CN101851298B - Sulfated galactan and preparation method thereof - Google Patents
Sulfated galactan and preparation method thereof Download PDFInfo
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Abstract
The invention discloses sulfated galactan and a preparation method thereof. As for the protein-free sulfated galactan, the molecular weight is 100-200kDa, the sulfate group content is 26-32wt%, and the galactan content is 60-69wt%. The sulfated galactan is prepared by the processes of water extracting, acid degrading, membrane filtering, alcohol precipitating, drying and the like. The preparation process of the invention is suitable for industrialized mass production, can realize preparation of the sulfated galactan with the molecular weight range of 100-200kDa from Grateloupia filicina, and can be used for manufacturing various orally-administrated preparations and being applicable to anticoagulant and antithrombotic therapies in clinically.
Description
Technical field
The invention belongs to natural medicine technical field, be specifically related to a kind of sulfated galactan and preparation method thereof with definite range of molecular weight distributions (molecular weight is 100-200kDa).
Background technology
As one Chinese patent application 200610026830.7 disclosed technology contents, the sulfated galactan of separation and Extraction has anticoagulation, antithrombotic, antiviral and anti-tumor activity from Grateloupia filicina (Wulf.) (Grateloupia filicina).Because polysaccharide is a macromolecular compound, its molecular weight height is not only active relevant, also closely related with its absorption with it.Oral medication has superior security and accessibility with respect to injecting drug use.Therefore to the sulfated galactan in Grateloupia filicina (Wulf.) source be applied to clinically, produce a kind of orally active medicine, also need study the relation between the drug effect of its molecular weight and oral absorption.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of sulfated galactan and preparation method thereof; Promptly the sulfated polysaccharides from the Grateloupia filicina (Wulf.) source is carried out new preparing method's research; Relation between distribution of screening different molecular weight and the anticoagulant active, thus a kind of new orally active sulfated polysaccharides obtained.
Sulfated galactan provided by the present invention, molecular weight are 100-200kDa, and sulfate group content is 26wt%～32wt%, and its repeat unit structure is:
R=H, CH
3, Xyl (wood sugar) or Glc (glucose)
[-(1→3)-β-D-Galactose-2-SO
4-(1→4)-β-D-Galactose-]
n
The content of Polygalactan is 60wt%～69wt% in the said sulfated galactan.
Said sulfated galactan does not contain protein.
Said sulfated galactan adopts following method to be prepared from, and specifically may further comprise the steps:
1) water extraction: get the Grateloupia filicina (Wulf.) medicinal material; Remove and desalt and silt, choose decon, put into extractor; 15-20 times of water of dosing material amount; Be heated to 90-100 ℃ and extract 1-2 hour (reaching 90 ℃ of timing), cross the spinning of 300 order filter clothes or 3000-4000rpm rotating speed and remove the dregs of a decoction, collect extracting solution from temperature.
2) acid degradation: said extracted liquid is warming up to 60-70 ℃ and maintenance, with 1mol/L hydrochloric acid or sulfuric acid adjust pH to 2～3, insulation 2h; Sampling detects the molecular weight of polysaccharide in the solution, to molecular weight be 180-200kDa, stop heating; Be neutralized to pH6～7 with the 1mol/L sodium hydroxide solution; Centrifugal (3000-4000rpm) discards residue, collects supernatant.
3) membrane filtration: centrifugal above-mentioned supernatant, the FM in 0.22-0.45 μ m aperture or fluorine filter membrane are excessively partially collected filtrating then; Filtrating uses molecular weight cut-off to be the pvdf of 100kDa or the ultra-filtration membrane of polysulfones material; Liquid to be filtered is long-pending to reduce to original volume 8～10% o'clock; Ultrafiltration limit, limit adds the pure water (add pure water speed and filtered solution reserve speed consistent) of original volume 8～10%, and the continuation ultrafiltration is 8～10% of an original volume to holding back filtrate volume.
4) alcohol precipitation: filtrating is held back in above-mentioned ultrafiltration go in the alcohol precipitation filling, stir 95% ethanol that adds 3 times of weight down, left standstill centrifugal (3000-4000rpm) collecting precipitation 12 hours.
5) drying: above-mentioned deposition is put vacuum drying oven, keeps 80-90 ℃ of vacuum-drying 24 hours, to water cut less than 5%, promptly get sulfated galactan.
Wherein, molecular weight of the present invention is meant the employing gel chromatography, is reference substance with standard polysaccharide (VISOSE), obtains through the GPC computed in software.Concrete grammar is following: 1～2mg standard polysaccharide (VISOSE) and sulfated galactan sample, be made into 2mg/ml solution with moving phase, and the centrifugal 10min of 10000rpm draws supernatant and changes the liquid phase sample bottle over to, and is subsequent use.Aglient 1100 high performance liquid chromatographs are equipped with the differential detector, KS-804, KS-805 columns in series (Shodex company); Moving phase is the 0.2mol/L sodium chloride solution, 40 ℃ of column temperatures, flow velocity 0.8ml/min; Sampling volume 25 μ l; With standard polysaccharide and sulfated galactan sample solution sample introduction successively, measure RT, with the molecular weight of GPC computed in software sulfated galactan.The range of molecular weight distributions of sulfated galactan of the present invention is 100-200kDa.
Show that through following method detection sulfated galactan of the present invention does not contain protein: the dissolving of polysaccharide samples with water is made into 0.1mg/ml solution, is blank with zero(ppm) water, the ultraviolet absorpting spectrum under scanning 200～400nm.The polysaccharide sample only has an absorption peak at 256nm as a result, and each polysaccharide sample does not all have obvious absorption peaks at the above wavelength of 280nm, can judge wherein not contain protein.Protein has obvious absorption peaks at the above wavelength of 280nm usually.
Adopt sulfuric acid-phynol method measure in the sulfated galactan of the present invention the content of Polygalactan be 60wt%～69wt%.Specific as follows:
1) reference substance solution preparation: precision takes by weighing 105 ℃ of semi-lactosi standard substance 4mg that are dried to constant weight, and with changing the 100ml volumetric flask behind the dissolved in distilled water over to, adding distil water is diluted to scale, shakes up, and promptly gets (every 1ml contains semi-lactosi 40 μ g).
2) typical curve preparation: accurately pipette reference substance solution 0.4ml, 0.7ml, 1.0ml, 1.3ml, 1.6ml; 2.0ml, to put respectively in the 20ml test tube, each pipe is mended and is added water to 2.0ml, adds 1ml 6% phenol, slowly adds the 5ml vitriol oil again; Shake up immediately, room temperature is placed 30min, and other gets the same operation of 2.0ml zero(ppm) water, as blank; Surveying absorbancy in the 490nm wavelength, is ordinate zou with the absorbancy, and galactose content is an X-coordinate, the drawing standard curve.
3) measure: precision takes by weighing 105 ℃ of Grateloupia filicina (Wulf.) polysaccharide sample 2mg that are dried to constant weight, puts in the 25ml volumetric flask, after the adding distil water dissolving; Be diluted to scale, shake up, accurately pipette 1ml; Press method under the typical curve item,, measure absorbancy in accordance with the law from " each pipe is mended and added water to 2.0ml "; Read the content of semi-lactosi the need testing solution from typical curve, calculate, promptly get.
Adopt bariumchloride-gelatin method measure in the sulfated galactan of the present invention the massfraction of sulfate be 26wt%-32wt%.Specific as follows:
1) reference substance solution preparation: precision takes by weighing 105 ℃ of vitriolate of tartar standard substance 27.2mg that are dried to constant weight, with changing the 25ml volumetric flask behind the 1mol/L dissolving with hydrochloric acid over to, adds 1mol/L hydrochloric acid and is diluted to scale, shakes up, and promptly gets (every 1ml sulfur-bearing acidic group 600 μ g).
2) typical curve preparation: accurately pipette reference substance solution 0 μ l, 20 μ l, 40 μ l, 70 μ l, 100 μ l; 130 μ l, 160 μ l, 200 μ l put respectively in the 20ml test tube, and each pipe is added 1mol/L hydrochloric acid to 200 μ l; Add 3.8ml 3% trichoroacetic acid(TCA), add 1ml 1% bariumchloride gelatin solution again, shake up, leave standstill 15min, other gets a test tube; Add 200 μ l water, add 3.8ml 3% trichoroacetic acid(TCA) solution, add 1ml 0.5% gelatin solution again, shake up, as blank; Surveying absorbancy at the 360nm place, is ordinate zou with the absorbancy, and sulfate content is X-coordinate, the drawing standard curve.
3) measure: precision takes by weighing 105 ℃ of Grateloupia filicina (Wulf.) polysaccharide sample 7mg that are dried to constant weight, puts in the 10ml ampoule, accurately adds 5ml 1mol/L hydrochloric acid, seals; Heating hydrolysis 6h in 100 ℃ of baking ovens takes out, and puts cold; Draw 1.5ml and place the 2ml centrifuge tube, the centrifugal 10min of 10000rpm draws two parts of 200 μ l supernatants; Put respectively in the 20ml test tube, each pipe adds 3.8ml 3% trichoroacetic acid(TCA) solution, and portion adds 1ml 1%BaCl
2Gelatin solution, another part adds 1ml 0.5% gelatin solution, shakes up, and surveys absorbancy behind the 15min in 360nm place, reads the content of sulfate the need testing solution from typical curve, and calculating promptly gets.
The relation of molecular weight and anticoagulating active.The in vitro method test shows: molecular weight is big more, and is strong more by the anticoagulating active of mole densitometer.Such as adopting the external coagulation time test method of test tube method rabbit; Compare the Grateloupia filicina (Wulf.) water extraction; Through acid-hydrolyzed different durations, make the anticoagulant active of 18 sulfated galactans (GFP) sample of molecular weight from 31kDa to 1500kDa, and compare with the Low molecular heparin of 10U/ml concentration.The result shows: molecular weight is 31,33,36,42,49,73,76,81,110,130,166,190,227,395,466,512,565, the GFP of 1500kDa is when concentration 0.01mmol/L; All the external clotting time of test tube method rabbit be can obviously prolong, P＜0.05 or P＜0.01 compared with the saline water control group; And be the more tangible trend of the big more blood coagulation resisting function of tangible molecular weight; Molecular weight is that the above external blood coagulation resisting function of 22.7 ten thousand (0.01mmol/L) is superior to Low molecular heparin (10U/ml).Concrete data are referring to table 1.
The GFP of table 1 different molecular weight is to the influence (
n=6) in external clotting time of rabbit
Annotate: compare with control group,
*Be P＜0.05,
*Be P＜0.01,
*Be P＜0.01.
But the animal drug effect test card of oral administration route is bright: the anticoagulation of sulfated galactan is different with the in vitro tests result, is not proportionate with molecular weight, in fact has the range of molecular weight distributions an of the best.Through comparing the anti thrombotic action that three batches of sulfated galactan molecular weight are respectively 193kDa, 136kDa and 112kDa sample mouse oral administration; Cause three experiments of mouse tail vein thrombosis through clotting time of mice, rat coagulation factor assay and X 5189, the anti thrombotic action of three batches of sulfated galactans of comparative observation (GFP) sample.The result shows: three crowdes of GFP all can prolong clotting time of mice, prolong thrombin time (TT), prothrombin time (PT), partial thromboplastin time (APTT); Suppress the formation that X 5189 causes the mouse tail vein thrombus, the effect of GFP-B (molecular weight 136kDa) and GFP-C (molecular weight 112kDa) is superior to GFP-A (molecular weight 193kDa).Specifically referring to embodiment 2.This is because for GI absorption, needs a suitable molecular weight ranges.
Therefore, it is essential controlling the sulfated galactan that is fit to oral administration through MWD.The preparation method of sulfated galactan of the present invention is fit to commercial scale prodn; Realization prepares the sulfated galactan of molecular weight ranges in 100-200kDa from Grateloupia filicina (Wulf.); Be used to make the various preparations of oral administration, clinically be used for anticoagulation and antithrombotic treatment.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described in further detail.
Embodiment 1
The suitability for industrialized production galactan sulfate
Plant and instrument: the key equipment that is used to control molecular weight ranges is the UF402M membrane sepn all-in-one that general film development in science and technology ltd is matched in the Wuxi, and 4040 type PS membranes of two U.S. GE companies are installed.
1) water extraction: get Grateloupia filicina (Wulf.) medicinal material (place of production is Qingdao and Ningde, Fujian) 10kg, use water rinse, remove and desalt and silt; Choose decon, put into extractor, add 200L water; 90 ℃ are extracted 1.5h (reaching 90 ℃ of timing from temperature), filter, and the dregs of a decoction extract twice again; Add 150L water at every turn, merge No. three times extracting solution.
2) acid degradation: the above-mentioned extracting solution that makes is warming up to 60 ℃; Treat after the solution temperature balance to continue 60 ℃ (60～65 ℃) insulation 2h, be neutralized to pH6～7 with the 1mol/L sodium hydroxide solution then with 1mol/L hydrochloric acid adjust pH 2～3 (needing 1mol/L hydrochloric acid 5L approximately); Centrifugal (4000rpm; 10min), discard residue, collect supernatant.
3) membrane filtration: centrifugal above-mentioned supernatant; Cross the filter membrane in 0.45 μ m aperture, filtrating is concentrated into about 50L through the UF402 ultrafilter, and ultrafiltration limit in limit adds 100kg pure water (adding pure water speed with filtered solution reserve speed consistent) then; Until adding, continue to be concentrated to 50L.
4) alcohol precipitation: ultrafiltration and concentration liquid stirs and adds 150kg 95% industrial alcohol deposition polysaccharide down, leaves standstill centrifugal collecting precipitation 12 hours.
5) drying: deposition is put the vacuum drying oven of tool condensing surface, 80 ℃ of vacuum-drying 24 hours, to water cut less than 5%.Yield 15-25%.
By six batches of above explained hereafter, measured six batches in the test agent result of Polygalactan, sulfate, molecular weight as shown in table 2.
Table 2
Embodiment 2
Relatively three batches of sulfated galactan sample anti thrombotic action experiments
1 material
1.1 trial drug
Sulfated galactan sample one (GFP-A), lot number: 20070701, molecular weight 193kDa.
Sulfated galactan sample two (GFP-B), lot number: 20070727, molecular weight 136kDa.
Sulfated galactan sample two (GFP-C), lot number: 20071019, molecular weight 112kDa.
Above-mentioned three lot sample article face with preceding and are made into desired concn solution with saline water.
Aspirin tablet: Xinhui Pharmaceutical Co., Ltd., Hunan, product batch number 060802.
1.2 equipment reagent
Capillary glass-tube (internal diameter 1mm, long 100mm), Huaxi Medical Univ instrument building and repair plant.Electronic balance, mettler Toledo, made by mettler-toledo group; System CA-530 coagulo meter (Japan).
1.3 animal
Kunming mouse, male, body weight 18～22g, conformity certification number: 2006A063; The SD rat, male, body weight 170～200g, conformity certification number: 2006A064 provides by Zhongshan University's Experimental Animal Center, and above animal is all used after this laboratory adapts to 3d.
The raising condition: after animal gets into the laboratory, sub-cage rearing, big mouse is 5 in every cage, by special messenger's feeding and management.Animal housing's illumination is sufficient, and heating ventilation and air-conditioning equipment is good, and room temperature is controlled at 20-25 ℃, and relative humidity is 50-70%, regularly sterilizes by routine in the laboratory.
1.4 dosage setting
By etc. molar mass dosage design, big mouse oral administration is: the GFP-A high and low dose is 19mg/kg and 9.5mg/kg; The GFP-B high and low dose is 13mg/kg and 6.5mg/kg; The GFP-C high and low dose is 11mg/kg and 5.5mg/kg.
The big mouse oral administration of positive control drug aspirin tablet dosage is 10mg/kg.
2. method and result
2.1 influence to clotting time of mice
80 of male mouse of kunming, body weight 18～22g divides 8 groups at random, 10 every group, is respectively: 1. control group; 2.GFP-A (19mg/kg); 3.GFP-A (9.5mg/kg); 4.GFP-B (13mg/kg); 5.GFP-B (6.5mg/kg); 6.GFP-C (11mg/kg); 7.GFP-C (5.5mg/kg); 8. aspirin tablet (10mg/kg).All irritate stomach every day and give soup once, continuous 7 days by 0.2mL/10g.60min after the last administration carries out coagulation time test with capillary tube technique, and the result sees table 3.
The influence of table 3 pair clotting time of mice (
n=10)
Annotate: compare with control group,
*Be P＜0.05,
*Be P＜0.01.
Can be found out by table 3: the sulfated galactan sample continuous oral administration 7d of three lot numbers (three kinds of molecular weight) all can obviously prolong the clotting time (comparing P＜0.05 or P＜0.01 with control group) of mouse.Wherein sample GFP-B (136kDa) and GFP-C (112kDa) effect are superior to sample GFP-A (193kDa).
2.2 influence to the rat thrombin
Male SD rat, body weight 170～200g divides 8 groups at random, 6 every group, is respectively: 1. control group; 2.GFP-A (19mg/kg); 3.GFP-A (9.5mg/kg); 4.GFP-B (13mg/kg); 5.GFP-B (6.5mg/kg); 6.GFP-C (11mg/kg); 7.GFP-C (5.5mg/kg); 8. aspirin tablet (10mg/kg).All irritate stomach every day and give soup once, continuous 7 days by 1.0mL/100g.60min after the last administration; With 3% vetanarcol (45mg/kg) intraperitoneal injection of anesthesia; From abdominal vein blood drawing 1.8ml; Adding rapidly has in the mensuration pipe of 1: 9 sodium citrate soln 0.2ml, send the content of biochemical investigation section of the attached First Academy of Zhongshan University with System CA-530 coagulo meter (Japan) mensuration thrombin time (TT), prothrombin time (PT), partial thromboplastin time (APTT) and Fibrinogen (Fbg.), and the result sees table 4.
The influence of table 4 pair rat thrombin (
n=6)
Annotate: compare with control group,
*Be P＜0.05,
*Be P＜0.01.
Can find out by table 4: continuous oral administration 7d; The sulfated galactan sample of three lot numbers (three kinds of molecular weight) all has the effect that prolongs PT, TT, APTT, and wherein GFP-B (136kDa) high dosage can obviously prolong PT and TT (comparing P＜0.05 or P＜0.01 with control group); GFP-C (112kDa) high dosage can obviously prolong PT.The sulfated galactan sample of three lot numbers (three kinds of molecular weight) is not remarkable to the influence of Fibrinogen (Fbg.), but the trend that reduces its content is all arranged.
2.3 to the thrombotic influence of mouse tail vein
80 of male mouse of kunming, body weight 18～22g divides 8 groups at random, 10 every group, is respectively: 1. control group; 2.GFP-A (19mg/kg); 3.GFP-A (9.5mg/kg); 4.GFP-B (13mg/kg); 5.GFP-B (6.5mg/kg); 6.GFP-C (11mg/kg); 7.GFP-C (5.5mg/kg); 8. aspirin tablet (10mg/kg).All irritate stomach every day and give soup once, continuous 7 days by 0.2mL/10g.1h after administration in the 5th day; The subcutaneous X 5189 of pressing 0.2ml/10g injection 0.5% in the back of mouse; 24h, 48h and 72h are measured mouse and black tail length (being thrombus length) and full tail length are occurred in injection back, calculate black tail length and tail length ratio and tail vein bolt rate of formation entirely.The result sees table 5 and table 6.
The influence of table 5 pair mouse tail vein thrombus length and rate of formation (
n=10)
Annotate: compare with control group,
*Be P＜0.05,
*Be P＜0.01,
* *Add＜0.001
Table 6 pair mouse tail vein thrombosis length accounts for the long percentile influence (
n=10) of tail
Annotate: compare with control group,
*Be P＜0.05,
*Be P＜0.01,
* *Be P＜0.001
Can find out by table 5 and table 6: successive administration 7d, the sulfated galactan sample of three lot numbers (three kinds of molecular weight) all can obviously suppress the formation of mouse tail vein thrombus, and wherein sample GFP-B (136kDa) and GFP-C (112kDa) effect are preferable.
3. brief summary
Three batches of sulfated galactans (GFP) sample all can prolong clotting time of mice; Prolong thrombin time (TT), prothrombin time (PT), partial thromboplastin time (APTT); Suppress the formation that X 5189 causes the mouse tail vein thrombus, the effect of GFP-B (136kDa) and GFP-C (112kDa) is superior to GFP-A (193kDa).
Should be noted that at last; Above embodiment is only unrestricted in order to technical scheme of the present invention to be described; Although with reference to preferred embodiment the present invention is specified, those of ordinary skill in the art should be appreciated that and can make amendment or be equal to replacement the technical scheme of invention; And not breaking away from the spirit and the scope of technical scheme of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (3)
1. sulfated galactan, molecular weight is 100-200kDa, it is characterized in that, and the content of sulfate group is 26wt%～32wt% in the said sulfated galactan, and its repeat unit structure is following:
Wherein: R=H, CH
3, Xyl or Glc;
The content of Polygalactan is 60wt%～69wt% in the said sulfated galactan;
The preparation method of said sulfated galactan may further comprise the steps:
1) water extraction: get the Grateloupia filicina (Wulf.) medicinal material, remove and desalt and silt, choose decon; Put into extractor; 15-20 times of water of dosing material amount is heated to 90-100 ℃ and extracted 1-2 hour, reaches 90 ℃ of timing from temperature; Cross the spinning of 300 order filter clothes or 3000-4000rpm rotating speed and remove the dregs of a decoction, collect extracting solution;
2) acid degradation: said extracted liquid is warming up to 60-70 ℃ and maintenance, with Hydrogen chloride or sulfuric acid adjust pH to 2～3, insulation; Sampling detects the molecular weight of polysaccharide in the solution, to molecular weight be 180-200kDa, stop heating; Be neutralized to pH6～7 with sodium hydroxide solution; Centrifugal, discard residue, collect supernatant;
3) membrane filtration: centrifugal above-mentioned supernatant, the FM in 0.22-0.45 μ m aperture or fluorine filter membrane are excessively partially collected filtrating then; Filtrating is with the ultrafiltration membrance filter of pvdf or polysulfones material; Liquid to be filtered is long-pending to reduce to original volume 8～10% o'clock; Ultrafiltration limit, limit adds the pure water of original volume 8～10%; Adding pure water speed and filtered solution, to reserve speed consistent, and the continuation ultrafiltration is 8～10% of an original volume to holding back filtrate volume;
4) alcohol precipitation: filtrating is held back in above-mentioned ultrafiltration go in the alcohol precipitation filling, stir adding ethanol down, leave standstill centrifugal collecting precipitation;
5) drying: above-mentioned deposition is put vacuum drying oven, keep 80-90 ℃ of vacuum-drying 24 hours,, promptly get sulfated galactan to water cut≤5%.
2. sulfated galactan according to claim 1 is characterized in that said sulfated galactan does not contain protein.
3. sulfated galactan according to claim 1 is characterized in that, said sulfated galactan is an oral prepns.
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