CN1647800A - Globefish oil preparation and its preparing method - Google Patents
Globefish oil preparation and its preparing method Download PDFInfo
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Abstract
The globefish oil preparation has tetrodotoxin as main effective component, and may be further prepared via conventional medicine preparing process into soft capsule, emulsion, nourishing tonic or suppository for relieving pain or stopping drug addiction. The preparation process of the globefish oil preparation includes the steps of: homogenating globefish internal organs via adding water and heating; hydrolyzing via adding weak alkali and ammonium salt to separate globefish oil; water washing globefish oil, mixing with organic solvent, crystallizing at low temperature and centrifugally filtering to eliminate organic solvent; and adding proper amount of stabilizer to form the globefish oil preparation. The said process is simple, high in globefish oil yield and stable in quality.
Description
Technical field
The present invention relates to a kind of globefish oil preparation and preparation method thereof, specifically, the present invention relates to extract the internal organs such as a kind of liver, ovary the preparation method of puffer oil and globefish oil preparation thereof from the puffer fish.
Background technology
The puffer fish is a kind of edible Fish of condition that contain severe toxicity, is the poisonous fishes of forbidding the pin aquatic foods on the market in China.The nearly kind more than 40 of known whole world puffer fish mainly is distributed in marine sites such as coastal area of china, the sea of Japan and the Indian Ocean of west of pacific ocean and Mediterranean, and the puffer fish also has artificial cultivation at present, and wherein, Chinese puffer fish crop accounts for 70% of world wide production.In the Far East Area, puffer is regarded as a kind of delicious food since ancient times, according to surveying and determination, contains protein 18.7% in the puffer meat, fat 0.26%, vitamin B
1Be 0.2PPM, B
2Be 1PPM.The puffer fish internal organs has very high physiologically active, and therefore, puffer is again a kind of marine pharmaceutical resource of preciousness.
Puffer is poisonous but can be medicinal, and ancient books doctor work has record more, as Compendium of Material Medica " ichthyotoxin the most very " is just arranged, the record of " liver and seed are very toxic, can cure mainly the copperworm scar "; " Kaibao Bencao " has the record of " main tonify deficiency, the gas that dries, reason waist foot, remove haemorrhoids, parasite killing ".Abroad, ancient Assyrian, Babylonian know that also " ball fish " is the puffer fish, and be poisonous, can cure the disease.This shows that the puffer fish is medicinal existing long and historical widely.The puffer fish is out of favour because of the toxic people of making fears, so, how the puffer fish is used, turn harm into good, improve its economic worth, paid close attention to by many scholars.At home, the fifties just the someone begin puffer liver oil industrial utilization and edible research (1958, aquatic science technological achievement compilation. " comprehensive utilization of puffer ", Shanghai science tech publishing house, IV-46～56); The scholar that the sixties have specially to the liver oil of worm stricture of vagina Fugu and Fugu rubripes (Temmincket Schlegel) liver oil carry out medical test (Hou Wenpu. west of pacific ocean fishery proceeding, P40-45,1962; High brightness. marine drug research paper collection, Qingdao City's medical science institute, P55-61,1979); The seventies has the people that the puffer liver oil is made new oil generation, be used for clinical tumor test (Wu Hanlin. Chinese poisonous fishes and medicinal fishes, P274,1977); The seventies is to the eighties, and Hebei Provincial Aquatic Products Research Institute etc. develop " removing malicious puffer liver oil " (.1983 such as Wei Jiying, marine drug, 2:85～88 of effects such as significantly pressing down cancer, analgesia, antiinflammatory, enhancing human body immunity function; .1988 such as Hou Junge, 1-2:55～56; .1987 such as Cai Xiande, 2:14～16; .1984 such as Jiang Yun, marine drug, 4:33～35; Shu Ronghua .1985,3:7～9), still, because the effective ingredient of " removing malicious puffer liver oil " is unclear, the result fails to obtain the national drug application for registration, and gives up the study of; The high reputation of Japanese tail man " medicine for external use that effluent Puffer liver oil is made " applying date this patent (clear 94317) in 1980; Wang Weiguos in 1997 etc. have applied for that (CN1193516A, CN1279957A), still, this patent does not have the effective ingredient of clear and definite puffer liver oil drug rehabilitation for the drug rehabilitation patent of puffer liver oil.
Above-mentioned achievement and patent are prepared removes malicious puffer liver oil, has two big shortcomings: the one, and, the active ingredient of puffer liver oil is unclear, is difficult to the stable curative effect and the drug safety of assurance medicine; The 2nd,, with decocting in water or the dirty extraction liver oil of lamp baked liver and traditional freezing stearic method of removing, exist oil yield low, quality problems such as precipitate appear after the puffer liver oil is deposited easily.
In order to solve an above-mentioned difficult problem, we have carried out various analyses and research, with a kind of opposite thinking, we find that tetraodontoxin has special dose-effect relationship, be that tetraodontoxin is in certain dilution intervals, there is not drug treatment function, and in specific dilution intervals, have good withdrawal drug dependence effect (Huang Zhiqiang appoints thunderous etc. Chinese patent ZL98102072.0), in view of the above, infer the active ingredient or the component of puffer liver oil, be two or more than, wherein, drug rehabilitation and analgesic effective ingredient, supposition are residual micro-tetraodontoxins in " removing malicious puffer liver oil ".In order to guarantee drug safety, must clear and definite puffer oil effective ingredient and research improves the quality and the preparation method of oil yield.
Summary of the invention
Purpose of the present invention is to provide a kind of analgesia, drug rehabilitation determined curative effect, and effective ingredient is clear, safely, do not have an addicted globefish oil preparation.
The invention provides a kind of globefish oil preparation, it is characterized in that, the effective ingredient of described globefish oil preparation is a tetraodontoxin.
Described globefish oil preparation is puffer liver oil preparation or globefish ovary oil formulation; The concentration of tetraodontoxin is 0.01 μ g/ml～15 μ g/ml in the described globefish oil preparation.
Another purpose of the present invention is, provides a kind of technology simple, implements oil yield height, the preparation method of stay-in-grade globefish oil preparation easily.
The preparation method of described above-mentioned globefish oil preparation is characterized in that,
(1) with homogenate after the globefish liver stripping and slicing, add 0.5～3 times of water in the liver weight ratio, be heated to 30～60 ℃ after, regulate pH value to 7～10, reheat to 60～90 ℃ are incubated 20～60 minutes, add 5%～20% ammonium salt by weight proportion, stirring makes its abundant hydrolysis, and the hydrolyzed solution filtered while hot is isolated oil reservoir, through washing, dehydration gets crude product oil
(2) crude product oil adds organic solvent, in-3 ℃～-20 ℃ following freezing and crystallizings, to be crystallized fully after, filter at low temperature, after oil strain steams and takes off organic solvent, the concentration of regulating tetraodontoxin in the oil strain is 0.01 μ g/ml～15 μ g/ml, adds stabilizing agent again and makes its mass percentage concentration in preparation reach 0.001%～0.2%, promptly gets globefish oil preparation.
Wherein said internal organs are globefish liver or globefish ovary; Described ammonium salt is selected from one or more in the following material: ammonium carbonate, ammonium sulfate, ammonium nitrate, ammonium chloride; Described weak base is ammonium hydroxide;
Described organic solvent is selected from one or more in the following material: n-hexane, acetone, isopropyl acetone, benzene, ethanol, and wherein thick oil is 1: 0.5～3 with the volume ratio of organic solvent;
Described stabilizing agent is selected from one or more in the following material: propyl gallate, tert-butylbenzene diphenol, butylated hydroxyarisol, Vc, Ve.
Between the various ammonium salts and the part by weight between the various stabilizing agent do not have special requirement.
Described globefish oil preparation when tetraodontoxin concentration is high in the puffer oil, adds medical oil; When tetraodontoxin concentration in the puffer oil is low, can add following one of them high puffer oil or the tetraodontoxin oil formulation of tetraodontoxin content.With the concentration adjustment of tetraodontoxin in the oil in the scope that requires.
The ammonium salt of described preparation usefulness, shared part by weight is 5%-20% in preparation solution.
Described medical oil is for Chinese Pharmacopoeia regulation injection oil or oral oil are Oleum Arachidis hypogaeae semen, Oleum Sesami, Oleum Glycines, Oleum Gossypii semen, almond oil, Oleum Camelliae and fish oil.
The ratio of described stabilizing agent shared volume in preparation is 0.001%～0.2%.
The globefish oil preparation of described preparation can be made capsule, Emulsion or suppository (work such as Zhuan Yue, " practical drug preparation technique ", People's Health Publisher, 1999, P263-276 according to the pharmaceutical preparation of routine; Lu Binzhu, " novel pharmaceutical formulation and new technique ", People's Health Publisher, 1998, P66-75; The Long Xiaoying work, " flow process pharmaceutics ", Chinese Medicine science and technology publishing house, 2003, P107-116).
Preparation of the present invention has the following advantages: it is tetraodontoxin that globefish oil preparation analgesia that 1, the present invention is clear and definite, drug rehabilitation main effectively becomes, and with tetraodontoxin as quality control standard; In addition, preparation of the present invention is rich in highly unsaturated fatty acid, has strengthened combined therapy effect and raise immunity.2, preparation of the present invention has significant analgesic activity, and curative effect of medication is definite, and characteristics are that onset is slow, and the prolongation of effect time is long, and still effective to morphine or dolantin tolerance addict, no addiction and toxic and side effects are safe.3, oral formulations of the present invention stores convenient, easy to carry, taking convenience, can be patient's medication and brings great convenience, alleviates patient's misery.4, preparation method of the present invention, the oil yield height, oil quality is good, and precipitate does not appear in steady quality, storage.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.
Embodiment 1:
(1) get globefish liver 1000 grams, stripping and slicing adds 1 times of water, stirs 20～60 minutes, centrifugal filtration (filtrate is used for extracting tetraodontoxin) after the liver piece homogenate of filter back, adds 0.5 times of water, be stirred and heated to 30 ℃, add 10% ammonia, be transferred to pH=8, continue to be heated with stirring to 70 ℃, be incubated 30 minutes, add ammonium carbonate 80g, continue to stir, make its abundant hydrolysis, hydrolyzed solution is centrifugalize while hot, and oil, water, liver slag are collected respectively;
(2) washing: with 50 ℃ of hot water washing oil (oil is 1: 1 with the volume ratio of water) 2 times, fully stir, leave standstill 45 minutes after, make the profit layering, the collection oil reservoir;
(3) dehydration: slough W/O with the vacuum machine, get crude product oil;
(4) take off solid fat: crude product oil is after preliminary cooling, and the n-hexane that adds 0.5 times of oil volume mixes with oil, carries out crystallization under-8 ℃ condition, and crystallization back is fully filtered down at-8 ℃～-6 ℃.After the oil strain vacuum concentration reclaims organic solvent, add Oleum Arachidis hypogaeae semen (TTX concentration is higher than requirement content in the oil), regulating tetraodontoxin proportion in oil is 0.01 μ g/ml, again with propyl gallate, making its concentration in preparation is 0.2%, promptly gets globefish oil preparation.
Embodiment 2:
(1) after the globefish liver 1000 gram stripping and slicing homogenate, add 1.5 times of water, be stirred and heated to 40 ℃, divide secondary to add 12% ammonia, be transferred to pH=7, continue to be heated with stirring to 90 ℃, be incubated 40 minutes, add ammonium carbonate, 150 grams, continue to stir, make its abundant hydrolysis, hydrolyzed solution is centrifugalize while hot, and oil, water, liver slag are collected respectively;
(2) washing: with 60 ℃ of hot water washing oil (oil is 1: 1.5 with the volume ratio of water) 2 times, fully stir, leave standstill 35 minutes after, make the profit layering, the collection oil reservoir;
(3) dehydration: add 3% anhydrous CaCl in the oil
2Dehydration after the filtration, gets crude product oil;
(4) take off solid fat: crude product oil adds 1.5 times of amount acetone and mixes after preliminary cooling, carry out crystallization under-3 ℃ condition, and crystallization back is fully filtered under-11 ℃～-8 ℃ conditions.After the oil strain vacuum concentration reclaimed organic solvent, TTX concentration was 0.6 μ g/ml (tetraodontoxin is consistent with the concentration of preparation requirement) in the oil, and adding the tert-butylbenzene diphenol, to make its concentration in preparation be 0.1%, promptly gets globefish oil preparation.
Embodiment 3:
(1) globefish liver 1000 gram strippings and slicings add 1 times of water, stir 20～60 minutes, centrifugal filtration (filtrate is used for extracting tetraodontoxin), filter back liver piece adds 1 times of water, is stirred and heated to 50 ℃, add 13% ammonia, be transferred to pH=9, continue to be heated with stirring to 60 ℃, be incubated 45 minutes, add ammonium chloride 140 grams, continue to stir, make its abundant hydrolysis, hydrolyzed solution is centrifugalize while hot, and oil, water, liver slag are collected respectively;
(2) washing: with 65 ℃ of hot water washing oil (oil is 1: 2 with the volume ratio of water) 1 time, fully stir, leave standstill 20 minutes after, make the profit layering, the collection oil reservoir;
(3) dehydration: add 4% anhydrous CaCl in the oil
2Dehydration after the filtration, gets crude product oil;
(4) take off solid fat: crude product oil adds 2 times of amount isopropyl acetones and mixes after preliminary cooling, under-15 ℃ condition, carry out crystallization, crystallization back is fully filtered under-15 ℃～-10 ℃ conditions, after the oil strain vacuum concentration reclaims organic solvent, add the high puffer oil (TTX is lower than requirement concentration in the oil) of tetraodontoxin content, regulating tetraodontoxin proportion in oil is 5 μ g/ml, promptly gets globefish oil preparation.
Embodiment 4:
(1) globefish ovary 1000 gram strippings and slicings, add 3 times of water, stir 20～60 minutes post-heating to 60 ℃, add 7% ammonia, be transferred to pH=8.5, continue to be heated with stirring to 80 ℃, be incubated 60 minutes, add ammonium nitrate 210 grams, continue to stir, make its abundant hydrolysis, hydrolyzed solution is centrifugalize while hot, and oil, water, ovary slag are collected respectively;
(2) washing: with 65 ℃ of hot water washing oil (oil is 1: 1.5 with the volume ratio of water) 2 times, fully stir, leave standstill 20 minutes after, make the profit layering, the collection oil reservoir;
(3) dehydration: slough W/O with the vacuum machine, get crude product oil;
(4) take off solid fat: crude product oil adds 2 times of amount n-hexane and acetone mixed liquor (15% n-hexane, 85% aqueous acetone (moisture 1.4%)) after preliminary cooling, under-14 ℃ condition, carry out crystallization, crystallization back is fully filtered under-10 ℃～-5 ℃ conditions, after the oil strain vacuum concentration reclaims organic solvent, add tetraodontoxin oil formulation (TTX is lower than requirement concentration in the oil), tetraodontoxin concentration is 10 μ g/ml in the adjusting oil, it is 0.2% that the adding butylated hydroxyarisol makes its concentration in preparation, promptly gets globefish oil preparation.
Experimental example 1: puffer liver oil fatty acid composition:
The liver of worm stricture of vagina Fugu, yellowfin Fugu, the yellow Fugu of chrysanthemum, Fugu rubripes (Temmincket Schlegel) and artificial cultivation Fugu rubripes (Temmincket Schlegel) is gone out liver oil with extracted with diethyl ether, be prepared into the fatty acid methyl ester mixture respectively, with fatty acid methyl ester hybrid standard sample (Sigma company), carry out gas chromatography retention time and compare under identical conditions, quantitative approach adopts the peak area normalization method.Result's (seeing Table 1): the kind of the liver oil institute fatty acids of liver oil of four kinds of wild puffer fishes and artificial cultivation puffer fish is basic identical, though various fatty acid percentage composition is not quite similar, difference is very not big.Can record 18 kinds of content fatty acids, wherein saturated fatty acid content accounts for about 25% of fatty acid total amount, with C
16Content is the highest; Unsaturated fatty acid accounts for 71% of total fat amount, is 2.8 times of satisfied fatty acid, and wherein, eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA) account for 9.3% and 17.3% of total fat amount.Polyenoic acid such as EPA and DHA is to constitute cell and component of organization, has special efficacy (anticarcinogen-C such as anti-angiocardiopathy, antiinflammatory, anticancer, enhancing immunity
20:5(Japan) openly speciallys permit communique, clear and 62-77319; Zhang Chaohui. " marine drug research and development ", the People's Health Publisher, 2003, P49).Do not find that in the content of puffer fatty acid oil unedible chemical compound exists.
The percentage ratio that five kinds of puffer liver oils of table 1 fatty acid is formed
| Fatty acid is formed | Wild Fugu | The artificial cultivation Fugu | |||
| The worm stricture of vagina | The chrysanthemum Huang | Yellowfin | Red fin | Red fin | |
| ??C 12:0 | ????0.1 | ????0.3 | ????0.2 | ????0.1 | ????- |
| ??C 14:0 | ????1.8 | ????2.5 | ????3.4 | ????2.7 | ????2.5 |
| ??C 15:0 | ????0.5 | ????0.7 | ????0.7 | ????0.6 | ????0.6 |
| ??C 16:0 | ????16.7 | ????17.1 | ????15.5 | ????15.7 | ????16.6 |
| ??C 17:0 | ????1.0 | ????1.5 | ????1.1 | ????1.2 | ????1.1 |
| ??C 18:0 | ????4.7 | ????4.3 | ????5.5 | ????4.0 | ????4.6 |
| ??C 20:0 | ????0.4 | ????0.4 | ????0.4 | ????0.3 | ????0.3 |
| ??C 16:1 | ????15.8 | ????14.7 | ????10.8 | ????13.9 | ????15.3 |
| ??C 18:1 | ????31.2 | ????23.0 | ????23.7 | ????28.3 | ????25.5 |
| ??C 18:2 | ????1.2 | ????1.0 | ????1.9 | ????1.5 | ????1.5 |
| ??C 18:3/C 20:1 | ????5.0 | ????7.0 | ????4.8 | ????7.0 | ????3.2 |
| ??C 18:4 | ????0.9 | ????0.6 | ????1.1 | ????1.0 | ????0.8 |
| ??C 20:4/C 22 | ????2.6 | ????1.8 | ????2.9 | ????2.0 | ????1.7 |
| ??C 20:5 | ????2.6 | ????2.2 | ????2.7 | ????2.8 | ????3.2 |
| ??C 22:6 | ????6.9 | ????8.6 | ????15.3 | ????14.5 | ????12.5 |
| Other | ????3.9 | ????5.5 | ????5.8 | ????3.9 | ????4.2 |
Experimental example 2
The tumor that presses down of puffer liver oil is tested
Get 60 of white mice (18～20 gram), the strain of inoculation hepatocarcinoma tumor selected tumor strain white mice of the same size to be divided into experimental group and matched group, 10 every group after 3 days.Wherein experiment divides three groups, 1. globefish liver oil; 2. globefish oil preparation; 3. tetraodontoxin aqueous solution (containing tetraodontoxin 0.2 μ g/ml).Every day the lumbar injection secondary, each 0.2ml/ only, administration 10 days stopped administration after 3 days, dissected to get tumor and main internal organs are checked, experimental group and matched group tumor are heavily compared, and calculated suppression ratio.Experimental result (seeing Table 2): 1. globefish liver oil is 54% to the suppression ratio of tumor, and tumor killing effect is obvious, P＜0.05; 2. globefish oil preparation reaches 59% to the suppression ratio of tumor, and tumor killing effect is very obvious, P＜0.01; 3. tetraodontoxin aqueous solution group is to tumor body unrestraint effect.Illustrate that but the puffer liver oil exists the tumor component really, but be not tetraodontoxin; Pressing down the tumor component may be relevant with puffer liver oil camber unsaturated fatty acid.
Table 2 globefish liver extract presses down the tumor experiment
| Group | Dosage is only inferior | The tumor strain | Number of mice (only) | Average tumor heavy (gram) | Suppression ratio | Value | ||
| Experimental group | Matched group | Experimental group | Matched group | |||||
| Globefish liver oil | ????0.2 | Hepatoma | ????10 | ????10 | ??1.1 | ????2.4 | ??54 | ??＜0.05 |
| Globefish oil preparation | ????0.2 | Hepatoma | ????10 | ????10 | ??1.38 | ????3.37 | ??59 | ??＜0.01 |
| Tetraodontoxin liquid (0.2 μ g/ml) | ????0.2 | Hepatoma | ????10 | ????10 | ??3.8 | ????3.5 | Do not have | |
Experimental example 3
The mice hot plate analgesic experiment of puffer liver oil
Select the female mice of body weight 18～22g for use, 10 every group, elder generation measures the normal pain valve of each Mus before the administration.Lumbar injection puffer liver oil preparation and normal saline matched group (0.2ml/ only), measures 30,60,90,120 and 150 minutes mice bitterly valve once, every day, secondary was administered five times altogether.Experimental result: mice pain valve raising percentage rate is after the first administration: 29%, do not show obvious effect (P＞0.05) as yet; After the 2nd to 4 administration, mice pain valve improves that percentage rate is 33%, 34%, 49% respectively, (P＜0.05 and P＜0.01); After the last administration 48 hours, mice pain valve improves percentage rate and is: 47% (P＜0.01), and this explanation globefish oil preparation analgesic effect onset is slow, and behind the successive administration, analgesic effect can continue to rise, and analgesic activity is obvious, and analgesia duration is long.Before the matched group medicine with medicine after the no significant difference of pain valve reaction.
Experimental example 4
The screening experiment of puffer liver oil analgesic effective component
One of chromatographic silica gel glass column is housed, add puffer liver oil 10ml, when liver oil is reduced to the silica gel face, add the petroleum ether eluting earlier, divide bottle to collect eluent, every bottle of 50ml checks that eluent does not have till the component outflow, press Same Way again, successively add ether, petroleum ether-ethyl acetate (10: 1), petroleum ether-ethyl acetate (10: 1) and ethanol.Vapor away the solvent in the receiving flask, and carry out tracking and measuring in conjunction with mouse writhing analgesia method.As a result, collect in the fraction in petroleum ether-ethyl acetate (10: 1), have several bottles to detect analgesic activity, other collects fraction, does not have analgesic activity.
Be associated with the fraction of analgesic activity, pour in the separatory funnel, add acetic acid water (pH4.8) jolting, profit is fully mixed, leave standstill, collect water layer solution.Oil reservoir with the deionized water washing several times, merges aqueous solution so repeatedly, uses D152
#Weak-acid cation-exchange resin exchanges, and 8% acetic acid eluting is followed the tracks of toxicity with white mice, collects toxic fraction, concentrating under reduced pressure.Get concentrated solution and carry out thin layer chromatography, with the contrast of tetraodontoxin Puffer product, developing solvent is a n-butyl alcohol: acetic acid: water=4: 2: 2, the colour developing of weber reagent spray.The thin layer chromatography result, tetraodontoxin Puffer product are a pink garden speckle, Rf=0.48, sample also have a pink mottle at the Rf=0.48 place.So, assert that tentatively puffer liver oil analgesic effective ingredient is a tetraodontoxin.
Experimental example 5
The confirmatory experiment of puffer liver oil analgesic effective component
Adopt the white mice writhing method.White mice body weight 18～23g, the male and female dual-purpose, experiment divides two groups, 10 of every group of white mice.Experimental pharmacy: 1. puffer liver oil preparation, 2. Oleum Arachidis hypogaeae semen adds tetraodontoxin (tetraodontoxin content is 0.2 μ g/ml), with patent " preparation method of tetrodotoxin oil phase formulation " preparation (it is strong etc. that Huang causes, Chinese patent application number 200410080557.7).
Give mouse stomach (0.1ml/10g) with experimental pharmacy respectively, every day, secondary was administered three times altogether.Measure each Mus writhing response number before the first administration earlier, after the administration 3 hours, lumbar injection 0.6% acetic acid 0.2ml/ only write down mouse writhing number in 20 minutes, compares with writhing response before the administration.Result's (seeing Table 3) mouse writhing reaction suppression ratio is: 1. group is 9%; 2. group is that 24%, two group is not all showed obvious effect, P＞0.05; After the administration 3 hours for the third time, measure acetic acid and be respectively white mice writhing response suppression ratio: 90% and 85%, the obvious P of analgesic activity＜0.01.And two groups of administration relatively, and difference is not remarkable, P＞0.05.This result proves that puffer liver oil preparation analgesic effective ingredient is a tetraodontoxin.
Table 3 mouse writhing method is to the analgesic activity of puffer oil
| Group | Number of animals (only) | Turn round the body number before the medicine | Medicine is turned round the body number | Writhing response suppression ratio % | Value | ||
| 3h behind the medicine | 3h behind the medicine for the third time | 3h behind the medicine | 3h behind the medicine for the third time | ||||
| Puffer liver oil preparation | ????10 | ????13.5 | ????12.1 | ????1.4 | ????9 | ????90 | ??＜0.01 |
| Oleum Arachidis hypogaeae semen+TTX (TTX0.2 μ g/ml) | ????10 | ????15.4 | ????11.7 | ????2.3 | ????24 | ????85 | ??＜0.01 |
Clinical trial analgesic effect
Cancer patient's 22 examples that admit to hospital, male's 16 examples, women's 6 examples, age, man 50 to 67 years old, woman 32 to 80 years old.Observing sick the kind altogether has: gastric cancer 4 examples, hepatocarcinoma 4 examples, pulmonary carcinoma 3 examples, rectal cancer 2 examples, Folium Nicotianae preparatum cancer 2 examples, colon cancer, thyroid carcinoma, cervical cancer, ovarian cancer, esophageal carcinoma, bladder cancer, each 1 example of lymphatic cancer.Cancer patient has other internal organs and lymphatic metastasis, and these patients mostly are mixed with persistence (majority) or paroxysmal (minority) pain.Dosage every day three times, 1～2 of each oral meal soft capsule (every contains one milliliter of Fugu ocellatus oil).It is to take medicine the result back about 3 hours that pain is observed: took medicine 1 day, pain relieving onset 4 examples account for 18.2%; 2 days onset 11 examples account for 50%; 3 days onset 5 examples account for 22.7%; 4 days not onset 2 examples account for 9%.From analgesic effect: no analgesic effect 2 examples account for 9.1%; Slight 1 example of alleviating accounts for 4.5%; Moderate pain relieving 10 examples account for 45.5%; Obviously pain relieving 5 examples account for 22.7%; Pain relieving 4 examples account for 18.2%, total effective rate 86.4% fully.The pain relieving characteristics are: onset is slow, but the pain relieving longer duration; To using narcosis analgesic tolerance addiction patient to still have analgesic activity.Its analgesia characteristics and zoopery be basically identical as a result.
Claims (9)
1, a kind of globefish oil preparation is characterized in that, the effective ingredient of described globefish oil preparation is a tetraodontoxin.
2, globefish oil preparation as claimed in claim 1 is characterized in that described globefish oil preparation is puffer liver oil preparation or globefish ovary oil formulation.
3, globefish oil preparation as claimed in claim 1 or 2 is characterized in that, the tetraodontoxin proportion is 0.01 μ g/ml～15 μ g/ml in the described globefish oil preparation.
4, the preparation method of globefish oil preparation as claimed in claim 1 is characterized in that,
(1) with homogenate after the globefish liver stripping and slicing, add 0.5～3 times of water in the liver weight ratio, be heated to 30～60 ℃ after, regulate pH value to 7～10, reheat to 60～90 ℃ are incubated 20～60 minutes, add 5%～20% ammonium salt by weight proportion, stirring makes its abundant hydrolysis, and the hydrolyzed solution filtered while hot is isolated oil reservoir, through washing, dehydration gets crude product oil
(2) crude product oil adds organic solvent, in-3 ℃～-20 ℃ following freezing and crystallizings, to be crystallized fully after, filter at low temperature, after oil strain steams and takes off organic solvent, the concentration of regulating tetraodontoxin in the oil strain is 0.01 μ g/ml～15 μ g/ml, adds stabilizing agent again and makes its mass percentage concentration in preparation reach 0.001%～0.2%, promptly gets globefish oil preparation.
5, preparation method as claimed in claim 4, wherein said internal organs are globefish liver or globefish ovary.
6, preparation method as claimed in claim 4 is characterized in that, described ammonium salt is selected from one or more in the following material: ammonium carbonate, ammonium sulfate, ammonium nitrate, ammonium chloride, described weak base are ammonium hydroxide.
7, preparation method as claimed in claim 4 is characterized in that, described organic solvent is selected from one or more in the following material: normal hexane, acetone, isopropyl acetone, benzene, ethanol.
8, preparation method as claimed in claim 4, wherein thick oil is 1: 0.5～3 with the volume ratio of organic solvent.
9, preparation method as claimed in claim 4 is characterized in that described stabilizing agent is selected from one or more in the following material: propyl gallate, tert-butylbenzene diphenol, butylated hydroxyarisol, Vc, Ve.
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| CNB2004101039096A Active CN100340246C (en) | 2004-12-30 | 2004-12-30 | Globefish oil preparation and its preparing method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107047809A (en) * | 2017-03-31 | 2017-08-18 | 福州海汇生物科技实业有限公司 | A kind of fish oil preparation technology |
| CN107115298A (en) * | 2017-05-22 | 2017-09-01 | 黄海枫 | A kind of TTX emulsio olei jecoris piscis |
| CN108524522A (en) * | 2018-06-12 | 2018-09-14 | 中国水产科学研究院淡水渔业研究中心 | Application of the tetraodotoxin in preparing the drug for suppressing lung carcinoma cell to migrate and be proliferated |
| CN108524521A (en) * | 2018-06-12 | 2018-09-14 | 中国水产科学研究院淡水渔业研究中心 | Application of the tetraodotoxin in preparing the drug for inhibiting lung carcinoma cell or tumour to increase |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1072486C (en) * | 1996-09-24 | 2001-10-10 | 王维国 | Medicament for giving up narcotic drugs and stopping pain and its prepn. |
| CN1060342C (en) * | 1997-03-13 | 2001-01-10 | 辽阳鸿宇制药有限公司 | Application of liver oil of globefish in preparation of medicines for drug dependence |
| CN1238356C (en) * | 2001-12-14 | 2006-01-25 | 上海华腾生物工程有限公司 | Method for extracting tetrodotoxin |
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2004
- 2004-12-30 CN CNB2004101039096A patent/CN100340246C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107047809A (en) * | 2017-03-31 | 2017-08-18 | 福州海汇生物科技实业有限公司 | A kind of fish oil preparation technology |
| CN107115298A (en) * | 2017-05-22 | 2017-09-01 | 黄海枫 | A kind of TTX emulsio olei jecoris piscis |
| CN108524522A (en) * | 2018-06-12 | 2018-09-14 | 中国水产科学研究院淡水渔业研究中心 | Application of the tetraodotoxin in preparing the drug for suppressing lung carcinoma cell to migrate and be proliferated |
| CN108524521A (en) * | 2018-06-12 | 2018-09-14 | 中国水产科学研究院淡水渔业研究中心 | Application of the tetraodotoxin in preparing the drug for inhibiting lung carcinoma cell or tumour to increase |
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| Publication number | Publication date |
|---|---|
| CN100340246C (en) | 2007-10-03 |
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