CN101011411A - Usage of algal polysaccharide sulfate in preparation of medicament for treating hepatic disease - Google Patents
Usage of algal polysaccharide sulfate in preparation of medicament for treating hepatic disease Download PDFInfo
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Abstract
The invention relates to a method for using sea-tangle algin polysaccharide sulfate to prepare the drug in the treatment of liver disease as hepatitis, fatty liver, cirrhosis or the like, wherein, the hepatitis can be viral hepatitis, heavy metal toxic hepatitis, or the like. The molecular weight of sea-tangle algin polysaccharide sulfate is 200KD-400KD.
Description
Technical field
The present invention relates to the pharmaceutical applications of Thallus Laminariae (Thallus Eckloniae) sulfated fucan, particularly the purposes of Thallus Laminariae (Thallus Eckloniae) sulfated fucan aspect preparation treatment liver disease drug.
Background technology
Sulfated fucan is a class sulfated polysaccharides, 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, he is with this polysaccharide called after fucoidin, now generally name and be that fucoidan, Chinese are fucoidin, fucoidin, fucosan, fucoidan, fucoidan or sulfated fucan according to the nomenclature principle of polysaccharide.Now people have comparatively clearly the composition of sulfated fucan and understand, and it is a class chemical composition and the very complicated polysaccharide of structure, based on fucose and sulfate, along with the kind difference of algae also contains other compositions such as galactose, xylose, alduronic acid.Thallus Laminariae (Thallus Eckloniae) Fucoidan is made up of monosaccharide such as fucose, galactose, xylose, glucuronic acid, arabinose.Based on fucose and galactose, fucose and galactose are probably at 3: 1.
The sulfated fucan chemical constitution is very complicated, and its structure of the sulfated fucan that is separated in the different Brown algaes has very big-difference.Up to the present, structural research to the sulfated fucan that derives from Fucus Vesiculosus (Fucus vesiculosus) and yellow tang (Ascophyllum nodosum) is maximum, the Fucus Vesiculosus sulfated fucan mainly connects with α (1 → 3) glycosidic bond, and sulphation mainly occurs in C
4The position.The multinomial research of yellow tang sulfated fucan all shown wherein have a large amount of α (1 → 3) and α (1 → 4) glycosidic bond.Also have the structure of several Brown algae sulfated fucan to be in the news in addition.Thallus Laminariae (Thallus Eckloniae) (Ecklonia kurome) sulfated fucan is mainly α (1 → 3) and connects, and sulphation is at C
4The position.The sulfated fucan main chain that derives from tap algae (Cladosiphonokamuranus) and Chorda filum (L.) Stackh. (Chorda filum) is the fucose of α (1 → 3), and sulphation is at C
4The position, and the two all has a spot of 2-O-acetylation.
Fucus Vesiculosus, yellow tang sulfated fucan structure
Thallus Laminariae (Thallus Eckloniae) sulfated fucan structure
Chorda filum (L.) Stackh. sulfated fucan structure
About the structure of Thallus Laminariae (Thallus Eckloniae) sulfated fucan, most research datas shows that the Thallus Laminariae (Thallus Eckloniae) sulfated fucan mainly is to form with the L-fucose that α-(1 → 3) connects, and sulphation occurs in C
4Or C
2The position, and part Study shows that the L-fucose that has part (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.
Existing many pieces of documents disclose the preparation method and the pharmaceutical applications thereof of sulfated fucan.The clear 46-2248 of Japan Patent adopts hexadecane pyridinium chloride or hexadecane trimethyl ammonium bromide and sulfated fucan to be reacted into the quaternary amine complex, utilize the dissolubility difference of this complex again to salt, with ethanol, methanol and ion exchange resin treatment, purification is removed Algin, neutral polysaccharide and other impurity, and obtains the fucoidin sulphuric acid acid esters of comparison purification.CN1129109A then discloses the alkali condensation method by dried kelp soaking, filtration for several times, secondary ethanol extraction, washing with alcohol, fit adjustment PH scope etc.CN1344565A then discloses another kind of preparation method, comprises steps such as pretreatment of raw material, temperature control stirring and leaching, centrifugal, concentrated, ethanol precipitation, dehydrated alcohol dehydration.CN1560086A then discloses a kind of preparation method of high sulfate radical content fucoidan, with hot water or sour water lixiviate Brown algae, make the extracting solution that contains Brown algae polysaccharide sulfuric ester, the percetage by weight that this extracting solution is concentrated into polysaccharide is 2-10%, transfers PH5-8, adds chitosan solution and stirs, centrifugal or cross collecting precipitation, precipitation is used for 5-10 times of saline solution extracts 2-4 time, clear liquid is collected in centrifugal or filtration, with this clear liquid dialysis or ultrafiltration desalination.In addition, CN1670028A, CN1392160A, CN1197674A also disclose methods such as adopting flocculation respectively and have prepared Sargassum polysaccharides.In the present invention, above disclosure of invention all is incorporated herein by reference in full.
In addition, more than invention also disclose sulfated fucan and had anticoagulation, improved immunity, antitumor, blood sugar lowering, radioprotective, inhibition ascites tumor isoreactivity, CN1547478A then discloses its purposes in treatment adhesion, arthritis and psoriasis.
Summary of the invention
The applicant finds that under study for action the Thallus Laminariae (Thallus Eckloniae) sulfated fucan has beat all good result comparing with other sulfated fucan aspect the treatment hepatic injury disease.Therefore, the purpose of this invention is to provide sulfated fucan, particularly Thallus Laminariae (Thallus Eckloniae) sulfated fucan, especially molecular weight are the purposes of Thallus Laminariae (Thallus Eckloniae) sulfated fucan aspect treatment hepatic injury disease of 200KD～400KD, and promptly it is in the purposes aspect hepatoprotective.Wherein, described hepatic injury is medicine source property or pathogenic hepatic injury, and concrete symptom includes but not limited to jaundice, transaminase's rising, bilirubin rising etc., and the disease that relates to includes but not limited to hepatitis, fatty liver, hepatic fibrosis and liver cirrhosis.Wherein hepatitis includes but not limited at common clinically viral hepatitis, alcoholic hepatitis, drug induced hepatitis, heavy metal poisoning hepatitis etc.
Sulfated fucan of the present invention can derive from the Thallus Laminariae (Thallus Eckloniae) of artificial cultivation or wild Thallus Laminariae (Thallus Eckloniae).Sulfated fucan molecular weight ranges among the present invention is 10KD～800KD, and preferably 50KD～600KD is more preferably 100KD～500KD, and the best is 200KD～400KD.
On the other hand, the invention provides the pharmaceutical composition that contains sulfated fucan.Comprise the sulfated fucan and at least a acceptable accessories for the treatment of effective dose in the described compositions.The administering mode of said composition can be but be not limited to through mode administrations such as intravenous injection, oral, muscle, subcutaneous, skin surface, internal rectum, local injections, its dosage form can but to be not limited to be injection, lyophilized injectable powder, injectable microsphere, liposome, tablet, capsule, water preparation, powder, paste, spray, granule, soft capsule, drop pill, gel, paster, unguentum etc., wherein preferred injection, lyophilized injectable powder, tablet and capsule.Those skilled in the art can prepare required dosage form easily according to the common practise of prior art and formulation art.
In the compositions of the present invention, the weight percentage of sulfated fucan 〉=50% is preferably 〉=70%, and more preferably 〉=90%, the best is 〉=95%.The content of sulfated fucan can be 1mg～1000mg in the unit formulation, preferred 10mg～800mg, and more preferably 30mg～500mg, 30mg～300mg most preferably, the best is 50mg～100mg.
Sulfated fucan of the present invention is extraction and purification, classification in the following manner:
1. extract
Sulfated fucan can water, diluted acid or calcium chloride solution extract, in extracting solution, add Lead oxide hydrate, aluminium hydroxide, ethanol or quaternary ammonium salts cationic surfactant then, sulfated fucan is precipitated out, in order to reduce the stripping of pigment, protein etc., can handle frond with high concentration alcohols or formalin earlier before extracting.
In recent years also successively the someone adopt methods such as microwave extraction, ultrasonic extraction and the extraction of flocculating polymer precipitation.
2 purification
The ethanol reprecipitation: the English one that exports to the west (the English first-class that exports to the west, the Japanese Chi of society of fisheries, 1982,48 (12): 1771) to the thick sulfated fucan aqueous solution of hot water extraction at 0.05M MgCl
2When existing, remove water solublity Algin as impurity with 20% ethanol precipitation.Wang Zuoyun, Zhao Xuewu (Wang Zuoyun. Zhao Xuewu. separating and purification of the fucoidan of Sargassum phyllocystum Tseng et Lu,Sargassum horneri (Turn.) C. Ag. (Fucus horneri (Turn.)C.Ag.,Spongocarpus horneri Kutz.), laminaran and Algin. aquatic product journal .1985; 9 (1): 71) in the research Sargassum phyllocystum Tseng et Lu,Sargassum horneri (Turn.) C. Ag. (Fucus horneri (Turn.)C.Ag.,Spongocarpus horneri Kutz.) during sulfated fucan, with the thick sulfated fucan that makes water-soluble after, successively with 4M CaCl
2Remove Algin with 30% ethanol precipitation, then with the settle out sulfated fucan of purification of 80% ethanol.
The quaternary ammonium salts sedimentation 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, for ion and the small-molecule substance of removing in the solution generally all adopts the method for dialysing.Also the someone adopts the ultra-filtration and separation method to get rid of the less material of molecular weight.Sometimes for to remove laminaran and the protein that is mingled in the extracting solution, can take enzyme digestion.(Fleury N andLahaye M.Studies on by-products from the industrlal extration of alglnate2.Chemieal structure analysis of fucans from the leach-water.J Appl Phycol such as Feury, 1993,5:605-610) when the side-product of the French Algin industry of research, just adopt glucanase and alcalase to remove wherein laminaran and protein.Separate laminaran and sulfated fucan and can also adopt ion-exchange-resin process, because the former is electroneutral, and the latter is the polyanion form.
3 classifications
Because the sulfated fucan chemical constituent is quite complicated, chromatograph and electrophoretic examinations to the thick sulfated fucan prepared generally all present inhomogeneity, so people progressively use stage division that miscellaneous polysaccharide is divided into different fractions to further investigate.Stage division commonly used can be an ethanol precipitation, promptly utilizes different concentration of alcohol to be settled out different fraction.Another kind is a chromatography, utilizes gel filtration chromatography and ion-exchange chromatography to carry out classification.Ion exchange chromatography can be divided into polysaccharide the different fraction of charge, and gel-filtration chromatography then carries out classification with polysaccharide according to the molecular weight size.Can also adopt the ultrafilter membrane of certain molecular weight to carry out ultrafiltration, it is carried out classification.
In addition, the disclosed extracting method of institute's referenced patents and also can at random be adopted herein by those skilled in the art by the product of these methods preparation.
The specific embodiment
Below by the specific embodiment the present invention is further specified.Here want to be pointed out that, below the specific embodiment only be used for illustrating the present invention, those skilled in the art are understanding under the prerequisite of spirit of the present invention, can carry out corresponding conversion to the present invention according to the prior art and the knowledge in present technique field, these technical schemes all fall within the scope of the present invention.
The preparation of embodiment 1 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 flowing 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.Crude product is heavy water-soluble, at 0.05mol/L MgCl
220% ethanol precipitation is removed the water solublity Algin under existing, and back 75% ethanol precipitation is dialysed, concentrated to filtrate, promptly obtains the sulfated fucan of purification after the drying.Prepare four kinds of Sargassum sulfated fucan according to the method described above, its chemical constituent is analyzed as follows shown in the table:
| Sargassum | Fucose (%) | Sulfate radical (%) | Peak molecular weight (kD) | Ash (%) | The monosaccharide molar ratio | |||
| Fucose | Galactose | Xylose | Glucose | |||||
| Thallus Sargassi Kjellmaniani | 26.5 | 14.8 | 980 | 20.8 | 1.00 | 0.24 | 0.05 | 0.04 |
| Mus tail algae | 25.4 | 17.0 | 650 | 22.6 | 1.00 | 0.24 | 0.03 | |
| The Folium Ilicis Purpureae Alga Sgrgassi Enerves | 13.3 | 12.5 | 588 | 20.8 | 1.00 | 0.35 | 0.16 | 0.08 |
| Thallus Laminariae (Thallus Eckloniae) | 28.8 | 30.2 | 220 | 31.2 | 1.00 | 0.36 | ||
The preparation of different molecular weight Thallus Laminariae (Thallus Eckloniae) sulfated fucan
The Thallus Laminariae (Thallus Eckloniae) sulfated fucan of above-mentioned preparation is soluble in water, be made into aqueous solution, adopt the small-sized cross-flow ultrafiltration of PallMinimate system that the Thallus Laminariae (Thallus Eckloniae) sulfated fucan is separated according to molecular weight, be that the ultrafilter membrane bag of 400KD, 200KD, 100KD, 10KD carries out ultrafiltration by molecular cut off respectively, obtain molecular weight 200～400KD, three polysaccharide components of 100～200KD and 10～100KD, the assay method of molecular weight adopts efficient gel permeation chromatography (HPGPC) method.Shown in the chemical constituent analysis result sees the following form
| Sulfated fucan | Fucose (%) | Sulfate radical (%) | Peak molecular weight (kD) | Ash (%) | The monosaccharide molar ratio | |
| Fucose | Galactose | |||||
| 200-400KD | 29.5 | 31.5 | 288 | 33.8 | 1.00 | 0.33 |
| 100-200KD | 28.4 | 30.1 | 147 | 32.6 | 1.00 | 0.38 |
| 10-100KD | 28.8 | 29.7 | 79 | 30.8 | 1.00 | 0.42 |
The preparation of embodiment 2 sulfated fucan injections
Get Thallus Laminariae (Thallus Eckloniae) sulfated fucan 50g, add water for injection 500ml, mannitol 50g transfers pH value to 7.0, packing, lyophilization.
The preparation of embodiment 3 sulfated fucan tablets
Get Thallus Laminariae (Thallus Eckloniae) sulfated fucan 50g, add microcrystalline Cellulose, polyvinylpyrrolidone mixes, and adds suitable quantity of water, and the system soft material is granulated drying.Particle adds cross-linking sodium carboxymethyl cellulose, magnesium stearate, mixes, and tabletting, every contains sulfated fucan 100mg.
Embodiment 4 sulfated fucan cause the effect of chmice acute liver injury model to carbon tetrachloride
Adopt carbon tetrachloride to be dissolved in olive oil, be mixed with 0.1%, injection gives, and 10ml/kg causes the acute liver damage model.
With the animal random packet, if Thallus Laminariae (Thallus Eckloniae) sulfated fucan molecular weight 200KD-400KD group (250mg/kg), 100KD-200KD group (250mg/kg), 10KD-100KD group (250mg/kg), Mus tail algae sulfated fucan group (250mg/kg), positive drug control group (bifendate, 280mg/kg), blank group and model control group.Each group 24h administration 7 times (except the blank group) in advance before the test, cervical region subcutaneous injection of carbon tetrachloride olive oil suspension; The beginning administration, bifendate oral administration 280mg/kg, all the other 3 administration group gastric infusions (i.g), 10ml/kg, model control group is irritated the water of stomach equivalent, and the normal control group is not done any processing, and similarity condition is raised down, once a day, successive administration 7 days.Behind the last administration 40min, serum is collected in the eyeball blood sampling, measures glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), albumin (ALB), albumins/globulins (A/G) ratio before putting to death.
Experimental result
After the carbon tetrachloride modeling, organize comparison with the intact animal, Mouse Liver function generation significance changes, and serum alt, AST significance occurs and raise (P＜0.05), show that carbon tetrachloride has caused the infringement of animal liver function, has caused liver injury model.The results are shown in Table 1
Behind the sulfated fucan gastric infusion, can obviously suppress CCl
4Serum ALT due to the acute liver damage that causes, the rising of AST (P＜0.05), and the reduction (P＜0.05) of serum ALB, A/G due to the acute liver model that raises show that sulfated fucan is to CCl
4The acute liver damage that causes has significant protective effect.Wherein, the effect of Thallus Laminariae (Thallus Eckloniae) sulfated fucan is better than Mus tail algae sulfated fucan, and the effect of Thallus Laminariae (Thallus Eckloniae) sulfated fucan molecular weight 200KD-400KD is better than other two molecular weight groups, the results are shown in Table 1.
Under the same experimental condition, 280mg/kg is oral to CCl for positive control medicine bifendate
4The acute liver damage that causes has significant protective effect equally.The results are shown in Table 1
Embodiment 5 sulfated fucan cause the effect of chmice acute liver injury model to D-Gal (DAG)
With the animal random packet, establish sulfated fucan molecular weight 200KD-400KD group (250mg/kg), 100KD-200KD group (250mg/kg), 10KD-100KD group (250mg/kg), Mus tail algae sulfated fucan group (250mg/kg), positive drug bifendate group (280mg/kg) and blank group and model contrast.Earlier respectively organize an ip DAG (except the blank group), each treated animal is irritated stomach (ig) administration behind the 30min, once a day, and continuous 7 days.In handling each treated animal the day after tomorrow with DAG7, from the blood sampling of eyeball rear vein beard, carry out biochemistry detection glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT, albumin, albumins/globulins, cut open simultaneously and get liver, fixing, do the pathology histological examination.
Result of the test
Biochemistry detection result:
After the DAG modeling, organize comparison with the intact animal, Mouse Liver function generation significance changes, and serum alt, AST significance occurs and raise (P＜0.05), show that DAG has caused the infringement of animal liver function, has caused liver injury model.The results are shown in Table 2
Sulfated fucan is behind the therapeutic oral administration; can obviously suppress the Serum ALT due to the acute liver damage that DAG causes, the rising (P＜0.05) of AST; significance rising ALB; A/G (P＜0.05); show that sulfated fucan can suppress the acute liver damage that DAG causes; significant protective effect is arranged; wherein; the effect of Thallus Laminariae (Thallus Eckloniae) sulfated fucan is better than Mus tail algae sulfated fucan group, and the effect of Thallus Laminariae (Thallus Eckloniae) sulfated fucan molecular weight 200KD-400KD is better than other two molecular weight groups.The results are shown in Table 2
Under the same experimental condition, the oral acute liver damage that DAG is caused of positive control medicine bifendate 280mg/kg has significant protective effect equally.The results are shown in Table 2
Pathological examination results:
Method of inspection censorship specimen is the ICR mouse liver tissue of 10% formalin fixed.Repair piece respectively, through gradient alcohol dehydration, paraffin embedding, section (thickness 5 μ), HE dyeing and Masson dyeing, light microscopic checks that the result is as follows down.
DAG acute liver damage model group: severe hepatocyte water degeneration in 10/10 example in the DAG acute liver damage model group, 1/10 routine moderate hepatic necrosis.Model control group possesses the pathological change behind the DAG acute liver damage.
Mus tail algae sulfated fucan group: severe hepatocyte water degeneration in 9/10 example, 1/10 routine moderate hepatic necrosis.
Sulfated fucan 200KD-400KD group: hepatic cell fattydegeneration, the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration are not seen in 6/10 routine hepatocyte water degeneration, all the other liver organizations.
Sulfated fucan 100KD-200KD group: hepatic cell fattydegeneration, the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration are not seen in 7/10 routine hepatocyte water degeneration, all the other liver organizations.
Sulfated fucan 10KD-100KD group: hepatic cell fattydegeneration, the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration are not seen in 7/10 routine hepatocyte water degeneration, 1/10 routine hepatic cell fattydegeneration, all the other liver organizations.Hepatic cell fattydegeneration may be relevant with the quality of animal own, and with to be tried thing irrelevant.
The bifendate group: the slight hepatocyte water degeneration of 7/10 example, all the other liver organizations are not seen hepatic cell fattydegeneration, the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration.Show that the hepatic lesions after the bifendate group is to the DAG acute liver damage has certain therapeutical effect.
Pathological observation is subordinate list as a result:
Model control group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | + | - | - | - |
| 2 | - | +++ | - | - | - |
| 3 | - | ++ | - | - | - |
| 4 | - | ++ | - | - | - |
| 5 | - | ++ | ++ | - | - |
| 6 | - | ++ | - | - | - |
| 7 | - | ++ | - | - | - |
| 8 | - | ++ | - | - | - |
| 9 | - | ++ | - | - | - |
| 10 | - | ++ | - | - | - |
Annotate :-do not see pathological changes+slight pathological changes ++ the moderate pathological changes +++severe pathological changes
Mus tail algae sulfated fucan group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | ++ | - | - | - |
| 2 | - | ++ | - | - | - |
| 3 | - | ++ | - | - | - |
| 4 | - | ++ | - | - | - |
| 5 | - | ++ | ++ | - | - |
| 6 | - | + | - | - | - |
| 7 | - | ++ | - | - | - |
| 8 | - | ++ | - | - | - |
| 9 | - | +++ | - | - | - |
| 10 | - | - | - | - | - |
Annotate :-do not see pathological changes+slight pathological changes ++ the moderate pathological changes +++severe pathological changes
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | + | - | - | - |
| 2 | - | + | - | - | - |
| 3 | - | + | - | - | - |
| 4 | - | + | - | - | - |
| 5 | - | - | - | - | - |
| 6 | - | + | - | - | - |
| 7 | - | + | - | - | - |
| 8 | - | - | - | - | - |
| 9 | - | - | - | - | - |
| 10 | - | - | - | - | - |
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | + | - | - | - |
| 2 | - | - | - | - | - |
| 3 | - | - | - | - | - |
| 4 | - | - | - | - | - |
| 5 | - | + | - | - | - |
| 6 | - | + | - | - | - |
| 7 | - | + | - | - | - |
| 8 | - | ++ | - | - | - |
| 9 | - | + | - | - | - |
| 10 | - | + | - | - | - |
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | - | - | - | - |
| 2 | - | ++ | - | - | - |
| 3 | - | + | - | - | - |
| 4 | - | + | - | - | - |
| 5 | + | - | - | - | - |
| 6 | - | + | - | - | - |
| 7 | - | + | - | - | - |
| 8 | - | - | - | - | - |
| 9 | - | ++ | - | - | - |
| 10 | - | + | - | - | - |
The bifendate group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | - | + | - | - | - |
| 2 | - | + | - | - | - |
| 3 | - | + | - | - | - |
| 4 | - | + | - | - | - |
| 5 | - | + | - | - | - |
| 6 | - | + | - | - | - |
| 7 | - | - | - | - | - |
| 8 | - | - | - | - | - |
| 9 | - | + | - | - | - |
| 10 | - | - | - | - | - |
Embodiment 6 sulfated fucan are to the effect of chronic hepatic injury model
Get rat, in 3 months, respectively organize secondary subcutaneous injection of carbon tetrachloride olive oil suspension weekly, poison after 1 month, the poisoning rat is again by the body weight grouping: model control group, positive drug control group (bifendate), reagent sulfated fucan 200KD-400KD group (200mg/kg), 100KD-200KD group (200mg/kg), 10KD-100KD organize (200mg/kg), Mus tail algae sulfated fucan group (200mg/kg), and set up the normal control group simultaneously.The beginning administration, bifendate oral administration 200mg/kg, all the other 3 administration group gastric infusions (i.g), 10ml/kg, model control group is irritated the water of stomach equivalent, and the normal control group is not done any processing, and similarity condition is raised down.Once a day, administration 2 months, 2h after the last administration, the eye socket rear vein beard is got blood, the centrifugal 15min of 3000 commentaries on classics/min gets determination of serum glutamic oxaloacetic transaminase, GOT (AST), glutamate pyruvate transaminase (ALT), sialic acid (SA), albumin (ALB), albumins/globulins (A/G) ratio.Dislocation is put to death after getting blood, gets hepatic tissue (fixed position is a leftlobe of liver), is divided into 2 parts, and a part of homogenate is used for measuring the content of hepatic tissue hydroxyproline, and another part is fixed in 10% formalin solution, is used for histopathologic examination.
The mensuration of serum sialic acid:
| Measure pipe | Standard pipe | Blank pipe | |
| Serum (ml) | 0.1 | ||
| 1mmol/L SA standard (ml) | 0.1 | ||
| Distilled water (ml) | 0.1 | ||
| Reagent one (ml) | 0.2 | 0.2 | 0.2 |
| Reagent two developers (ml) | 4.0 | 4.0 | 4.0 |
Mixing, 100 ℃ of water-baths (perhaps uncap and boil) 15min, after the flowing water cooling, the centrifugal 10min of 3500 commentaries on classics/min gets supernatant, the 560nm wavelength, the 1cm optical path, blank pipe zeroing is measured and is respectively managed absorbance.
Calculate:
The sample hepatic tissue is handled and the hydroxyproline determination step:
1) tissue hydrolysis: accurately take by weighing the hepatic tissue weight in wet base, add hydrolyzed solution 1ml, mixing.After grournd glass test tube with cover added a cover, 95 ℃ or boiling water bath hydrolysis 20min.
2) transfer pH value to 6.0～6.8:, shake up with respectively adding 1 of indicator after each rub oral examination tube flowing water cooling; Each pipe adds PH first liquid 1.0ml, mixing (this moment, solution should be red); Draw the second liquid of bar pH value with the sample injector of 200ul, all will shake up after whenever being added dropwise to, the color of indicator to the liquid become yellow green.This moment, pH value was in 6.0～6.8 (adding approximately about PH second liquid 100ul～500ul); Adding distil water is to 10ml then, mixing; Get 3～4ml and add proper amount of active carbon (about about 20～30mg) mixing with colourless being as the criterion of the centrifugal back clarification of supernatant, the centrifugal 10min of 3500 commentaries on classics/min, get supernatant 1ml and press the step operation:
| Blank pipe | Standard pipe | Measure pipe | |
| Distilled water (ml) | 1.0 | ||
| 5 μ g/ml titers (ml) | 1.0 | ||
| Detect liquid (ml) | 1.0 | ||
| Reagent one (ml) | 0.5 | 0.5 | 0.5 |
| Mixing leaves standstill 10min | |||
| Reagent two (ml) | 0.5 | 0.5 | 0.5 |
| Mixing leaves standstill 5min | |||
| Reagent three (ml) | 0.5 | 0.5 | 0.5 |
Mixing, 60 ℃ of water-bath 15min, after the cooling, the centrifugal 10min of 3500 commentaries on classics/min.Get supernatant 2ml
3) measure, get supernatant at the 550nm place, the 1cm optical path, the distilled water zeroing is measured and is respectively managed absorbance.
4) calculating of hydroxyproline content, calculate according to the following equation:
The heavy ÷ 13.4%* of liver collagen protein μ g/mg liver weight=hydroxyproline μ g/mg liver
(the * hydroxyproline accounts for 13.4% in collagen protein)
Result of the test
Biochemistry detection result:
After carbon tetrachloride causes the rat chronic hepatic injury, significance rising (P＜0.01, P＜0.01, P＜0.05) all appears in transaminase ALT, AST, G in the serum, significance decline (P＜0.01, P＜0.01) all appears in ALB, A/G, fibrosis appears in hepatic tissue, and significance rising (P＜0.01, P＜0.01, P＜0.01) appears in hydroxyproline, sialic acid and liver collagen in the hepatic tissue.The results are shown in Table 3, table 4
After sulfated fucan continuous oral administration February, transaminase ALT, the AST of rising significantly reduced (P＜0.05, P＜0.01), the ALB of reduction is significantly raise (P＜0.05, P＜0.01), the remarkable inverse ratio of rising A/G (P＜0.01), significantly reduce the sialic acid content (P＜0.05, P＜0.01) that raises, 100-200mg/kg dosage significantly reduces the hydroxyproline content (P＜0.05, P＜0.01) of rising.Show that the Thallus Laminariae (Thallus Eckloniae) sulfated fucan causes chronic hepatic injury to carbon tetrachloride and has significant therapeutic effect; The results are shown in Table 3, table 4
Under the same experimental condition, bifendate 200mg/kg causes chronic hepatic injury to carbon tetrachloride and has significant therapeutic effect equally.The results are shown in Table 3, table 4
Pathological examination results:
CCl
4Chronic hepatic injury model group: CCl
414/14 routine hepatic cell fattydegeneration in the chronic hepatic injury group, 8/14 routine hepatic necrosis, 8/14 routine liver proliferation of fibrous tissue, 7/14 routine kitchen range shape cell infiltration.CCl
4Chronic hepatic injury model group shows as light moderate hepatic cell fattydegeneration, kitchen range shape hepatic necrosis, and liver proliferation of fibrous tissue in various degree, visible pseudolobuli forms, and the while is with the cell infiltration of kitchen range shape.Possesses CCl
4Pathological change behind the chronic hepatic injury.
The bifendate group: 12/12 routine hepatic cell fattydegeneration in the bifendate group, 2/12 routine hepatic necrosis, 6/12 routine liver proliferation of fibrous tissue, all the other liver organizations are not seen the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration.Bifendate is to CCl
4Hepatic lesions behind the chronic injury has certain therapeutical effect.
Mus tail algae sulfated fucan group: CCl
414/14 routine hepatic cell fattydegeneration in the chronic hepatic injury group, 7/14 routine hepatic necrosis, 7/14 routine liver proliferation of fibrous tissue, 8/14 routine kitchen range shape cell infiltration.
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group: 13/13 routine hepatic cell fattydegeneration, 5/13 routine liver proliferation of fibrous tissue, all the other liver organizations are not seen the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration.
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group: 12/12 routine hepatic cell fattydegeneration, 6/12 routine liver proliferation of fibrous tissue, all the other liver organizations are not seen the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration.
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group: 13/13 routine hepatic cell fattydegeneration, 8/13 routine liver proliferation of fibrous tissue, all the other liver organizations are not seen the degeneration of hepatocyte water, hepatic necrosis, liver proliferation of fibrous tissue and cell infiltration.
Conclusion: pathologic finding prompting tried thing Thallus Laminariae (Thallus Eckloniae) sulfated fucan gastric infusion after 60 days to animal subject SD rat CCl
4Hepatic lesions has certain therapeutical effect behind the chronic hepatic injury.
Pathological observation is subordinate list as a result:
CCl
4Chronic hepatic injury model group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | - | + |
| 2 | ++ | - | + | ++ | - |
| 3 | ++ | - | + | ++ | - |
| 4 | ++ | - | + | ++ | + |
| 5 | ++ | - | - | - | + |
| 6 | + | - | - | +++ | - |
| 7 | ++ | - | + | +++ | + |
| 8 | ++ | - | + | - | + |
| 9 | ++ | - | + | ++ | - |
| 10 | ++ | - | + | - | + |
| 11 | ++ | - | + | +++ | + |
| 12 | ++ | - | - | - | - |
| 13 | ++ | - | - | +++ | - |
| 14 | ++ | - | - | - | - |
Annotate :-do not see pathological changes+slight pathological changes ++ the moderate pathological changes +++severe pathological changes
The bifendate group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | - | - |
| 2 | ++ | - | - | + | - |
| 3 | ++ | - | - | - | - |
| 4 | ++ | - | - | - | - |
| 5 | ++ | - | - | + | - |
| 6 | ++ | - | - | + | - |
| 7 | ++ | - | + | + | - |
| 8 | ++ | - | - | - | - |
| 9 | ++ | - | + | + | - |
| 10 | ++ | - | - | + | - |
| 11 | + | - | - | - | - |
| 12 | ++ | - | - | - | - |
Mus tail algae sulfated fucan group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | ++ | + |
| 2 | ++ | - | + | ++ | + |
| 3 | ++ | - | + | ++ | - |
| 4 | ++ | - | + | ++ | + |
| 5 | ++ | - | + | - | + |
| 6 | + | - | + | +++ | - |
| 7 | ++ | - | + | - | + |
| 8 | ++ | - | + | - | + |
| 9 | ++ | - | - | +++ | - |
| 10 | ++ | - | - | - | + |
| 11 | ++ | - | - | +++ | + |
| 12 | ++ | - | - | - | - |
| 13 | ++ | - | - | - | - |
| 14 | ++ | - | - | - | - |
Annotate :-do not see pathological changes+slight pathological changes ++ the moderate pathological changes +++severe pathological changes
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | - | - |
| 2 | ++ | - | - | - | - |
| 3 | ++ | - | - | + | - |
| 4 | + | - | - | - | - |
| 5 | ++ | - | - | - | - |
| 6 | + | - | - | ++ | - |
| 7 | ++ | - | - | - | - |
| 8 | ++ | - | - | ++ | - |
| 9 | ++ | - | - | - | - |
| 10 | ++ | - | - | - | - |
| 11 | + | - | - | ++ | - |
| 12 | ++ | - | - | + | - |
| 13 | ++ | - | - | - | - |
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | + | - |
| 2 | ++ | - | - | - | - |
| 3 | + | - | - | ++ | - |
| 4 | ++ | - | - | ++ | - |
| 5 | ++ | - | - | + | - |
| 6 | ++ | - | - | - | - |
| 7 | ++ | - | - | - | - |
| 8 | ++ | - | - | - | - |
| 9 | ++ | - | - | - | - |
| 10 | ++ | - | - | + | - |
| 11 | ++ | - | - | - | - |
| 12 | ++ | - | - | + | - |
Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group:
| The pathological changes content | Hepatic cell fattydegeneration | The degeneration of hepatocyte water | Hepatic necrosis | The liver proliferation of fibrous tissue | Cell infiltration |
| 1 | ++ | - | - | + | - |
| 2 | ++ | - | - | + | - |
| 3 | ++ | - | - | - | - |
| 4 | ++ | - | - | + | - |
| 5 | ++ | - | - | - | - |
| 6 | ++ | - | - | - | - |
| 7 | ++ | - | - | ++ | - |
| 8 | ++ | - | - | + | - |
| 9 | ++ | - | - | + | - |
| 10 | ++ | - | - | + | - |
| 11 | ++ | - | - | ++ | - |
| 12 | ++ | - | - | - | - |
| 13 | ++ | - | - | - | - |
Table 1 Thallus Laminariae (Thallus Eckloniae) sulfated fucan and bifendate are to CCL
4Cause the effect of chmice acute liver injury model
| Group | Dosage (mg/kg) | Number of animals (only) | A/G | ALT (U/L) | AST (U/L) | ALB (g/L) |
| The normal control group | - | 8 | 1.598±0.106 | 31.7±5.5 | 91.0±16.1 | 29.3±2.2 |
| Model control group | - | 10 | 1.389±0.324△ | 80.0±55.3△ | 115.6±38.6△ | 23.9±2.9△ |
| The bifendate group | 280 | 10 | 1.584±0.208 * | 34.6±14.4 * | 91.0±17.1 * | 26.6±4.1 * |
| Mus tail algae sulfated fucan group | 250 | 10 | 1.411±0.385 | 62.8±26.7 | 108.9±27.5 | 24.7±3.5 |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group | 250 | 10 | 1.592±0.166 * | 33.2±8.2 * | 88.9±19.8 * | 28.0±3.9 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group | 250 | 10 | 1.560±0.135 * | 28.7±11.4 * | 90.0±19.9 * | 26.4±3.1 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan, 10KD-100KD | 250 | 10 | 1.431±0.087 | 27.5±5.6 * | 90.5±25.8 | 25.4±1.6 |
Compare △ P＜0.05, △ △ P＜0.01 with the normal control group; Compare with model control group,
*P＜0.05,
*P＜0.01
Table 2 Thallus Laminariae (Thallus Eckloniae) sulfated fucan and bifendate cause the effect of chmice acute hepatic injury to D-Gal
| Group | Dosage (mg/kg) | Number of animals (only) | A/G | ALT (U/L) | AST (U/L) | ALB (g/L) |
| The normal control group | - | 8 | 1.632±0.091 | 29.3±6.3 | 98.5±18.3 | 28.6±3.8 |
| Model control group | - | 10 | 1.435±0.227△ | 100.6±88.0△ | 119.9±24.8△ | 24.5±3.4△ |
| The bifendate group | 280 | 10 | 1.644±0.172 * | 29.0±10.9 * | 94.1±17.4 * | 27.5±2.2 * |
| Mus tail algae sulfated fucan group | 250 | 10 | 1.418±0.268 | 57.4±38.7 | 114.7±21.4 | 23.7±2.4 |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group | 250 | 10 | 1.667±0.164 * | 28.6±8.7 * | 94.9±20.1 * | 28.5±3.8 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group | 250 | 10 | 1.530±0.091 | 33.5±11.9 * | 102.8±18.5 | 28.4±2.5 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group | 250 | 10 | 1.415±0.241 | 31.4±12.8 * | 110.4±17.5 | 24.6±3.3 |
Compare △ P＜0.05, △ △ P＜0.01 with the normal control group; Compare with model control group,
*P＜0.05,
*P＜0.01
Table 3 Thallus Laminariae (Thallus Eckloniae) sulfated fucan and bifendate are to CCL
4Cause the influence of rat chronic hepatic injury blood biochemistry
| Dosage (mg/kg) | Number of animals | ALB(g/L) | ALT(U/L) | AST(U/L) | |
| The normal control group | - | 8 | 35.1±4.9 | 45.7±7.8 | 151.8±20.6 |
| Model control group | - | 14 | 27.6±4.6△△ | 337.9±282.2△△ | 530.0±298.7△△ |
| The bifendate group | 200 | 12 | 32.3±3.5 ** | 53.7±13.9 ** | 206.8±34.9 ** |
| Mus tail algae sulfated fucan group | 200 | 12 | 28.7±4.9 | 281.8±187.5 | 328.7±74.1 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group | 200 | 12 | 33.8±3.5 ** | 101.4±90.3 ** | 242.0±132.0 ** |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group | 200 | 13 | 31.4±4.0 * | 156.0±110.6 * | 326.3±173.0 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group | 200 | 13 | 31.3±3.9 * | 144.9±103.8 * | 322.3±83.2 * |
| Dosage (mg/kg) | Number of animals | G(g/L) | A/G | ||
| The normal control group | - | 8 | 29.9±5.8 | 1.215±0.268 | |
| Model control group | - | 14 | 36.8±9.2△ | 0.796±0.224△△ | |
| Bifendate group Mus tail algae sulfated fucan group | 200 200 | 12 12 | 28.4±3.0 ** 32.4±6.4 | 1.146±0.137 ** 0.897±0.246 * | |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group | 200 | 12 | 26.4±8.5 ** | 1.121±0.214 ** | |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group | 200 | 13 | 28.1±8.0 * | 1.245±0.324 ** | |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group | 200 | 13 | 29.1±7.4 * | 1.307±0.441 ** |
Compare △ P＜0.05, △ △ P＜0.01 with the normal control group; Compare with model control group,
*P＜0.05,
*P＜0.01
Table 4 Thallus Laminariae (Thallus Eckloniae) sulfated fucan and bifendate are to CCL
4Cause the Fibrotic influence of rat chronic hepatic injury
| Group | Dosage (mg/kg) | Number of animals (only) | Sialic acid (mg/L) | Hydroxyproline (ug/mg) | Liver collagen (ug/mg) |
| The normal control group | - | 8 | 1177.06±118.87 | 0.108±0.020 | 0.802±0.148 |
| Model control group | - | 14 | 1520.97±167.14△△ | 0.268±0.056△△ | 2.000±0.417△△ |
| The bifendate group | 200 | 12 | 1334.57±155.33 ** | 0.205±0.046 ** | 1.529±0.341 ** |
| Mus tail algae sulfated fucan group | 200 | 12 | 1457.19±247.67 | 0.251±0.076 | 1.914±0.348 |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 200KD-400KD group | 200 | 13 | 1267.34±209.26 ** | 0.212±0.045 ** | 1.584±0.334 ** |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 100KD-200KD group | 200 | 12 | 1356.34±206.50 * | 0.226±0.047 * | 1.683±0.351 * |
| Thallus Laminariae (Thallus Eckloniae) sulfated fucan 10KD-100KD group | 200 | 13 | 1350.87±228.01 * | 0.248±0.046 | 1.848±0.342 |
Compare △ P＜0.05, △ △ P＜0.01 with the normal control group; Compare with model control group,
*P＜0.05,
*P＜0.01
Claims (9)
- The purposes of 1 sulfated fucan in the medicine of preparation treatment hepatic injury disease.
- 2 purposes according to claim 1, wherein said hepatic injury disease is selected from one or more in hepatitis, fatty liver, hepatic fibrosis and the liver cirrhosis.
- 3 purposes according to claim 2, wherein said hepatitis is selected from one or more in viral hepatitis, alcoholic hepatitis, drug induced hepatitis, the heavy metal poisoning hepatitis.
- 4 purposes according to each claim in the claim 1～3, sulfated fucan wherein are the Thallus Laminariae (Thallus Eckloniae) sulfated fucan.
- 5 purposes according to claim 4, sulfated fucan molecular weight wherein is 10KD～800KD.
- 6 purposes according to claim 5, sulfated fucan molecular weight wherein is 50KD～600KD.
- 7 purposes according to claim 6, sulfated fucan molecular weight wherein is 100KD～500KD.
- 8 purposes according to claim 7, sulfated fucan molecular weight wherein is 200KD～400KD.
- 9 purposes according to claim 1, the dosage form of sulfated fucan wherein are injection, oral formulations, local administration preparation or nasal cavity administrated preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101361799B (en) * | 2008-09-01 | 2011-07-20 | 北京世纪博康医药科技有限公司 | Composition containing brown alga polysaccharide sulfuric ester and schisandra chinensis and use thereof |
| CN103446165A (en) * | 2013-09-12 | 2013-12-18 | 中国海洋大学 | Application of guluronic acid oligomers in preparing medicines, health products or dietary supplements for preventing and treating alcoholic liver injury |
| CN112513104A (en) * | 2018-07-27 | 2021-03-16 | Arc医疗器械股份有限公司 | Highly sulfated fucoidan for the treatment of fibrous adhesions |
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2006
- 2006-12-08 CN CN 200610164945 patent/CN101011411A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101361799B (en) * | 2008-09-01 | 2011-07-20 | 北京世纪博康医药科技有限公司 | Composition containing brown alga polysaccharide sulfuric ester and schisandra chinensis and use thereof |
| CN103446165A (en) * | 2013-09-12 | 2013-12-18 | 中国海洋大学 | Application of guluronic acid oligomers in preparing medicines, health products or dietary supplements for preventing and treating alcoholic liver injury |
| CN103446165B (en) * | 2013-09-12 | 2016-04-13 | 中国海洋大学 | Oligoguluronic acid is preparing the application in the medicine of prevention and therapy alcoholic liver injury, health product or dietary supplement |
| CN112513104A (en) * | 2018-07-27 | 2021-03-16 | Arc医疗器械股份有限公司 | Highly sulfated fucoidan for the treatment of fibrous adhesions |
| US11628183B2 (en) | 2018-07-27 | 2023-04-18 | ARC Medical Ine. | Highly purified fucans for the treatment of fibrous adhesions |
| US11642368B2 (en) | 2018-07-27 | 2023-05-09 | ARC Medical Inc. | Highly purified and/or modified fucan compositions for the treatment of fibrous adhesions |
| US11938145B2 (en) | 2018-07-27 | 2024-03-26 | ARC Medical Inc. | Low endotoxin fucan compositions, systems, and methods |
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