CN1542015A - Preparation method and application of harmel seed alkaloid - Google Patents
Preparation method and application of harmel seed alkaloid Download PDFInfo
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- CN1542015A CN1542015A CNA2003101096412A CN200310109641A CN1542015A CN 1542015 A CN1542015 A CN 1542015A CN A2003101096412 A CNA2003101096412 A CN A2003101096412A CN 200310109641 A CN200310109641 A CN 200310109641A CN 1542015 A CN1542015 A CN 1542015A
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- seed
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- total alkaloids
- peganum harmala
- solution
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- 229930013930 alkaloid Natural products 0.000 title claims abstract description 48
- 240000005523 Peganum harmala Species 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 23
- 238000010992 reflux Methods 0.000 claims abstract description 22
- 230000006837 decompression Effects 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 8
- 239000007924 injection Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 55
- 235000005126 Peganum harmala Nutrition 0.000 claims description 37
- 238000000605 extraction Methods 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000001476 alcoholic effect Effects 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 7
- 238000011084 recovery Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 229920000858 Cyclodextrin Polymers 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
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- 239000001116 FEMA 4028 Substances 0.000 claims description 5
- 235000011941 Tilia x europaea Nutrition 0.000 claims description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- 229960004853 betadex Drugs 0.000 claims description 5
- 238000000151 deposition Methods 0.000 claims description 5
- 239000004571 lime Substances 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000003637 basic solution Substances 0.000 claims description 3
- 239000003560 cancer drug Substances 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
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- 238000005057 refrigeration Methods 0.000 claims description 3
- 235000014347 soups Nutrition 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- PHOXAYNAAKFGRN-UHFFFAOYSA-N CN(C)C.CN(C)C.CN(C)C.NP(N)(N)=O Chemical compound CN(C)C.CN(C)C.CN(C)C.NP(N)(N)=O PHOXAYNAAKFGRN-UHFFFAOYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 206010062129 Tongue neoplasm Diseases 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
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- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229960004756 ethanol Drugs 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- -1 polyoxyethylene Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000571 coke Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000005238 degreasing Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000242583 Scyphozoa Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000159213 Zygophyllaceae Species 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
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- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention provides the preparation process of harmel peganum seed total alkaloid with high conversion rate and low cost and suitable for industrial production and the application of the product in preparing medicine for cancer, especially human digestive system tumor. The preparation process of the total alkaloid from harmel peganum seed includes the steps of: alkali lye soaking; extracting total alkaloid; alkalifying and dissociating; reflux separation; hot decompression filtering with the mixed medium of diatomite and active carbon, decompression recovering solvent at 60-80 deg.c and stoving; re-dissolving for fining; water precipitation and spray drying; etc. The obtained extractive or inclusion compound may be compounded with pharmaceutically acceptable supplementary material to prepare oral preparation and injection.
Description
Technical field
The present invention relates to the application of extracting and purifying method with the product that is obtained of Herba pegani harmalae total alkaloids, belong to the extracting method technical field of medicinal plant efficient part.
Background technology
Herba pegani harmalae is the zygophyllaceae per nnial herb, and arid areas such as roadside, riverbank, Gobi desert, desert are born in happiness.Seed of peganum harmala is Uygur, Kazak, Tibetan's conventional crude drugs, record in Drug Standard of Ministry of Public Health of the Peoples Republic of China (drug standard WS3-BW-0080-98 of Uygur), Chinese patent open source literature CN1104507A, CN1220162A, CN1299664A mostly are harmel preparation and preparation method; About the method for extraction separation Herba pegani harmalae total alkaloids, summary has following several at present:
1. the acetic acid lixiviate seed of the described usefulness 5% of The alkaloid:SanKen (1952), the sodium-chlor with 10% changes acetate into hydrochloride cold and hot then repeated treatments promptly.
2. Brit:CA.1964.61:9365h system reclaims ethanol jellyfish liquid ether defatting with ethanol percolation, and depositing in water transfers PH6.5 to add ammonium sulfate with ammoniacal liquor, uses coke filtration, adds KI, uses the coke disposal that contains HI again, and salt with 10% ammonia treatment promptly.
3. Li Chunjie (Xinjiang Medical College journal 1,987 10 (1) 27-30) is the hydrochloric acid lixiviate with 5%, the acid solution resin cation exchange, and with ammoniacal liquor alkali flower resin, and with ether, chloroform or dehydrated alcohol wash-out promptly.
4. the prestige that benefits the nation (herbal medicine 1,988 19 (1) 2-4) is the alcohol reflux with 95%, is concentrated into syrupy shape, changes molten with dilute hydrochloric acid, and the acid solution after the chloroform degreasing alkalizes with ammoniacal liquor, separates out precipitation, promptly
5. Zhang Xuenong (Xinjiang Medical College journal 1,993 16 (4) 350-1) alternately decocts merging solution with sour water and buck to be drying to obtain.
6. Munir etc. (Fitoterapia 1,995 66 (1) 73-6) is to use extraction using alcohol, and extracting solution is handled with mercury chloride yageine and banisterine are precipitated with mixture, uses H then
2S handles promptly.
Though 1. method technology is simple in the above-mentioned Herba pegani harmalae extracting method, extraction yield is not high, just separates yageine and has lost other biological alkali and acetate and hydrochloride transforms not thorough; 2. method extracted with diethyl ether degreasing, suitability for industrialized production is very difficult and dangerous; 3. method is handled alkaloid with H type Zeo-karb, and resin regeneration and pre-treatment complexity are used EC in the subsequent disposal, unfriendly to environment; Be difficult for when 4. method dilute hydrochloric acid changes molten carrying out,, can not fully contact alkaloid with dilute hydrochloric acid because contain a large amount of phlegmatic temperaments, resin, natural gum, fatty wet goods in the seed of peganum harmala, even stirring is also difficult, and the aqueous acid filtration difficulty; 5. method sour water and buck decocting herbs, although technology is simple, concentrate drying is very difficult, because carry out along with spissated, solution surface can form thick oil film shape material, and heat utilization efficiency is reduced; The easily sticking wall of spray drying soln; 6. method is with heavy metal and H
2S handles, and causes environmental pollution and human body to be poisoned, and is inadvisable.
Summary of the invention
The purpose of this invention is to provide a kind of low cost, the high rate of transform is suitable for the preparation method of seed of peganum harmala total alkaloids of suitability for industrialized production and the product of acquisition, especially treats the application of digestion tumour as preparation treatment cancer drug.
Technical scheme of the present invention is achieved in that the preparation method of this seed of peganum harmala total alkaloids comprises:
A, alkali lye soak into: seed of peganum harmala is ground into thick end, with the alkaline aqueous solution or the alkaline alcohol solution of PH＞8, with 1-3 doubly the amount of (W/W) soak and made it swelling in 8-12 hour;
B, extract total alkaloids: the alkaline alcohol solution heating and refluxing extraction of using PH＞8 is more than 3 times; The alcoholic solution consumption is 3-10 a times of crude drug, and each extraction time is 1-2 hour, united extraction liquid; Decompression and solvent recovery, being concentrated into soup proportion is 1.01-1.3, filters;
C, alkalization are free: to fluid extract in the B step, add lime according to the part by weight of crude drug 0.05-15%, 60-80 ℃ vacuum-drying 48-96 hour; Moisture controlled is ground into smalls below 7%;
D, backflow separate: with the extract powder of step C, carry out the free total alkaloids of refluxing extraction with formic acid second fat, methyl acetate, ethyl acetate, ethyl acetate, acetone one or more solvents wherein, backflow 2-3 time, each consumption be medicinal extract 4-8 doubly, the time is 1-2 hour;
E, the blending agent of forming with diatomite and gac carry out filtration under diminished pressure while hot; 60-80 ℃ of decompression and solvent recovery, and oven dry;
F, change molten refining: the medicinal extract of step D is added alcoholic solution carry out that temperature is soaked or refluxing extraction; Consumption is 2-6 a times of medicinal extract, and number of times is 1-2 time, each 1-2 hour, merges above-mentioned alcoholic solution; Filter with the medium in the step e again, then decompression and solvent recovery;
G, depositing in water: the mother liquor of step F is carried out depositing in water, and amount of water is (w/w) more than 30 times, refrigerates more than 4 hours Plate Filtration, spraying drying.
Be used to soak into the suitable alkali of crude drug basic solution among the preparation method of described seed of peganum harmala total alkaloids and comprise ammoniacal liquor, K
2CO
3, KHCO
3, Na
2CO
3, NaHCO
3, KOH, NaOH, Ca (OH)
2Ethamine, diethylamine, triethylamine, N, dinethylformamide, N,N-dimethylacetamide, trimethylammonium phosphoryl triamide.
Alcoholic solution described in the preparation method of described seed of peganum harmala total alkaloids comprises the 70-85% solution of methyl alcohol, ethanol, propyl alcohol, Virahol.
Go back the available slow diacolation among preparation method's step B of described seed of peganum harmala total alkaloids and replace refluxing extraction, the alkaline alcohol solution consumption is more than 20 times of crude drug; Till no tangible alkaloid reaction; United extraction liquid.
The free total alkaloids of ethyl acetate refluxing extraction among the described step D of the preparation method of described seed of peganum harmala total alkaloids.
The blending agent ratio that diatomite and gac are formed in the described step e of the preparation method of described seed of peganum harmala total alkaloids is 1: 1.
The preparation method of described seed of peganum harmala total alkaloids, is that 1: 6 above ratio is carried out high-speed stirring more than 2 hours with the alcoholic solution of described step F in saturated beta-cyclodextrin/hydroxypropyl solution according to the spice ratio, stop to stir refrigeration more than 4 hours, inclining supernatant liquid, filters promptly to get beta-cyclodextrin/hydroxypropyl inclusion compound.
The yageine that the preparation method of described seed of peganum harmala total alkaloids obtains reaches more than 50%.
Extract or inclusion compound that the preparation method of described seed of peganum harmala total alkaloids obtains as the application of preparation treatment cancer drug, can carry out compatibility with pharmaceutic adjuvant acceptable clinically and prepare oral preparations, injection formulations.
Extract or inclusion compound that the preparation method of described seed of peganum harmala total alkaloids obtains, tumour as preparation treatment digestion, as cancer of the stomach, the application of esophagus cancer, liver cancer, colorectal carcinoma, the rectum cancer, oral carcinoma, tongue cancer, courage cancer, cholangiocarcinoma, carcinoma of the pancreas, laryngocarcinoma medicine, can be used to prepare that dripping pill, tablet, glue are former, granule, emulsion, powder ampoule agent for injection, suspensoid.
An important feature of the present invention is continuous three employing alkaline matter for processing seed of peganum harmala in infiltration, extraction, free process, improved the extraction yield of dehydrogenation total alkaloid of harmaline on the one hand greatly, make it to reach more than 50%, improve nearly one times than the 20-30% of present bibliographical information; On the other hand, behind the adding life/white lime, accelerate rate of drying greatly; Impel alkaloid free completely simultaneously; For processing condition have been created in the large batch of industrialization extraction of seed of peganum harmala.
Another important feature of the present invention is with beta-cyclodextrin inclusion compound Herba pegani harmalae extract, to increase its solubleness, makes it have more practicality in follow-up preparation step.
Yageine＞50% in the seed of peganum harmala total alkaloids of the present invention's preparation, extracorporeal anti-tumor result of study show that along with yageine content increases effect is (seeing Appendix 1) significantly.Acute toxicity test shows that Benexate Hydrochloride of seed of peganum harmala total alkaloids (seeing Appendix 2) and direct spray dried prod all can reach medicinal requirements (seeing Appendix 3)
Embodiment
Biology total alkali extraction and formulation examples explanation below in conjunction with seed of peganum harmala are of the present invention concrete
Embodiment.
Embodiment 1: the preparation method 1 of seed of peganum harmala total alkaloids
Get seed of peganum harmala 40 purpose powder, 1% ammoniacal liquor that adds two times of doses of living again, stir, placed 8 hours, alkaline alcohol solution with 85% (Ph=9) heating and refluxing extraction three times, each 1.5 hours, the alcoholic solution add-on is respectively 6 times of amount of crude drug, 4 times, 4 times, merge alcohol extract, decompression recycling ethanol, concentrating does not have the alcohol flavor, adds 5% white lime (pressing crude drug weight calculates), stirs, 70 ℃ of vacuum-dryings 72 hours (to moisture＜15%), pulverize, use ethyl acetate refluxing extraction three times, each 2 hours, the ethyl acetate amount is 10 times of medicinal extract, 8 times, 8 times, merge the ethyl acetate extracting solution, the blending agent of forming with diatomite and gac (1: 1) filters the reclaim under reduced pressure ethyl acetate, vacuum-drying 24 hours, 10 times of amounts of ethanol with 85% were measured refluxing extraction 2 times (2 hours for 2 times, 0.5 hour), united extraction liquid, the blending agent of forming with diatomite and gac (1: 1) filters, decompression recycling ethanol adds 45 times of sour water heating for dissolving to there not being the alcohol flavor, and refrigeration is spent the night, the blending agent of forming with diatomite and gac (1: 1) filters, and the filtrate concentrate drying promptly.
Do dripping pill as raw material, granule, tablet, enteric coated capsule, capsule.Preparation prescription is as follows respectively:
1, dropping pill formulation
Prescription: total alkali: 200mg matrix: polyoxyethylene glycol (polymerization degree 6000), 14.5g
Technology: raw material and matrix are ground in 80 ℃ and are dissolved, and add several tween-80s, stir, and refrigerant is a dimethyl silicone oil, and from the speed of 15 of per minutes, the system of dripping forms.
Other dosage form is as shown in table 1:
Table 1
| Tablet | Total alkali 5g | Microcrystalline cellulose 40g | Magnesium Stearate 5g |
| Granule | Total alkali 5g | Starch 40g | Alcohol is an amount of |
| Enteric coated capsule or capsule | Total alkali 10g | Lactose 110g | Magnesium Stearate 10g |
Embodiment 2: the preparation method 2 of seed of peganum harmala total alkaloids
Get seed of peganum harmala and pulverize 40 purpose powder, it is even with duple crude drug amount soaking and stirring to add 1% yellow soda ash ethanolic soln, placed 8 hours, run through, alkaline ethanol solution with 85% (PH=11) heating and refluxing extraction three times, each 1.5 hours, consumption is respectively 6 times of crude drug, 4 times, 4 times, merge alcohol extract, decompression recycling ethanol, concentrating does not have the alcohol flavor, adds 5% unslaked lime (pressing crude drug weight calculates), stir, 70 ℃ of vacuum-dryings 72 hours (moisture＜15%) are pulverized, and use ethyl acetate refluxing extraction three times, each 2 hours, consumption is 10 times of medicinal extract, 8 times, 8 times, merge the ethyl acetate extracting solution, the blending agent of forming with diatomite and gac (1: 1) filters, the reclaim under reduced pressure ethyl acetate, 10 times of amounts of ethanol of 85% are used in vacuum-drying 24 hours respectively, measure refluxing extraction 2 times for 2 times, each 2 hours, 0.5 hour, united extraction liquid, the blending agent of forming with diatomite and gac (1: 1) filters, and decompression recycling ethanol is to there not being the alcohol flavor, add 6 times of beta-cyclodextrin solution, speed with 60 of per minutes under 60 ℃ of stirred in water bath states adds above-mentioned soup, continues to stir 2 hours, refrigerates 4 hours, filter, vacuum-drying promptly.
The dry thing that obtains is used to prepare injection, can cooperate with distilled water for injection, physiological saline, D/W, injection vegetables oil, polyoxyethylene glycol etc., can also add suitable vehicle, solubility promoter, sanitas.
Embodiment 3: Herba pegani harmalae soaks into the influence of the different basic solutions of crude drug use:
(1), gets and pulverize 40 purpose seed of peganum harmala crude drug 20g, adding Na
2CO
3Adjusting pH is 12 aqueous solution 50ml soaked overnight, filters, and getting water-intake rate is 1.9 times.
(2), pulverize 40 purpose seed of peganum harmala crude drug 20g, add that to regulate pH with diethylamine be 9 ethanolic soln 50ml soaked overnight, filter, water-intake rate is 1.8 times.
Embodiment 4: pH value in the Herba pegani harmalae refluxing extraction step, and alcohol concn, the influence of consumption and extraction time is as shown in table 2:
Table 2
Interpretation of result: orthogonal experiments is that the pH value is higher, and effect was better when alcohol concn was also higher.
Embodiment 5: the add-on influence of lime in the free step of Herba pegani harmalae alkalization
Respectively get the 400g crude drug, extract, be concentrated into the extracting solution that does not have the alcohol flavor, be divided into four parts and add Ca (OH) respectively by above-mentioned condition
220g, 15g, CaO25g, 30g mix thoroughly, and respectively at following 60 ℃ of dryings of normal pressure 1.5 hours, 2 hours, 3 hours, 4 hours, 60 ℃ of drying under reduced pressure were 7 days then, adopt oven drying method to survey moisture, and the result is as shown in table 3:
Table 3
| Numbering | Time | Moisture | Yageine |
| ????1 | ????1.5 | ????4.98 | ????0.062mg/ml |
| ????2 | ????2 | ????3.38 | ????0.046mg/ml |
| ????3 | ????3 | ????2.99 | ????0.044mg/ml |
| ????4 | ????4 | ????2.83 | ????0.058mg/ml |
Embodiment 6: the influence of different solvents in the Herba pegani harmalae backflow separating step
Respectively get the Ca (OH) among the embodiment 4
2Dry thing 15g adds benzene, toluene, ethyl acetate, chloroform, methylene dichloride, each 150ml of acetone, in there-necked flask under whipped state heating and refluxing extraction three times, each 1.5 hours, suction filtration on the clarification plate, decompression and solvent recovery with a small amount of bright novel solvent washing, volatilizes in the water-bath, 80 ℃ of vacuum-drying 48 hours, the yield of surveying each solvent is as shown in table 4:
Table 4
| Title | Weight (g) | To Ca (OH) 2The yield % of thing | Yageine (mg) |
| Benzene medicinal extract | ????2.9 | ????19 | ????221 |
| Toluene medicinal extract | ????2 | ????13 | ????276.6 |
| Chloroform medicinal extract | ????4.6 | ????31 | ????1483.1 |
| Ethyl acetate medicinal extract | ????4.4 | ????29.3 | ????1783.5 |
| Methylene dichloride medicinal extract | ????2.5 | ????17 | ????346.25 |
| Acetone medicinal extract | ????2.3 | ????17. | ????897 |
Interpretation of result: from yield, with chloroform and ethyl acetate for well, from the content of total alkaloid of harmaline, with ethyl acetate and chloroform for well, but it is obviously better that ethyl acetate is compared with chloroform the extraction efficiency of total alkaloids, and all friendly to environment and people, so preferred ethyl acetate.
Embodiment 7: Herba pegani harmalae changes in the molten purification step Different concentrations of alcohol and changes molten influential effect
With 10 times of Different concentrations of alcohol reflux 1.5 hours, 2 times were refluxed 0.5 hour, merging filtrate, and the content of surveying yageine is as shown in table 5:
Table 5
| ????90％ | ????139mg/ml |
| ????85％ | ????156mg/ml |
| ????80％ | ????128mg/ml |
| ????75％ | ????119mg/ml |
Embodiment 8: β--and cyclodextrin is the inclusion temperature as shown in table 6 with influence ratio to total alkaloids:
Table 6
| Temperature | Proportioning |
| ????60 | ????1∶6 |
| ????80 | ????1∶8 |
Every part of 10g of total alkaloids, after adding the alcohol reflux dissolving, join in the saturated solution of beta-cyclodextrin, stirring operation is 2 hours under the condition of corresponding temperature and proportioning, refrigerate 4 hours, filter, with a little washing sample of ethanol, 70 ℃ of vacuum-drying 4 hours, rapid weighing. it is as follows to obtain the inclusion compound result:
1. 60 ℃ 1: 6, the result obtains 56g; 2. 60 ℃ 1: 8, the result obtains 56.5g;
3. 80 ℃ 1: 6, the result obtains 56.5g; 4. 80 ℃ 1: 8, the result obtains 57g.
Consider cost factor, tentatively drafting is 1: 6, adds material with the speed of 60 of per minutes, and 60 ℃ of stirring operations 2 hours refrigerates 4 hours, filter, and a little washing sample of usefulness ethanol, 70 ℃ of vacuum-drying 4 hours, promptly.
Claims (10)
1, the preparation method of seed of peganum harmala total alkaloids is characterized in that basic step comprises:
A, alkali lye soak into: seed of peganum harmala is ground into thick end, with the alkaline aqueous solution or the alkaline alcohol solution of PH＞8, with 1-3 doubly the amount of (w/w) soak and made it swelling in 8-12 hour;
B, extract total alkaloids: the alkaline alcohol solution heating and refluxing extraction of using PH＞8 is more than 3 times; The alcoholic solution consumption is 3-10 a times of crude drug, and each extraction time is 1-2 hour, united extraction liquid; Decompression and solvent recovery, being concentrated into soup proportion is 1.01-1.3, filters;
C, alkalization are free: to fluid extract in the B step, add lime according to the part by weight of crude drug 0.05-15%, 60-80 ℃ vacuum-drying 48-96 hour; Moisture controlled is ground into smalls below 7%;
D, backflow separate: with the extract powder of step C, carry out the free total alkaloids of refluxing extraction with formic acid second fat, methyl acetate, ethyl acetate, ethyl acetate, acetone one or more solvents wherein, backflow 2-3 time, each consumption be medicinal extract 4-8 doubly, the time is 1-2 hour;
E, the blending agent of forming with diatomite and gac carry out filtration under diminished pressure while hot; 60-80 ℃ of decompression and solvent recovery, and oven dry;
F, change molten refining: the medicinal extract of step D is added alcoholic solution carry out that temperature is soaked or refluxing extraction; Consumption is 2-6 a times of medicinal extract, and number of times is 1-2 time, each 1-2 hour, merges above-mentioned alcoholic solution; Filter with the medium in the step e again, then decompression and solvent recovery;
G, depositing in water: the mother liquor of step F is carried out depositing in water, and amount of water is (w/w) more than 30 times, refrigerates more than 4 hours Plate Filtration, spraying drying.
2, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that describedly being used to soak into the alkali that the crude drug basic solution is suitable for and comprising ammoniacal liquor, K
2CO
3, KHCO
3, Na
2CO
3, NaHCO
3, KOH, NaOH, Ca (OH)
2Ethamine, diethylamine, triethylamine, N, dinethylformamide, N,N-dimethylacetamide, trimethylammonium phosphoryl triamide.
3, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that described alcoholic solution comprises the 70-85% solution of methyl alcohol, ethanol, propyl alcohol, Virahol.
4, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that using among the described step B diacolation replacement refluxing extraction at a slow speed, and the alkaline alcohol solution consumption is more than 20 times of crude drug; Till no tangible alkaloid reaction; United extraction liquid.
5, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that the free total alkaloids of ethyl acetate refluxing extraction among the described step D.
6, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that the blending agent ratio that diatomite and gac are formed in the described step e is 1: 1.
7, the preparation method of seed of peganum harmala total alkaloids according to claim 1, it is characterized in that the alcoholic solution with described step F is that 1: 6 above ratio is carried out high-speed stirring more than 2 hours in saturated beta-cyclodextrin/hydroxypropyl solution according to the spice ratio, stop to stir refrigeration more than 4 hours, inclining supernatant liquid, filters promptly to get beta-cyclodextrin/hydroxypropyl inclusion compound.
8, the preparation method of seed of peganum harmala total alkaloids according to claim 1 is characterized in that the yageine that obtains reaches more than 50%.
9, the extract or the inclusion compound that obtain of the preparation method of seed of peganum harmala total alkaloids according to claim 1 or 5, application as preparation treatment cancer drug, it is characterized in that: can carry out compatibility with pharmaceutic adjuvant acceptable clinically and prepare oral preparations, injection formulations.
10, extract or the inclusion compound of wanting the preparation method of 9 described seed of peganum harmala total alkaloidss to obtain according to right, tumour as preparation treatment digestion, be applicable to cancer of the stomach, the application of esophagus cancer, liver cancer, colorectal carcinoma, the rectum cancer, oral carcinoma, tongue cancer, courage cancer, cholangiocarcinoma, carcinoma of the pancreas, laryngocarcinoma medicine, it is characterized in that can being used to prepare that dripping pill, tablet, glue are former, granule, emulsion, powder ampoule agent for injection, suspensoid.
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286085A (en) * | 2011-07-25 | 2011-12-21 | 新疆大学 | Peganum harmala lipid transfer protein and preparation method and use thereof |
| CN101433565B (en) * | 2008-11-26 | 2013-06-05 | 上海中医药大学 | Total alkaloid extract of seeds of harmel genus, and preparation thereof |
-
2003
- 2003-11-06 CN CN 200310109641 patent/CN1250560C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433565B (en) * | 2008-11-26 | 2013-06-05 | 上海中医药大学 | Total alkaloid extract of seeds of harmel genus, and preparation thereof |
| CN102286085A (en) * | 2011-07-25 | 2011-12-21 | 新疆大学 | Peganum harmala lipid transfer protein and preparation method and use thereof |
| CN102286085B (en) * | 2011-07-25 | 2014-06-11 | 新疆大学 | Peganum harmala lipid transfer protein and preparation method and use thereof |
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|---|---|
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