CN1411816A - New anticoagulant medicine - Google Patents
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- CN1411816A CN1411816A CN 02128867 CN02128867A CN1411816A CN 1411816 A CN1411816 A CN 1411816A CN 02128867 CN02128867 CN 02128867 CN 02128867 A CN02128867 A CN 02128867A CN 1411816 A CN1411816 A CN 1411816A
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Abstract
The preparation method of anticoagulant medicine includes the following steps: adding excessive SO3-DMF in water soluble chitosan, stirring and fitlering, using dilute methanoic acid solution to regulate pH of filtrate to 2-4, drop-adding dilute CuSO4 solution while stirring to produce precipitation, continuous stirring for several hr, and filtering precipitate, washing with DMF, further drop-adding mixture solution of pyridine, sulfur oxide sulfur trioxide and micro DMF, stirring for several hr., adding saturated NaHCO3 solution, fitering, freeze-drying, dissolving dried matter in water to obtain 1-15% solution, adding concentrated perchloric acid solution, stirring, filtering, precipitation, washing with ethyl alcohol, dissolving the obtained material in concentrated acetic acid, further adding perchloric acid solution.
Description
Invention field
The present invention relates to a kind of novel anti blood-clotting agent.
Background technology
Heparin sodium is important anticoagulation medicine, finds to can be used for preventing and treating the ADIS disease recently.But the heparin sodium that extracts from the mammal intestinal mucosa owing to antibiotic remains being arranged and also can bringing out reasons such as bovine spongiform encephalopathy, was forbidden by European and American countries in nearly 2 years, cause heparin market raw material in short supply, so people was seeking a kind of better substitute products.
Summary of the invention
The present invention extracts a kind of seemingly heparin material from free of contamination marine organisms in order to solve this difficult problem.
An object of the present invention is to provide a kind of anticoagulative substance that from water-soluble chitosan, extracts.
Another object of the present invention provides a kind of complex that a kind of anticoagulative substance that extracts and low molecular chitosan and low molecule sodium alginate are composited from water-soluble chitosan, be referred to as extra large plain sodium again.
Product of the present invention is through the zoopery (dog, sheep, white mouse, Carnis Coturnicis japonicae) of Chinese Academy of Medical Sciences's zoopery field strictness, and the result shows that product anticoagulant efficiency of the present invention is higher 2.7 times than heparin.Antihypertensive effect is better than heparin, has two to be better than heparin in three indexs of lipid-reducing function.
The preparation technology of anticoagulative substance of the present invention comprises: the water intaking soluble chitosan adds excessive SO
3Stir among-the DMF, filter, filtrate is transferred pH2-4 with dilute formic acid solution, stirs to drip rare CuSO down
4Solution is to there being precipitation to produce, and continues stirred for several hour, and the leaching precipitate with the DMF washing, drips pyridine again, sulfur monoxide, and sulfur trioxide, and after the mixed liquor stirred for several of micro-DMF hour, add saturated NaHCO
3Solution, stop the agitation and filtration lyophilization, again dry thing water is dissolved into 1-15% solution, stir fast down, the enriching perchloric acid solution filters, and precipitation is with after the washing with alcohol, commentaries on classics is dissolved in an amount of spirit acid and (is typically about 10-30%, best 30%) in, adds perchloric acid solution stirred for several hour, leaching precipitation washing with alcohol again, vacuum drying under the room temperature, this dry thing is dissolved in again and under agitation adds excess chlorine sulfonic acid in appropriate solvent such as the pyridine, neutralization at last is behind the ethanol precipitation, precipitation with washing with alcohol for several times, vacuum drying below 60 ℃ obtains anticoagulative substance, i.e. product A.
Wherein water-soluble chitosan and SO
3-DMF reaction ingredient proportion is 0.5-1: 2-5, and the best is 1: 3.
Wherein formic acid solution concentration is preferably 1-5%, and the best is 3%.Transfer pH2-4, best 2.6.
CuSO
4The solution concentration scope is generally 1-10%, and best 2%.The stirring reaction time is preferably 5-8 hour, and the best is 6 hours.
Pyridine: sulfur monoxide: the sulfur trioxide ratio is about 3-5: 0.25-1: 0.25-1, best 4: 0.5: 0.5.
Speed of agitator is preferably 100-140 rev/min fast, best 120 rev/mins.
Perchloric acid solution concentration is preferably about 40-70%, and is preferred 60%, addition be 1-4 doubly, best 2 times.
The preparation technology of complex of the present invention comprises: the food stage chitosan of getting molecular weight＜80,000 adds suitable quantity of water, adds protease, and reaction is degraded a few hours under proper temperature, slowly stir simultaneously, use an amount of ethanol precipitation, collecting precipitation, wash for several times with dehydrated alcohol, drying gets product B; Get sodium alginate with an amount of rare hydrogen peroxide dissolving, in 50-60 ℃ of following stirring reaction a few hours, the reuse ethanol precipitation, drying, product C; And with above-mentioned product A, B and C according to 0.5-1: 0.5-2: 0.5-1, preferred 1: 0.6: 0.8 mass ratio mixes, water is dissolved into weak solution, abundant stirred for several hour, after resin anion (R.A.) post (for example 725 type resin anion (R.A.)s), filter effluent, behind ethanol precipitation, wash with dehydrated alcohol, precipitation, the washing of reuse ether, vacuum drying below 60 ℃, obtain complex of the present invention, promptly extra large plain sodium product (anticoagulant efficiency 60-110u/mg).Wherein enzymatic degradation can be used alkaline protease, and addition is 0.1-0.5%, and best 0.2%.
Embodiment
Embodiment 1
Get the 100g water-soluble chitosan and add 450ml SO
3Stir among-the DMF, filter, filtrate is transferred pH2-4 with 1-3% formic acid liquid, stirs slowly to drip 1-2% CuSO down
4Solution 170ml-200ml to there being precipitation to produce, continuing to stir and filtered in 6 hours, and collecting precipitation washs with DMF, drips pyridine: sulfur monoxide: the mixed liquor of sulfur trioxide (4: 0.5: 0.5) and micro-DMF a little, stirs the saturated NaHCO of adding after 6 hours
3Solution 265ml, filter, freezing vacuum drying-4 ℃, lyophilized products becomes 10% solution with dissolved in purified water, under stirring fast, add 60% perchloric acid solution (water: perchloric acid 100: 2) filter, collecting precipitation is dissolved in its commentaries on classics in 30% acetic acid, adds 60% perchloric acid that 1-4 doubly measures again, stir after 1 hour, collecting precipitation is with 95% washing with alcohol 3-5 time, and mud chamber's relaxing the bowels with purgatives of warm nature vacuum drying gets the 45g product, the 45g product is dissolved in adding 2-5 in the 120ml pyridine and doubly measuring again, chlorosulfonic acid stirs, with 3% NaOH neutralization, use 95% ethanol precipitation, precipitation washing with alcohol 5 times, vacuum drying below 60 ℃ gets product A 32g.
Embodiment 2
As embodiment 1, prepare product A.
Get 100g food stage chitosan (MG＜80,000) and add water 300ml, add about alkaline protease 0.2g, 45 ℃ were reacted 12 hours down, and slow the stirring is with 10 times of amount 95% acetic acid precipitations, collecting precipitation absolute ethanol washing 3-4 time, the dry B product 22g that gets.
Get 1000g sodium alginate 2000ml 5%H
2O
2Dissolving was stirred 24 hours down in 50 ℃, 5 times of amounts of reuse, 95% ethanol precipitation, and drying precipitate gets C product 80g.
A, B, C product are dissolved into 1% solution in 1: 0.6: 0.8 ratio with pure water, fully stir after 2 hours, slowly by the resin anion (R.A.) post, effluent filters, and after filtrate was measured 95% ethanol precipitations with 5 times, the reuse dehydrated alcohol was washed 3 times, wash 1 time with ether at last, vacuum drying below 60 ℃ gets extra large plain sodium product, anticoagulant efficiency 105u/mg.One, animal blood anticoagulating active test
1, material and method
1.1 the reagent heparin sodium is provided by the biological company limited of Erie's health.The plain sodium in sea is provided by the applicant.
1.2 instrument 721 type spectrophotometers, 80-2 type centrifuge, RA-50 semi-automatic biochemical analyzer.
2.1 experimental technique accurately takes by weighing 1 milligram of moisture 8% heparin sodium, 1 milligram in extra large plain sodium, and deionized water dilutes 60,000 times, fully mixing for standby use.
2.2 got clotting time 1.5 minutes to 3 minutes, 30 of goats are divided 1,2,3 group, 10 every group.
2.3 first group, in goat body weight 180,000/ respectively intravenous injection of ratio, deionized water, writing time.
2.4 second group, in goat body weight 180,000/ respectively intravenous injection of ratio, heparin sodium writing time.
2.5 the 3rd group, in goat body weight 180,000/ the ratio plain sodium in intravenous injection sea writing time respectively.
2.6 after the week, 168h draws blood three groups of sheep respectively, measures the blood clotting time.
Table 1
| Numbering | ?1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 | ?8 | ?9 | ?10 | On average |
| ?I | ?2.37 | ?2.81 | ?2.40 | ?1.23 | ?2.90 | ?1.16 | ?1.08 | ?2.1 | ?1.92 | ?1.68 | ?1.965 |
| ?II | ?8.23 | ?9.10 | ?8.952 | ?9.46 | ?8.21 | ?9.01 | ?8.78 | ?8.80 | ?9.62 | ?9.37 | ?8.95 |
| ?III | ?37.6 | ?31.6 | ?34.7 | ?29.8 | ?36.3 | ?32.1 | ?27.1 | ?31.2 | ?35.5 | ?33.6 | ?32.94 |
Conclusion is injected the same raising of three kinds of same medicines of different pharmaceutical respectively through three groups of goats, and same temperature is with for the moment, same dosage, the heparin sodium anticoagulant time is 4.55 times of deionized water, and the extra large plain sodium anticoagulant time is 16.76 times of deionized water, is 3.68 times of anticoagulant time of heparin sodium.Two, extra large plain sodium is to animal atherosclerosis prevention and the treatment effect with heparin sodium
1, material and method
1.1 material
The plain sodium in sea, vitamin E, cholesterol, isopropyl alcohol (A, R), chloroform, aluminium oxide, methanol, malonaldehyde, cholesterol (CT), triglyceride (TC), highdensity lipoprotein-cholesterol (LDL-C) test kit.
1.2 instrument: 721 type spectrophotometers, gas bath, constant temperature oscillator, the automatic seriation analyser of RA-50
1.3 the male Carnis Coturnicis japonicae of animal Japan
1.4 feedstuff includes:
Corn 62%, wheat bran 6%, bean cake 15%, give birth to the dregs of rice 5%, egg albumen powder 5%, fish flour 2%, bone meal 2%, salt 0.3%, multiannensional-sine 0.03%, trace element 0.15%, choline 0.1%, methionine 0.06%, lysine 0.04%, vitamin A, D0.05%, high lipid food, contain Adeps Sus domestica 15% in the 100g normal diet, cholesterol 1%.
2.1 method
Select for use with general raising, 140 of the healthy male Carnis Coturnicis japonicaes behind the IW, body weight 98.11 ± 13.54g is divided into 7 groups by body weight.The I group, the general group of raising, the II group, height is raised group, the III group, heparin sodium 0.003mg/kg, IV organizes (extra large plain sodium group 0.003mg/kg), and V organizes (extra large plain sodium 0.0025mg/kg), and VI organizes (extra large plain sodium 0.05mg/kg), VII (heparin sodium+VE), raise in the Rotating Stainless Steel Cage of 47 * 31CM illumination every day 14 hours, 22 ± 4 ℃ of room temperatures respectively, behind medicine 2,4, the 8W end weighs, and after 14 hours, get blood by vein in fasting, adopt test kit to detect serum total cholesterol (TC, three ketone sheets), triglyceride, highdensity lipoprotein-cholesterol, low-density albumen-cholesterol.
The 8W end is with every group of 8 Carnis Coturnicis japonicae sacrificed by decapitation before the experiment, take out aorta and right brachiocephalic trunk tremulous pulse, blot with filter paper behind the normal saline flushing serum, the extracting arterial wall lipid of weighing, preparation arterial wall tissue homogenate, centrifuging and taking supernatant 1ml is after the oven dry, measure arterial wall TC, the content of free cholesterol (FC).Left brachiocephalic trunk tremulous pulse with glacial phosphoric acid pH of buffer=7.4, is prepared tremulous pulse arm tissue homogenate, measure MDA content.
The extra large plain sodium of table 2 is to the image (g) of Carnis Coturnicis japonicae body weight
| All numbers (W) | ||||
| Group h | ?0 | ?2 | ?4 | ?7.5 |
| ?I | ?96.50±13.88 | ?116.58±11.36 | ?141.75±8.20 | ?156.25±4.97 |
| ?II | ?96.50±13.61 | ?114.25±11.86 | ?141.75±9.12 | ?157.00±4.58 |
| ?III | ?98.00±14.18 | ?114.50±14.31 | ?142.00±11.00 | ?156.80±7.11 |
| ?IV | ?99.25±12.68 | ?117.50±10.55 | ?143.00±8.72 | ?159.50±7.05 |
| ?V | ?99.25±13.16 | ?116.25±10.94 | ?144.25±9.39 | ?160.00±6.89 |
| ?VI | ?98.25±12.48 | ?116.75±10.99 | ?142.75±9.81 | ?157.00±9.41 |
| ?VII | ?100.25±15.44 | ?118.00±14.00 | ?144.01±11.25 | ?156.5±7.09 |
The image of table 3 couple HDLHC (%, X ± S)
| Cycle | |||
| Group | ?2 | ?4 | ?8 |
| ?I | ?53.71±19.47 | ?52.06±21.97 | ?56.60±21.96 |
| ?II | ?28.48±8.00 | ?5.22±2.28 | ?5.10±1.36 |
| ?III | ?6.00±1.12 | ||
| ?IV | ?40.83±7.13 | ?8.56±8.12 | ?6.10±1.95 |
| ?V | ?43.46±13.14 | ?5.66±2.88 | ?5.38±2.15 |
| ?VI | ?36.98±9.71 | ?5.11±2.43 | ?5.09±2.20 |
| ?VII | ?44.24±16.55 | ?6.36±2.91 | ?5.86±2.40 |
The influence (mmol/g) of table 4 pair arterial wall cholesterol level
| Cholesterol level | |||
| Group | T-CHOL (TC) | Free cholesterol (FC) | Cholesterol ester (CE) |
| ?I | ?8.66±1.94 | ?5.64±1.58 | ?2.31±1.12 |
| ?II | ?21.59±4.20 | ?8.34±0.76 | ?3.21±4.22 |
| ?III | ?18.46±2.64 | ?8.17±1.33 | ?10.28±3.30 |
| ?IV | ?17.53±2.19 | ?8.05±1.16 | ?8.88±2.24 |
| ?V | ?15.56±2.37 | ?7.52±1.58 | ?8.05±2.46 |
| ?VI | ?19.18±6.04 | ?8.14±1.72 | ?11.05±5.52 |
| ?VII | ?15.12±2.57 | ?7.97±1.60 | ?7.70±2.02 |
Conclusion is according to table 2, and the time of Carnis Coturnicis japonicae body weight changes and the generally observation of situation, and results suggest: extra large plain sodium does not influence growth and the survival rate of Carnis Coturnicis japonicae during medication, toxicity is little.Shown in the table 3, all medication groups are measured arterial wall TC and HDL and are obviously reduced, and relevant with dosage, and not medication group is obviously high.The also identical minimizing of heparin group, distance is little.Serum TC shown in the table 4, FC, CE and medication, medication does not have obvious distance.Three, to the hypotensive effect of rat
1, material
1.1 medicine
The plain sodium in sea is provided by the application company, and propranolol hydrochloride, acecoline, histamine phosphate are that Shanghai chemical reagent factory produces.
1.2 Hypertensive Rats is essential hypertension rat (SHR), the Wistar rat, and Cavia porcellus is provided by experimental center, medical courses in general institute zoopery field.
1.3 instrument
Polygraph (SB-42 type) XH-II type toy body surface blood pressure measuring device, Hunan Medical University cardiovascular physiology research department produces.
2, method
2.1 get 28 of essential hypertension rats, for male, body weight 216 ± 12g divides 4 groups, with body surface blood pressure measurement apparatus and polygraph, surveys and respectively organizes rat artery contraction and diastolic pressure and mean blood pressure, presses the 0.80mg/kg administration then.After 30 days, measure rat arteria caudalis blood pressure once more.
Change seeing Table 5 relatively, normal arterial pressure rat method is the same, sees Table 6.
Table 5
| Group | Consumption (mg/kg) | Blood pressure mmHg before the medicine | Blood pressure mmHg behind the medicine | Blood pressure value mmHg |
| ?I | ?0.80 | ?198±12 | ?172±6 | -26±8 |
| ?II | Spraying | ?196±7 | ?180±14 | -16±9 |
| ?III | ?10 | ?196±11 | ?161±13 | -35±4 |
| ?IV | ?209±12 | ?214±17 | 5±6 |
Table 6
| Group | Blood pressure mmHg before the medicine | Blood pressure mmHg behind the medicine | Blood pressure value mmHg |
| ?I | ?135±7 | ?133±7 | -2±1 |
| ?II | ?128±6 | ?128±6 | ±2 |
Conclusion finds out that from table administration can make the essential hypertension rat at the average 20mmHg of reduction.Little to normal rat blood pressure effect.Four, the curative effect of extra large plain sodium and heparin sodium treatment Canis familiaris L. hyperlipemia and high blood viscosity relatively
1, materials and methods
(1) reagent: heparin sodium is provided by the biological company limited of Erie's health.The plain sodium in sea is provided by the application company.
(2) heritability hyperlipemia and high blood viscosity Canis familiaris L. are by Japanese import.
2, method
(1) gets 156 of high fat high blood viscosity Canis familiaris L.s, divide the treatment group 90 example and matched group 66 examples.In the treatment group, male 76, female 66, wherein coronary heart disease is 39,19 of cerebrovascular, 19 of hypertension, 6 of diabetes, 10 of simple hyperlipemia fat and high blood viscositys.Male 56 of matched group, female 10, wherein coronary heart disease is 27,16 of cerebrovascular, 12 of hypertension, 5 of diabetes, sick 6 of simple high fat.
2, the extra large plain sodium of quiet notes 0.03 unit/kg is organized in treatment, and once a day, each observes 30 days is a course of treatment, check blood fat and blood viscosity observation index.See Table 7, table 8.
The comparison of the table 7 liang every index of group treatment back blood fat
| Group | TC (cholesterol) (mmol/L) | TG (three fat) (mmol/L) | HDL (high-density lipoprotein) (mmol/L) | LDL (low density lipoprotein, LDL) (mmol/L) |
| Matched group | 6.82±1.06 | ?2.09±0.78 | ?0.84±0.32 | ?4.75±0.71 |
| The treatment group | 5.03±0.87 | ?1.28±0.58 | ?1.16±0.28 | ?3.24±0.76 |
The every index of table 8 treatment back blood viscosity relatively
| Group | Hn | ?Hl | ?Hp | ?IR | ?HCT(％) | ?FIb(g/l) |
| Matched group | 5.94±0.5 | ?11.12±1.04 | ?1.89±0.16 | ?4.06±0.47 | ?0.46±0.05 | ?3.87±1.14 |
| The treatment group | 4.12±0.38 | ?8.24±1.36 | ?1.71±0.11 | ?2.81±0.38 | ?0.42±0.06 | ?2.95±0.97 |
Conclusion is organized most of effect and is better than matched group from the treatment of reaching a conclusion of table 1 and table 2 in large animal experiment, and removing the plain sodium in high density lipoprotein sea is 67% of heparin sodium therapeutic effect, and all other indexs are all above the heparin sodium level.
Claims (6)
1, anticoagulative substance, preparation method is as follows: the water intaking soluble chitosan adds excessive SO
3Stir among-the DMF, filter, filtrate is transferred pH2-4 with dilute formic acid solution, stirs to drip rare CuSO down
4Solution is to there being precipitation to produce, and continues stirred for several hour, and the leaching precipitate with the DMF washing, drips pyridine again, sulfur monoxide, and sulfur trioxide, and after the mixed liquor stirred for several of micro-DMF hour, add saturated NaHCO
3Solution, stop the agitation and filtration lyophilization, again dry thing water is dissolved into 1-15% solution, stir fast down, the enriching perchloric acid solution filters, precipitation with washing with alcohol after, change and to be dissolved in an amount of spirit acid, add perchloric acid solution stirred for several hour again, leaching precipitation washing with alcohol, vacuum drying under the room temperature is dissolved in this dry thing and under agitation adds excess chlorine sulfonic acid in appropriate solvent such as the pyridine, at last neutralization, behind the ethanol precipitation, precipitation with washing with alcohol for several times, vacuum drying below 60 ℃ obtains anticoagulative substance.
2, the anticoagulative substance of claim 1, wherein water-soluble chitosan and SO
3-DMF reaction ingredient proportion is 0.5-1: 2-5, and the best is 1: 3.
3, the anticoagulative substance of claim 1, wherein pyridine: sulfur monoxide: the sulfur trioxide ratio is about 3-5: 0.25-1: 0.25-1, best 4: 0.5: 0.5.
4, a kind of complex, it is obtained by following method: the food stage chitosan of getting molecular weight＜80,000 adds suitable quantity of water, adds protease, and reaction is degraded a few hours under proper temperature, slowly stir simultaneously, use an amount of ethanol precipitation, collecting precipitation, wash for several times with dehydrated alcohol, drying gets product B; Get sodium alginate with an amount of rare hydrogen peroxide dissolving, in 50-60 ℃ of following stirring reaction a few hours, the reuse ethanol precipitation, drying, product C; And with product, B and the C of claim 1 weight ratio according to 0.5-1: 0.5-2: 0.5-1, water is dissolved into weak solution, and abundant stirred for several hour is after the resin anion (R.A.) post, filter effluent, behind ethanol precipitation, wash precipitation with dehydrated alcohol, the washing of reuse ether, vacuum drying below 60 ℃ obtains complex of the present invention, promptly extra large plain sodium product (anticoagulant efficiency 60-110u/mg).
5, the purposes of the anticoagulative substance of claim 1 in the medicine of preparation treatment cardiovascular and cerebrovascular disease.
6, the purposes of the complex of claim 3 in the medicine of preparation treatment cardiovascular and cerebrovascular disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02128867 CN1411816A (en) | 2002-08-16 | 2002-08-16 | New anticoagulant medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02128867 CN1411816A (en) | 2002-08-16 | 2002-08-16 | New anticoagulant medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1411816A true CN1411816A (en) | 2003-04-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02128867 Pending CN1411816A (en) | 2002-08-16 | 2002-08-16 | New anticoagulant medicine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641259A (en) * | 2011-02-21 | 2012-08-22 | 中国药科大学 | Application of glaucocalyxin A in preparation of anticoagulation medicaments |
-
2002
- 2002-08-16 CN CN 02128867 patent/CN1411816A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641259A (en) * | 2011-02-21 | 2012-08-22 | 中国药科大学 | Application of glaucocalyxin A in preparation of anticoagulation medicaments |
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