CN101991598A - Use of sulfated fucan in preparing medicines for treatment of gastrointestinal diseases - Google Patents
Use of sulfated fucan in preparing medicines for treatment of gastrointestinal diseases Download PDFInfo
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- CN101991598A CN101991598A CN2010105738697A CN201010573869A CN101991598A CN 101991598 A CN101991598 A CN 101991598A CN 2010105738697 A CN2010105738697 A CN 2010105738697A CN 201010573869 A CN201010573869 A CN 201010573869A CN 101991598 A CN101991598 A CN 101991598A
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Abstract
The invention relates to a new pharmaceutical use of sulfated fucan, more particularly to a use of sulfated fucan in preparing medicines for the treatment of gastrointestinal diseases. Gastric diseases include gastritis, gastric ulcer, doudenal ulcer, enteritis or colitis. The gastritis include a variety of acute and chronic gastritises such as superficial gastritis, hypertrophic gastritis and the like. The main pharmacodynamics tests of sulfated fucan as gastrointestinal diseases show that sulfated fucan includes particular protective effect for both gastric ulcer induced by ethanol in mice and reserpine gastric ulcer. The preliminary statistics on the clinical treatment results of 50 different patients with gastric disease represents that, 22% of the patients are cured after the administration of sulfated fucan, 40% is effective, 22% is excellent, 16% is ineffective and the total effective rate is 84%, thus the sulfated fucan can obtain remarkable curative effect, has no toxic and side effect and is safe and reliable.
Description
Technical field
The present invention relates to new pharmaceutical applications, the particularly sulfated fucan purposes in preparation treatment gastrointestinal disease medicine of sulfated fucan.
Background technology
Sulfated fucan is a class sulfated polysaccharides that contains fucose, is present in the Brown algae, is at first extracted from the palmate Thallus Laminariae (Thallus Eckloniae) with diluted acid in 1913 by Kylin.Kylin isolates the L-fucose after with the extract hydrolysis.Sulfated fucan (English name: sulfated fucan, FPS.Another name: fucoidin, fucoidan, fucoidan, fucoidin, fucosan) be a class sulfated polysaccharides that from Brown algae, extracts, mainly containing fucose (26-32%) and sulfate and form, is (1-2) or the α-L-fucose-4-sulfuric ester that (1-3) connects of height 3-collateralization.Composition source: Thallus Laminariae (Thallus Eckloniae), Brown algae and echinoderm.The cotton-shaped powder of white.Active component: L-fucose-4-sulfuric ester.Other compositions: metal ions such as a spot of galactose, mannose, xylose, glucose, arabinose, alduronic acid, protein and potassium, sodium, calcium, magnesium.Sulfated fucan is the macromolecular compound of chemical constitution complexity, based on fucose and sulfate, along with the structure difference of the kind different sugar of algae, monosaccharide such as Thallus Laminariae (Thallus Eckloniae) Fucoidan is half congealed by the rock algae, galactose, xylose, gluconic acid acid, arabinose form, serve as that main its ratio is probably at 3: 1 with fucose and galactose.
The chemical constitution that derives from the fucoidin nucleic acid ester of black angle algae (Fucus vesiculosus) mainly connects with α (1 → 3) glucosides, and sulphation mainly occurs in C
4The position.Thallus Laminariae (Thallus Eckloniae) (Ecklonai Kurome) sulfated fucan also is mainly to connect with α (1 → 3), and sulphation is in the C4 position.The sulfated fucan main chain that derives from tap algae (Cladosiphon okamuranus) and Chorda filum (L.) Stackh. (Chorda filum) is the fucose of α (1 → 3), and sulphuric acid is in the C4 position, and the two all has a spot of 2-O-acetylation.
About the vitriolic structure of laminarin, most research datas show, the laminarin sulfuric ester is mainly formed with the L-fucose that α (1 → 3) connects, and sulphation occurs in C4 or C2 position, and part Study shows that the L-fucose that has (1 → 2) connection is as side chain.With Chorda filum (L.) Stackh. sulfated fucan structure among the last figure similarity is arranged.But the part acetyl group is arranged in the Chorda filum (L.) Stackh..And the shared ratio of different substituents group is also different.Certainly also have monosaccharide such as galactose, xylose, rhamnose in the molecule, galactose may participate in the composition of main chain, and xylose, rhamnose etc. to be form with side chain exist.
People have understanding comparatively clearly to the composition of sulfated fucan now.The preparation of sulfated fucan has been mature technology.It is more outstanding that sulfated fucan is commercially produced in " extra large elder brother's kidney happiness capsule " of Jilin Province Huinan Changlong Biochemistry Medicine Co., Ltd embodiment.According to document and patent, the multiple method for preparing sulfated fucan is arranged, as the preparation method of sulfated fucan, Granted publication CN1044607; Sulfated fucan is controlled application in the renal prostration disease medicine, Granted publication CN1069523 in preparation.Sulfated fucan and some reagent reactings form quaternary ammonium compound, utilize the method for complex to the differential separation of the different solubility of salt again; The isolating method with the different solubility in the alcoholic solvent behind the water extraction; Use ethanol extraction, the alkali condensation method of fit adjustment PH etc.; Use water extraction, transfer pH, add the method for the refining and preparation of chitosan etc.The comprehensive foregoing of the present invention as a reference.
In addition, more than invention also discloses sulfated fucan and has had anti-ageing year dementia, treatment hepatopathy, anticoagulation, raising immunity, antitumor, blood sugar lowering, radioprotective, inhibition ascites tumor isoreactivity.The applied range of sulfated fucan aspect pharmacology, the patent of application is also more complete, especially Jilin Province Huinan Changlong Biochemistry Medicine Co., Ltd " extra large elder brother's kidney happiness capsule " (the accurate word Z20030052 of traditional Chinese medicines) that produce, composition is a sulfated fucan, and function cures mainly: change turbid toxin expelling.Be used for chronic renal failure (compensatory phase lose the compensatory phase and uremia early stage) turbid damp card, that card is seen is nauseating, vomiting, poor appetite, abdominal distention, sleepy, oliguria, edema, thick and greasy fur cautiously.Adorning 0.22 gram for every, contain 100 milligrams of sulfated fucan, is the typical medical usage of sulfated fucan in preparation nephropathy medicine.By literature search and new patent searching, do not find applied research or the patent of sulfated fucan aspect the treatment gastroenteropathy.
Summary of the invention
The objective of the invention is provides a kind of sulfated fucan preparing the purposes for the treatment of in the gastrointestinal disease medicine at above-mentioned situation.
Technical solution of the present invention is: the purposes of sulfated fucan in preparation treatment gastrointestinal disease medicine.Described gastropathy disease is gastritis, gastric ulcer, duodenal ulcer, enteritis or colitis.Gastritis comprises various acute or chronic gastritis such as superficial gastritis, hypertrophic gastritis.Sulfated fucan is preferably the Thallus Laminariae (Thallus Eckloniae) sulfated fucan.
Of the present invention group had once been carried out the research of gastroenteropathy aspect to mushroom polysaccharide (as lentinan, blazei polysaccharide); found that the mushroom polysaccharide has certain effect of curing the disease to gastritis and gastric ulcer, its possible mechanism of action is for increasing immunologic function and protection gastric mucosa and antiinflammatory action.According to the active characteristics of this mushroom polysaccharide, of the present invention group is intended to find, sulfated fucan has carried out laboratory observation in the effect aspect treatment stomach, the intestinal tract disease, found that to have therapeutical effect preferably.
Sulfated fucan of the present invention can derive from the Thallus Laminariae (Thallus Eckloniae) of artificial cultivation, also can be wild Brown algae Alga Sgrgassi Enerves, Thallus Laminariae, Sargassum fusiforme (Harv.) Setch, Mus tail algae, Thallus Sargassi Kjellmaniani, Thallus Laminariae (Thallus Eckloniae).Sulfated fucan molecular weight ranges among the present invention is 10-800KD, can be 100KD-500KD, 200KD-400KD or 150-650KD.
The invention provides the pharmaceutical composition that contains sulfated fucan.Comprise the sulfated fucan and at least a acceptable auxiliary clinically for the treatment of effective dose in the described compositions, as starch, sodium chloride, microcrystalline Cellulose, sorbic acid or mannitol etc.The pharmaceutical dosage form of this group thing can be by pharmaceutical carrier commonly used in above-mentioned medicinal raw material and the pharmacy, can be mixed and made into oral formulations as excipient or adjuvant, as tablet, capsule (soft capsule), granule, powder, pill, liquid preparation, as injection, or other conventional formulation.
The preparation of sulfated fucan has been mature technology.Sulfated fucan extraction and purification, classification example now are provided, but are not limited thereto.
1. extract
Sulfated fucan can water, dilute acid soln extracts, in extracting solution, add ethanol or quaternary ammonium salts cationic surfactant then and can make the sulfated fucan precipitation, invade out in order to reduce pigment, protein etc., handle the algae extract with high concentration alcohol earlier before extracting.Extracting method can adopt methods such as warm water immersion extraction, microwave extraction, supersound extraction and the extraction of polymer substance flocculating agent precipitation.
2. purification
Ethanol precipitation: method 1, extract the water-soluble back of the thick sulfated fucan that obtains successively with 4M CaCl by last process
2Remove Algin with 30% ethanol precipitation, then with the settle out sulfated fucan of purification of 80% ethanol.Method 2, sulfated fucan hot water extraction liquid is removed water solublity Algin as impurity with 20% ethanol precipitation.
Quaternary salt deposit method: utilize cationic surfactant such as hexadecylpyridinium chloride (CPC) or cetyl trimethyl ammonium bromide (CTAB) to produce sedimentary character sulfated fucan is precipitated with polyelectrolyte.
In extraction and purge process, with ion and the small molecular weight impurity in the dialysis removal solution.Also can be with hyperfiltration process to get rid of the less material of molecular weight.Separate laminaran and sulfated fucan and adopt ion-exchange-resin process, because laminaran is neutral, sulfated fucan is the polyanion form, can be adsorbed and separate by anion exchange resin.
3 classifications
Because polysaccharose substance chemical constitution complexity, molecular weight distribution is also wide, therefore needs further staged care, separates.Method commonly used can be an ethanol precipitation, promptly utilizes different concentration of alcohol to be settled out different fraction.Also can adopt column chromatography, utilize gel filtration chromatography and resinbed to analyse classification.Gel filtration is to vary in size by molecular weight to carry out classification, and it is polysaccharide to be divided into the different fraction of charge that resinbed is analysed.Can also adopt ultrafilter membrane.
Advantage of the present invention is: 1, sulfated fucan shows as the Pharmacodynamic test of active extract of gastrointestinal disease medicine, and sulfated fucan all has the certain protection effect to mice dehydrated alcohol type gastric ulcer and reserpine type gastric ulcer.2, through tentatively 50 routine different patients with gastric disease clinical treatment results statistics being shown, take sulfated fucan, recovery from illness 22%, effective 40%, produce effects 22%, invalid 16%, total effective rate is 84%, obtains significant curative effect, has no side effect, and is safe and reliable.
Below in conjunction with embodiment embodiments of the present invention are described in further detail.
The specific embodiment
Embodiment 1
The preparation of sulfated fucan: Sargassum is pulverized the back with 3.7% formalin soaked overnight, add the distilled water boiling water extraction then, extracting solution helps with kieselguhr and filters filter, filtrate is earlier with tap water dialysis one day, then with distill water dialysis one day, dialysis solution is concentrated, and adding ethanol to concentration is 75% precipitation, precipitates the dry thick sulfated fucan that gets.The sulfated fucan crude product is water-soluble, at 0.05mol/L MgCl
220% ethanol precipitation is removed the water solublity Algin under existing, and the filtrate dialysis concentrates back 75% ethanol precipitation, promptly obtains the sulfated fucan of purification after the drying.
Embodiment 2
The preparation of sulfated fucan: will take by weighing 1kg after the dry Thallus Laminariae (Thallus Eckloniae) pulverizing, add the about 10 times of amounts of 0.1mol/L hydrochloric acid solution, extract 2 times, filter cloth removes by filter extracting solution, uses the ultrafiltration ultrafiltration, and molecular cut off is the part of 10-800KD, the sodium hydroxide solution of reuse 0.5mol/L transfers PH to 5-7, get concentrated solution through the ultrafiltration desalination, lyophilization promptly gets lurid sulfated fucan.
Embodiment 3
The preparation of sulfated fucan: Sargassum is pulverized back 20 times of distilled water boiling water of interpolation scooped up-3 hours, extracting solution helps with kieselguhr and filters filter, filtrate is earlier with tap water dialysis one day, then with distill water dialysis one day, dialysis solution is concentrated, adding ethanol to volumetric concentration is 75% precipitation, precipitates the dry thick sulfated fucan that gets.Crude product is heavy water-soluble, exist lower volume concentration 20% ethanol precipitation to remove the water solublity Algin at 0.05mol/L MgCl2, back volumetric concentration 75% ethanol precipitation is dialysed, concentrated to filtrate, promptly obtains the sulfated fucan of purification after the drying.Prepare multiple Sargassum polysaccharides sulfuric ester according to the method described above.
Embodiment 4
The preparation of sulfated fucan tablet: get sulfated fucan 100g, add microcrystalline Cellulose, polyvinylpyrrolidone mixes, and adds suitable quantity of water, makes the material of cooking a meal, and granulates drying.Particle adds cross-linking sodium carboxymethyl cellulose, magnesium stearate, mixes, and tabletting, every contains sulfated fucan 100mg.
Experimental example 1
Sulfated fucan is to the influence of mice dehydrated alcohol type and reserpine type gastric ulcer
1, materials and methods
1.1 the material sulfated fucan is provided by the Jilin Province Huinan Changlong Biochemistry Medicine Co., Ltd.Reserpine is people pharmaceutical Co. Ltd of a Guangdong nation product, and lot number is 080814; Cimetidine is a Shandong side bright Pharmaceutical limited company product, and lot number is 040716; The MDA test kit builds up bio-engineering research institute available from Nanjing; Other reagent is homemade analytical pure.Laboratory animal is got Kunming mouse, and body weight is 18-22g, and male and female half and half are provided by medical board laboratory animal section of Yanbian University.Used instrument has IGMA95308 centrifuge (Germany) and FD-Tp40723 type spectrophotometer.
1.2 method
1.2.1 sulfated fucan is to the influence of mice dehydrated alcohol type gastric ulcer
Get 50 of mices, male and female half and half are divided into 5 groups at random, be respectively model group (normal saline), sulfated fucan little, in, heavy dose of group, dosage is respectively 39mg/kg, 78mg/kg, 156mg/kg, and cimetidine group (240mg/kg).Continuous 5d gastric infusion, every day 1 time, fasting 24h after the 4th administration, freely drink water, irritate stomach behind the last administration 30min and give respectively to organize mice dehydrated alcohol 0.2ml, eyeball blood sampling behind the 1h, preparation serum, standby, take off neck execution mice immediately after getting blood, cut open the belly and get stomach, the result is as follows: ulcer level is divided into 6 grades as ulcer index, be that complete mucosa is 0 grade, 1-5 petechia (the petechia diameter is greater than 1mm) is 1 grade, and 6-10 is 2 grades, is 3 grades more than 10,1-5 bar strip is hemorrhage, and (diameter≤1mm counts 1, meter is 2 between 1-2mm, and meter is 3 between the 2-3mm, by that analogy) is 4 grades, the 6-10 bar is 5 grades, is 6 grades more than 10.Require mensuration respectively to organize mice serum MDA content in strict accordance with the test kit explanation.
1.2.2 sulfated fucan is to the influence of reserpine type gastric ulcer
Identical under grouping, administration and observational technique and the 1.2.1 item.Subcutaneous injection gives 10ml/kg reserpine when causing the gastric ulcer method and be the last administration, puts to death behind the 6h.
1.2.3 statistical procedures
Use SPSS 10.0 statistical softwares to carry out one factor analysis of variance and handle, all data are all used mean ± standard deviation (X scholar SD) expression, adopt the t check.
2, result
By table 1 as seen, compare with model group, the ulcer index of the large, medium and small dosage group of sulfated fucan dehydrated alcohol type gastric ulcer mice obviously reduces the significant difference of having compared (P＜0.01); Ulcer inhibition rate raises with the increase of dosage; Content of MDA obviously reduces, and with model group significant difference (P＜0.05) is arranged more all.Visible and the model group comparison by table 2, the ulcer index of the large, medium and small dosage group of sulfated fucan reserpine type gastric ulcer mice obviously reduces, the significant difference of having compared (P＜0.01), ulcer inhibition rate raises with the increase of dosage.
Table 1 sulfated fucan is to the influence of ulcer index, ulcer inhibition rate and the Content of MDA of mice dehydrated alcohol type gastric ulcer (n=10, x ± SD)
Compare * P＜0.05, * * P＜0.01 with model group
Table 2 sulfated fucan is to the influence of ulcer index, ulcer inhibition rate and the Content of MDA of mice reserpine type gastric ulcer (n=10, x ± SD)
Compare * P＜0.01 with model group
Dehydrated alcohol type gastric ulcer experimental result shows, sulfated fucan can significantly reduce mice ulcer index and Content of MDA, the prompting sulfated fucan may have DNA in the mucosa tissue of promotion, and RNA and proteinic synthetic reduces the effect of Content of MDA.Reserpine type gastric ulcer is sour dependency ulcer, its genesis mechanism may relevant this research reserpine type gastric ulcer experimental result with vagal excitement show, sulfated fucan can obviously reduce the ulcer index of mice, and the prompting sulfated fucan has the excretory effect of gastric acid inhibitory.In a word, sulfated fucan all has the certain protection effect to mice dehydrated alcohol type gastric ulcer and reserpine type gastric ulcer.
Experimental example 2
Through the clinical observation of 50 routine patients with gastric disease systems, take medicine of the present invention according to variety classes gastropathy symptom, 1 month observation period, 10 days is a course of treatment, totally 3 courses of treatment.Dose: every 100mg of sulfated fucan capsule, each 2, every day 2 times.
| Disease | The example number | Recovery from illness | Effectively | Produce effects | Invalid | Effective percentage % |
| Chronic superficial gastritis | 13 | 2 | 5 | 4 | 2 | 84.6 |
| Chronic atrophic gastritis | 10 | 1 | 4 | 2 | 3 | 70.0 |
| Chronic erosive gastritis | 11 | 2 | 6 | 2 | 1 | 90.9 |
| Gastric ulcer | 12 | 6 | 3 | 2 | 1 | 91.6 |
| Duodenal ulcer | 4 | 2 | 1 | 1 | 75.0 | |
| Add up to | 50 | 11 | 20 | 11 | 8 | 84 |
To 50 routine different gastropathy, disease patient's clinical treatment result statistics shows, takes sulfated fucan according to above-mentioned, and recovery from illness 22% is effective 40%, and produce effects 22% is invalid 16%, and total effective rate is 84%, obtains significant curative effect, has no side effect, and is safe and reliable.
Claims (4)
1. sulfated fucan is preparing the purposes for the treatment of in the gastrointestinal disease medicine.
2. purposes according to claim 1 is characterized in that described gastropathy disease is gastritis, gastric ulcer, duodenal ulcer, enteritis or colitis.
3. purposes according to claim 1 is characterized in that sulfated fucan is the Thallus Laminariae (Thallus Eckloniae) sulfated fucan.
4. purposes according to claim 1, the dosage form that it is characterized in that sulfated fucan is oral formulations or injection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110731432A (en) * | 2019-11-18 | 2020-01-31 | 青岛锦慧盛源生物科技发展有限公司 | seaweed prebiotics stomach-protecting beverage and preparation method thereof |
| CN110833535A (en) * | 2019-11-29 | 2020-02-25 | 中国科学院海洋研究所 | Preparation method and application of fucoidan capsule |
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| CN1108572A (en) * | 1993-09-24 | 1995-09-20 | 株式会社雅库路特本社 | Antiulcer agent and adhesion inhibitor for helicobacter pyroli |
| JP2003146888A (en) * | 2001-11-14 | 2003-05-21 | Yakult Honsha Co Ltd | Preventive and therapeutic agent of inflammatory intestinal disease |
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| JP2010235528A (en) * | 2009-03-31 | 2010-10-21 | Kikkoman Corp | Immunostimulation composition having il-10 production promotion action |
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2010
- 2010-12-06 CN CN2010105738697A patent/CN101991598A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1108572A (en) * | 1993-09-24 | 1995-09-20 | 株式会社雅库路特本社 | Antiulcer agent and adhesion inhibitor for helicobacter pyroli |
| JP2003146888A (en) * | 2001-11-14 | 2003-05-21 | Yakult Honsha Co Ltd | Preventive and therapeutic agent of inflammatory intestinal disease |
| JP2010235528A (en) * | 2009-03-31 | 2010-10-21 | Kikkoman Corp | Immunostimulation composition having il-10 production promotion action |
| CN101671399A (en) * | 2009-10-10 | 2010-03-17 | 山东大学威海分校 | Preparation method of fucoidan sulfuric ester with high purity and high-sulfate radical content |
Non-Patent Citations (1)
| Title |
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| 巫协宁 沈浩: "十二指肠和胃溃疡的发病和愈合机理的研究", 《国外医学消化系疾病分册》, vol. 13, no. 4, 31 December 1992 (1992-12-31), pages 205 - 1 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110731432A (en) * | 2019-11-18 | 2020-01-31 | 青岛锦慧盛源生物科技发展有限公司 | seaweed prebiotics stomach-protecting beverage and preparation method thereof |
| CN110833535A (en) * | 2019-11-29 | 2020-02-25 | 中国科学院海洋研究所 | Preparation method and application of fucoidan capsule |
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Application publication date: 20110330 |