
The tetraodotoxin acidic aqueous solution is dissolved in pure water by tetraodotoxin and citric acid or acetic acid or phosphoric acid and is made, The quantity of water is complete molten for the upper limit with tetraodotoxin.
The tetraodotoxin acidic aqueous solution such as uses citric acid to make solvent, and Ying Tianjia citrate makees combination agent, The weight ratio of solid-state composition and tetraodotoxin is 5:1.
With tetraodotoxin carboxylate of the invention to intragastric administration on mice (mouse weight 22g/ is only), the peace of tetrodotoxin towards mice Full dosage is every 60 μ of mouse g/ times (theoretical content).
With tetraodotoxin carboxylate of the invention and Purple Perilla Seed Oil, angelica dahurica tincture, Flos Magnoliae oil, asarol and perilla leaf oil, etc. Deng, form compound preparation, can be used for easing pain.
It is oily with tetraodotoxin carboxylate and Resina Ferulae oil of the invention, valerian oil, datura flower oil, rhizoma corydalis oil and Morinda officinalis, Etc., compound preparation is formed, can be used for quitting drug abuse.
With tetraodotoxin carboxylate and Chinese yew seed oil, Rhizoma Atractylodis Macrocephalae oil, tangerine oil, oil of zedoary turmeric and Java brucea of the invention Oil, etc. forms compound preparation, can be used for anticancer.
Difference with the prior art of the present invention is as follows:
The prior art uses common vegetable and animals oils, and during fused, tetraodotoxin can not be formed with vegetable and animals oils Chemical reaction, this is the emulsion process of a kind of oil-in-water and Water-In-Oil, and what is obtained is the oil phase formulation containing tetraodotoxin, filefish Toxin is suspended in finish with microgranular.This is a kind of physical reactions, does not change the chemical structure of tetraodotoxin.
The grease that the present invention uses is the Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride of single component, is being changed It learns in reaction process, oleic acid or linoleic acid or linolenic acid or stearic acid or palmitic acid etc. in glyceride, with tetraodotoxin Periphery 5 hydroxyls formation combine closely, while by tetraodotoxin aqueous solution citric acid or other acid replace away, generation Be a kind of new compound with molecular structure alone.
Since tetraodotoxin has chemical structure special, that terrestrial animal seldom sees.Its molecular structural formula shows that it has One carbocyclic ring, a guanidine radicals, five hydroxyls, one and half aldoniolactone groups, almost all of carbon atom is all in its molecule Replace with asymmetry.This extremely complex molecular structure makes the molecular structure of tetraodotoxin carboxylate become more multiple It is miscellaneous.
The present invention is only to prepare tetraodotoxin carboxylate, since inventor's condition limits, to its unique molecular structure Formula is not yet understood, can only be remained scientist and be continued to study.
The present invention has the following technical effect that
One, tetraodotoxin acidic aqueous solution is directly dissolved in the Unsaturatcd fatty acid glycerides or saturated fat of single component by the present invention Fatty acid glyceride, obstructed Over emulsfication agent transition, method are easy.
Two, tetraodotoxin carboxylate of the invention is by tetraodotoxin and Unsaturatcd fatty acid glycerides or saturated fatty acid Glyceride is after chemically reacting, the new compound of generation.
Three, tetraodotoxin carboxylate of the invention does not have the high toxicity of tetraodotoxin, is used to have human body when oral preparation There is absolute safety.
Four, tetraodotoxin carboxylate of the invention can only as individual medicine material, can be used for it is other Pharmaceutical composition is at compound preparation, or is used in combination.It is formed into compound preparation with other medicines or is used in combination, can amplify and share The curative effect of drug inhibits the dependence, tolerance and side effect of concomitant medication
Specific embodiment
Effect of the present invention is confirmed With reference to embodiment.
Tetraodotoxin used in the present invention is purchased from Taizhou Kangte Biological Engineering Ltd., Jiangsu Province.
Glyceryl monooleate used in the present invention, glyceryl linolenate and olein, purchased from the remote city science and technology in Wuhan Development Co., Ltd.
1 tetraodotoxin carboxylate preparation method of embodiment
The glyceryl monooleate 20ml for taking purity >=98%, sets in 50ml beaker, heating water bath, and 50-80 DEG C of constant temperature, magnetic agitation. Tetraodotoxin sterling 5mg is taken, sets 2ml cillin bottle, is added citric acid 9.45mg, sodium citrate salt 15.55mg, pure water 1ml are quiet It sets, until it is complete molten, it is extracted out with small syringe, instills in the glyceryl monooleate stirred, continuously stir 24 hours, stood, obtain The evaporation of tetraodotoxin monoleate compound 20ml(moisture), 250 μ g/ml of tetraodotoxin theoretical value.
2 tetraodotoxin carboxylate preparation method of embodiment
The glyceryl linolenate 25ml for taking purity >=98%, sets in 50ml beaker, heating water bath, and 50-80 DEG C of constant temperature, magnetic agitation. Tetraodotoxin 5mg is taken, 2ml cillin bottle is set, citric acid 9.45mg, sodium citrate salt 15.55mg, pure water 1ml is added, is stood, directly It to Quan Rong, is extracted out with small syringe, instills in the glyceryl linolenate stirred, continuously stir 24 hours, stood, obtain fugutoxin Plain linolenate compound 25ml(moisture evaporation), 200 μ g/ml of tetraodotoxin theoretical value.
3 tetraodotoxin carboxylate preparation method of embodiment
The olein 20ml for taking purity >=98%, sets in 50ml beaker, heating water bath, and 50-70 DEG C of constant temperature, magnetic agitation. Tetraodotoxin 5mg is taken, sets 2ml cillin bottle, the acetic acid 1ml for being added that concentration is 1% is warm slightly, rocks to Quan Rong, is taken out with small syringe Out, it instills in the olein stirred, continuously stirs 24 hours, stand, obtain tetraodotoxin trioleate compound The evaporation of 20ml(moisture), 250 μ g/ml of tetraodotoxin theoretical value.
Measurement of the 4 tetraodotoxin aqueous solution of embodiment to intragastric administration on mice lethal dose
Purpose: tetrodotoxin towards mice lethal dose generally with intraperitoneal injection (ip) measurement, there are no to intragastric administration on mice lethal dose Measurement.In order to detect tetraodotoxin carboxylate to the safe handling dosage of intragastric administration on mice, it is necessary to first measure tetraodotoxin aqueous solution To the lethal dose of intragastric administration on mice.
Method: taking 22 grams of weight kunming mice 6, divides 3 groups, male and female is fifty-fifty.With tetraodotoxin aqueous solution to intragastric administration on mice, Tetraodotoxin is respectively 5 μ g/, and only, only, after stomach-filling 15min, the death of 25 μ g/ only, remaining is not dead by 25 μ g/ by 20 μ g/.It is more afterwards Secondary verifying, it was demonstrated that experiment is reliable.
Conclusion: tetraodotoxin aqueous solution is 25 μ g/ to the lethal dose of 22 grams of intragastric administration on mice.
5 tetraodotoxin carboxylate of embodiment tests intragastric administration on mice safe dose
Method: 22 grams of weight kunming mice 6 is taken, male and female is fifty-fifty.It is filled with tetraodotoxin carboxylate made from embodiment 1 to mouse Stomach, every intragastric administration on mice amount 0.25ml, the wherein 62.5 μ g of theoretical content of tetraodotoxin.After stomach-filling 15min, mouse is not dead, and 2 is small Shi Hou, mouse activity are complete normal.Hereafter, normal water supply is to food.To backward, mouse is without toxic reaction within second day.
Discuss: embodiment 4 the results show that tetraodotoxin aqueous solution to weight 22g intragastric administration on mice lethal dose be 25 μ g/ only/ It is secondary.This experiment with 0.25ml tetraodotoxin carboxylate to intragastric administration on mice, wherein 62.5 μ g of tetraodotoxin theoretical content, mouse not in It poisons with poison and dies.Show that tetraodotoxin carboxylate is 62.5 μ g/ to the safe dose of mouse, is equivalent to aqua stomach-filling lethal dose 2.5 again.In prediction on such basis, identical tetraodotoxin carboxylate such as being taken orally to 50kg adult, safe dose should be 625ml/ times, wherein Tetraodotoxin theoretical content is 156.25mg.Root it is documented that, the toxic dose of the oral tetraodotoxin of adult is 300 micrograms (ip).But it is such as changed to oral tetraodotoxin carboxylate, safety coefficient will be 520.8 times for taking orally tetraodotoxin.
Conclusion: tetraodotoxin carboxylate is intended only as an ingredient of composition compound preparation, presses filefish in practical applications Toxin theory content calculates, everyone each dosage is usually 10-20 microgram.As calculated by this dosage, its safety coefficient be should be 15625-7812 times.Therefore, tetraodotoxin carboxylate is used for oral preparation with absolute safety.
Experiment of the 6 tetraodotoxin carboxylate of embodiment to mouse stomach-filling in 30 days
Method: tetraodotoxin carboxylate made from embodiment 1 is diluted 5 times with soybean oil, makes 50 μ of tetraodotoxin theoretical content g/ml.Kunming mice 18 of 22 grams of weight are taken, male and female is fifty-fifty, is divided into 3 groups, wherein the 1st group, the 2nd group is filled with flux oil Stomach, the 3rd group of filling soybean oil.Daily stomach-filling is primary, when the time is the morning 9.1st group of filling flux oil 0.2ml(TTX-10 μ g), the 2nd Group fills flux oil 0.3ml(TTX-15 μ g), the 3rd group of filling soybean oil 0.2ml.During filling oil, the weight to 3 groups of mouse, work daily Emotionally condition compares.After 30 days, weighs and dissect mouse, take out internal organs and be compared.
As a result: the result shows that, during filling oil, the weight no significant difference of three groups of mouse, behavior is without significantly different.30 days After dissect, the equal no significant difference of liver and gallbladder kidney of three groups of mouse, mouse do not have teratogenesis, it is carcinogenic, disable, mutagenesis etc. it is existing As.
Conclusion: oral dosage only 10-20 microgram of the tetraodotoxin carboxylate for people therefore can absolute guarantee's human body Safety, teratogenesis, carcinogenicity, crippling, mutagenicity will not be generated.
7 tetraodotoxin carboxylate of embodiment adds Purple Perilla Seed Oil to the analgesic experiment of mouse
Preparatory work of experiment: tetraodotoxin carboxylate prepared by embodiment 1 is diluted with Purple Perilla Seed Oil, and tetraodotoxin theory is made Content is the medicinal oil of 10 μ g/ml.
Taking weight is 22 grams maternal instinct kunming mice 24, is divided into 3 groups, including low dose group, high dose group, blank group. Stomach-filling is carried out to first two groups with 0.2ml, 0.3ml medicinal oil respectively, blank group carries out stomach-filling with 0.2ml soybean oil.
Experimental method: mouse is carried out using hot plate plate method and adds sufficient test.Method is that 1000ml beaker is set water-bath, control 55 DEG C of weighing apparatus temperature.Before stomach-filling, the pain threshold of mouse is first tested and recorded, 10 minutes after stomach-filling, tests respectively and records mouse and lick foot Interval time.
Experimental result: the pain threshold average out to before administration group stomach-filling 3.5 seconds, the pain threshold average out to after stomach-filling 23.5 seconds, Show that analgesic effect has significant difference (P < 0.01), after administration group stomach-filling compared with after blank group stomach-filling, the threshold of pain of blank group Value average out to 3.8 seconds, showing the analgesic effect of administration group, there were significant differences (P < 0.01).
Experiment conclusion: tetraodotoxin carboxylate adds flux oil made of Purple Perilla Seed Oil to have obvious action (P to mouse analgesia < 0.01).
Preparation of the embodiment 8 for the tetraodotoxin esterification compound pharmaceutical of anticancer
Tetraodotoxin 24mg is taken, tetraodotoxin carboxylate 120ml is made as described in Example 2.Take Chinese yew seed expressed oil 2560ml is heated to 50-60 DEG C, and constant temperature, stirring instills above-mentioned tetraodotoxin carboxylate 120ml wherein.Rhizoma Atractylodis Macrocephalae is added to wave Hair oil, Curcuma Aromatic Oil, citrus volatile oil and each 80ml of Java brucea volatile oil, continue to stir, until it is uniform, obtain tetraodotoxin esterification The composition 3000ml of object and vegetable oil.Wherein, tetraodotoxin theoretical content is 8 μ g/ml.Soft capsule is made in above-mentioned composition 6000, every capsule net weight 0.5g, tetraodotoxin theoretical content is 4 μ g/.Application method: it is oral, it is 2-3 times daily, every time 3.
9 tetraodotoxin of embodiment is esterified the example observation of compound pharmaceutical treating cancer
Wang Qiyou, male, 66 years old, Liyang village party branch secretary.In March, 2019, in Shanghai Ruijin Hospital inspection, discovery is suffered from Advanced stage Small Cell Lung Cancer, because area is larger, lesion surrounds artery, cannot perform the operation, can only chemotherapy.After first time chemotherapy, 2019 3 Started the dispersing blood stasis capsule for taking the production of embodiment 8 by the moon 24.When having arrived second of chemotherapy, check on May 2nd, 2019, Rui Jin doctor The expert of institute has surprisingly found that lesion reduces 42% in the middle part of two lungs.The inspection on July 5th, 2019 shows the lung cancer tumor of patient It is basic to disappear.It continues to take dispersing blood stasis capsule at present, and is cooperated with dietotherapy.
Wang Hongmei, female, 39 years old, Heilungkiang Daqing oilfield worker.It checks that discovery has ovarian cancer, performs the operation in October, 2018 When have been transferred to lymph.Postoperative tumor undergoing continuous chemotherapy 8 times causes the enlargement of butt crack Lymph Nodes to exceed plus serious, and butt crack pain, from head to foot without Power, both legs are slightly swollen, have the pins and needles, and vomit, and appetite is poor.Start the dispersing blood stasis capsule for taking the production of embodiment 8 on April 9th, 2019, The hairyvein agrimony that takes traditional Chinese medicine simultaneously adds dandelion, and focuses on dietotherapy.Currently, above-mentioned all symptoms disappear, the enlargement of lymph nodes of ditch position by It is tapered small, it checks in the recent period, cancer index and blood routine are normal.
Zhou Guiyue, female, 60 years old, Jiangsu Xinghua City retired employees.The low differentiation of both ovaries is suffered from 16 daily inspection May in 2017 discovery Cancer, 5 course for the treatment of of postoperative chemotherapy.After in April, 2018, continue 3 course for the treatment of of chemotherapy, in September, 2018 is transferred to liver, blood examination, cancer index CA125 is 157.8 Iu/ml.The dispersing blood stasis capsule that the production of embodiment 8 is taken since in October, 2018, accompanies by dietotherapy and linseed Oily acid adding milk.It checks in the recent period, CA125 is 35.2 Iu/ml, CEA 1.98ng/ml, and indices belong to normal.
Xia Wenqin, female, 33 years old, the Jiangsu township Xinghua City Lin Tan peasant.Right lung gland cancer is suffered from 28 daily inspection March in 2017, discovery T4N2MIa(pleura, to lung)-IV phase, it is diffused into pleura.It carries out chemotherapy afterwards and targeted therapy, the state of an illness does not take a favorable turn.2018 7 Month, stop targeted therapy, starts the dispersing blood stasis capsule for taking the production of embodiment 8, accompany by dietotherapy and linseed oil acid adding milk.Currently, Patient profiles' indices are normal, and physical condition is good.
Zhang Fengyun, female, 60 years old, Heilungkiang Daqing retired worker.In October, 2017 checks, suffers from the low differentiation of cervical carcinoma, evening Phase shifts lymph and butt crack position on right clavicle.Non- chemotherapy, non-targeted therapy.So far from August, 2018, implementation is taken always The dispersing blood stasis capsule that example 8 makes, and accompany by dietotherapy and linseed oil acid adding milk.Currently, lymph metastasis of cancer is effectively controlled, it is every Index is normal, and physical condition is good.
Qu Juan, female, 51 years old, Heilungkiang Qitaihe City professional.Check that 3 phase of cervical carcinoma is suffered from discovery in October, 2016 B cannot perform the operation, and implement chemicotherapy three months.It checks that discovery cancer index increases in March, 2018, and is transferred to left side pelvic cavity leaching Bar.So far from September, 2018, the dispersing blood stasis capsule of the production of embodiment 8 is taken always, and accompanies by dietotherapy and linseed oil acid adding milk. Currently, lymph metastasis of cancer is effectively controlled, indices are normal, and physical condition is good.
Fourth grandmother, female, 80 years old, Jiangsu Taixing City Huangqiao Zhen resident.In June, 2017 checks, has ovarian cancer, because older, It does not perform the operation.There is pain and with bleeding, diet decline, both legs edema in May, 2018.So far from September, 2018, one The dispersing blood stasis capsule of the production of embodiment 8 is directly taken, and accompanies by dietotherapy and linseed oil acid adding milk.During this, until currently, patient Pain and bleeding disappear, and diet is normal, is in a good state of health, especially the good news is gradually blackening covered with silver hair.
Lv little E, female, 49 years old, Jiangsu Xinghua City was retired due to illness teacher.It checking in October, 2017, the low differentiation of adenocarcinoma of lung is suffered from discovery, Advanced stage.Minimally Invasive Surgery, postoperative chemotherapy, rear targeted therapy, but not can control the metastasis of cancer.In March, 2019, cancer cell be diffused into bone, The positions such as liver, meninx, lymph.Start in April, 2019 to take the dispersing blood stasis capsule that embodiment 8 makes, stops all meat dish, and accompany by Three meals in a day eat the food therapy of sweet potato.It checks in the recent period, discovery brain tumor is obviously reduced, stalemate at other position cancerous swellings. Blood examination indices are all normal.Patient mental's state and constitution are good at present.
Tang little Bin, female, 49 years old, Jiangsu Xinghua City was retired due to illness doctor.It checks in April, 2019, near the spray doorway of discovery stomach lower end It with larger malignant tumour, and has festered, tumour blocking causes to feed, cannot defecate.On May 7th, 2019, because of patient Brain has postoperative complication, can not perform the operation, and can not implement chemotherapy and targeted therapy, have to be in Jiangsu Prov. People's Hospital open flow door branch Frame, bracket are at right angles bent greatly because of tumour.Since on May 9th, 2019 so far, disappearing for the production of embodiment 8 is taken to it always Stasis of blood capsule 's content acid adding milk accompanies by stream juice food and carries out dietotherapy.Currently, patients diet and stool belong to normal, indicate swollen Tumor does not continue to grow up, and rotten position take a favorable turn possibility.

Claims (9)

1. a kind of preparation method of tetraodotoxin carboxylate, which is characterized in that the method includes the following steps: fugutoxin Element dissolves in Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride, and new compound is generated after chemically reacting.
2. the preparation method of tetraodotoxin carboxylate according to claim 1, which is characterized in that the tetraodotoxin is The tetraodotoxin extracted from filefish internal organ.
3. the preparation method of tetraodotoxin carboxylate according to claim 1, which is characterized in that the tetraodotoxin is The sterling of purity >=99% is also possible to the crude product of purity≤98%.
4. tetraodotoxin carboxylate according to claim 1, which is characterized in that the tetraodotoxin is in unsaturated fat In acid glyceride or saturated fatty acid glyceride can dissolved amount be 1-1500 μ g/ml, dissolved amount is such as more than 255 μ g/ml, filefish Toxin is in saturation state.
5. the preparation method of tetraodotoxin carboxylate according to claim 1, which is characterized in that the unsaturated fat Acid glyceride refers to that the single component Unsaturatcd fatty acid glycerides of purity >=98%, the Unsaturatcd fatty acid glycerides are Olein, glyceryl linoleate or glyceryl linolenate.
6. the preparation method of tetraodotoxin carboxylate according to claim 1, which is characterized in that the saturated fatty acid Glyceride refers to that the single component saturated fatty acid glyceride of purity >=98%, the saturated fatty acid glyceride are lauric acid Glyceride, tristerin or tripalmitin.
7. tetraodotoxin carboxylate according to claim 1, which is characterized in that in the preparation method using a kind of or Two or more Unsaturatcd fatty acid glycerides or saturated fatty acid glyceride, the Unsaturatcd fatty acid glycerides Or the source of saturated fatty acid glyceride is the extraction or artificial synthesized from animals and plants.
8. the preparation method of tetraodotoxin carboxylate according to claim 1, which is characterized in that the preparation method packet It includes following steps: taking the single component Unsaturatcd fatty acid glycerides of purity >=98% or the single component saturation of purity >=98% Fatty glyceride is set in beaker, heating water bath, and 50-80 DEG C of constant temperature, magnetic agitation, then tetraodotoxin acidic aqueous solution is dripped Enter wherein, after 24 hours continuously stir, stands, obtain tetraodotoxin carboxylate.
9. the preparation method of tetraodotoxin carboxylate according to claim 8, which is characterized in that in the preparation method Tetraodotoxin acidic aqueous solution, be dissolved in pure water with acid by tetraodotoxin and be made, the acid be selected from citric acid, acetic acid or phosphorus The quantity of acid, water is complete molten for the upper limit with tetraodotoxin.
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