CN1376675A - Arginine-aescin with functions of detumescence, relieving inflammation and improving blood circulation and its preapring process - Google Patents
Arginine-aescin with functions of detumescence, relieving inflammation and improving blood circulation and its preapring process Download PDFInfo
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- CN1376675A CN1376675A CN 02113591 CN02113591A CN1376675A CN 1376675 A CN1376675 A CN 1376675A CN 02113591 CN02113591 CN 02113591 CN 02113591 A CN02113591 A CN 02113591A CN 1376675 A CN1376675 A CN 1376675A
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- 230000004054 inflammatory process Effects 0.000 title abstract description 4
- 230000008569 process Effects 0.000 title abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 44
- 239000004475 Arginine Substances 0.000 claims description 42
- 235000009697 arginine Nutrition 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 14
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 10
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Abstract
The present invention relates to an arginine-aescin with the functions of detumescence, relieving inflammation and improving blood circulation, its isomer, and its preparing process. The solubility of asescin in water is solved to reduce the generation of angiospasm and increase its safety.
Description
Affiliated technical field:
The present invention relates to a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to.
Technical background:
Aescine (Sodium Aescinate) is the triterpenoid saponin that extracts in the dry mature fruit of the Chinese medicine Wilsom Buckeye Seed that recorded by one one of Chinese Pharmacopoeia.External crude drug Europe Ma Su (the Aesculus hippocastanum L. that records by Ph.G, English name horse chestnut) mature fruit is extracted, former moral Dr.Madaus has carried out deep research to it in the pharmaceutical factory, find it anti-inflammatory, exudation resistance, detumescence expand aspect effect remarkable, can recover the normal permeability of capillary vessel, increase intravenous tension, microcirculation improvement.
Because Aescine is not dissolved in water, present stage uses clinically be aescine, and through a large amount of clinical observation for a long time, aescine externally injures peripheral vascular disease very high therapeutic value.Aescine is an intravenously administrable, and in the administration process, blood vessel easily produces spasm, so there are side effects such as transfusion part pain, life-time service easily produces phenomenons such as phlebitis.
Summary of the invention:
The invention provides a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to, arginine is the NO prodrug, in body, after the effect of NO enzyme, produce NO, and NO has the effect of vasodilator unstriated muscle, with arginine and Aescine salify, solved the solvability of Aescine in water on the one hand, can reduce angiospastic generation simultaneously, thereby improve the security of medication.
The invention is characterized in: with arginine and Aescine reaction salify, and with the salt or the corresponding isomer of following structural (I) expression:
Preparation method of the present invention is as follows:
(A) add Aescine, L-arginine and distilled water successively in reactor, stirring reaction is to clear liquor, and the evaporated under reduced pressure solvent adds ethanol or acetone in residue, grind to such an extent that off-white color precipitates, and filters, and drying under reduced pressure gets the off-white color solid;
Or (B) in reaction flask, add Aescine, L-arginine and distilled water successively, stirring reaction is to clear liquor, from-40 ℃ of temperature-gradient method vacuum lyophilizations, the off-white color solid.
Aescine of the present invention, the arginic mole of L-proportioning are: 1: 1.
Arginine of the present invention comprises the L-arginine, or the D-arginine, or D, L-arginine.
Aescine of the present invention comprises aescine A, or aescine B.
Temperature-gradient method vacuum lyophilization of the present invention is specific as follows :-40 ℃ of following pre-freezes are after 8 hours, continued to vacuumize freezing 2 hours, and under-30 ℃ ,-20 ℃ ,-10 ℃ ,-5 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃ temperature, vacuumized freezing 2 hours, 2 hours, 4 hours, 8 hours, 8 hours, 4 hours, 2 hours, 2 hours respectively again.
The present invention brings out rat toes swelling test through egg white, the scorching method test of mouse ear caused by dimethylbenzene xylene, acute toxicity test, proofs such as blood vessel irritation test: the present invention is when keeping detumescence, anti-inflammatory and improving the blood circulation purposes, solved the solvability of Aescine in water, can reduce angiospastic generation, improve the security of medication.
Embodiment:
Embodiment 1: the preparation of arginine Aescine
In reaction flask, add Aescine 113.1g (0.1mol), L-arginine 17.4g (0.1mol) and 1000ml distilled water successively, stirring reaction is to clear liquor, the evaporated under reduced pressure solvent, in residue, add 500ml ethanol, grind to such an extent that off-white color precipitates, filter 80 ℃ of drying under reduced pressure, get off-white color solid 95.4g, yield 73.1%.
With Aescine is that reference substance carries out assay, and product content is 99.5%.
Embodiment 2: the preparation of arginine Aescine
In reaction flask, add Aescine 113.1g (0.1mol), L-arginine 17.4g (0.1mol) and 1000ml distilled water successively, stirring reaction is to clear liquor, the evaporated under reduced pressure solvent, in residue, add 500ml acetone, grind to such an extent that off-white color precipitates, filter 80 ℃ of drying under reduced pressure, get off-white color solid 81.3g, yield 62.3%.
With Aescine is that reference substance carries out assay, and product content is 99.7%.
Embodiment 3: the preparation of arginine Aescine
Add Aescine 113.1g (0.1mol), L-arginine 17.4g (0.1mol) and 1000ml distilled water in reaction flask successively, stirring reaction is to clear liquor, lyophilize, and actual conditions sees the following form.
The lyophilize condition
Temperature (℃) time (hour) remarks
-40 8 pre-freezes
-40 2 vacuumize
-30 2 vacuumize
-20 2 vacuumize
-10 4 vacuumize
-58 vacuumize
08 vacuumize
10 4 vacuumize
20 2 vacuumize
30 2 vacuumize
Get off-white color solid 129.7g, yield 99.3%.
With Aescine is that reference substance carries out assay, and product content is 99.6%.
Embodiment 4 egg white bring out rat toes swelling test
Choosing body weight is 60 of 160～180 SD male rats that restrain, and is divided into 6 groups at random, and 10 every group, after the right back sufficient pawl volume of rat was respectively organized in measurement, to right back toes subcutaneous injection 20% Ovum Gallus domesticus album of each group rat, 0.1ml/ only caused inflammation.Cause scorching back 1 hour, first, second, third and fourth, five groups of rats respectively abdominal injection give arginine Aescine dosage and count 4.082mg/kg, 2.857mg/kg, 2mg/kg, 1.4mg/kg, 0.98mg/kg with Aescine, compound concentration is respectively 0.41 0.29 0.2 0.14 0.1mg/ml, volume injected is 1ml/100 gram body weight, the 6th group of rat injection equal volume sodium chloride injection.Respectively surveyed the right back sufficient pawl volume-variation of rat one time in 1.5 hours, 3 hours, 4.5 hours after the administration, so that the sufficient pawl volumetrical difference in scorching front and back is as the swelling degree.
Calculate and respectively organize rat foot claw swelling degree average and standard deviation, and do the t check: relatively between each administration group and blank group there was no significant difference is arranged.The results are shown in following table.
The arginine Aescine to egg white bring out rat foot claw swelling influence dosage group number of animals body weight cause scorching front foot cause scorching metapedes corpus unguis long-pending (ml) (mg/kg) (only) (g) corpus unguis amass (ml)
1.5hr 3hr 4 .5hr4.082 arginine Aescines 10 172 ± 7 0.835 ± 0.071 0.411 ± 0.063
*0.401 ± 0.054
*0.519 ± 0.0252.857 arginine Aescine 10 171 ± 6 0.836 ± 0.080 0.47 ± 0.122
*0.476 ± 0.109
*0.61 ± 0.101
*2.000 arginine Aescine 10 171 ± 5 0.822 ± 0.063 0.602 ± 0.09
*0.632 ± 0.092
*0.7723 ± 0.092
*1.400 arginine Aescine 10 171 ± 6 0.826 ± 0.071 0.74 ± 0.039
*0.814 ± 0.54
*0.898 ± 0.06
*0.980 blank groups in arginine Aescine 10 171 ± 5 0.831 ± 0.065 0.923 ± 0.095 0.939 ± 0.091 1.001 ± 0.095 (with the volume sodium chloride injection) 0.841 ± 0.038 0.993 ± 0.025 0.993 ± 0.05 0.983 ± 0.035 are compared+P＜0.05 with blank
*P＜0.01
By table as seen, compare with the blank group, arginine Aescine after administration 1.5,3,4.5 hours, dosage 4.082,2.857,2.000mg/kg organize, and significant differences is all arranged.Test-results shows, the arginine Aescine presents tangible anti-inflammatory action to the rat foot claw swelling due to the Ovum Gallus domesticus album.
The scorching method test of embodiment 5 mouse ear caused by dimethylbenzene xylene
Choose 60 of body weight 26-30g male mices, be divided into 6 groups at random, 10 every group.Dimethylbenzene is dripped in mouse right ear every mouse 30 μ l, left ear contrast.After causing scorching 1 hour, the the 1st to the 5th group of mouse respectively abdominal injection arginine Aescine solution dosage with Aescine count 6.67,4.67,3.27,2.29,1.06mg/kg, liquor strength is respectively 0.267,0.187,0.131,0.091,0.0641mg/ml, the administration volume is 0.5ml/20g, and the 6th group with method abdominal injection sodium chloride injection 0.5ml/20g.
After the administration 2 hours, the dislocation of mouse cervical vertebra is caused death, cut two ears along the auricle baseline, be that the punch tool of 8mm is laid the garden auricle at the same position of left and right ear respectively with diameter, weigh, ask the poor of the left and right auricle weight of every mouse, as the swelling degree.The swelling degree is carried out statistical procedures, relatively between each administration group and blank group there was no significant difference is arranged, the results are shown in following table.
What arginine Aescine p-Xylol caused mice ear influences (mg) 6.670 arginine Aescines 10 4.65 ± 1.076 of dosage group number of animals swelling degree (mg/ml) (only)
*4.670 arginine Aescine 10 5.64 ± 1.085
*3.270 arginine Aescine 10 6.28 ± 0.705
*2.290 arginine Aescine 10 6.93 ± 1.059
*1.061 arginine Aescine 10 7.67 ± 0.866 blank is compared with blank+P＜0.05 with volume N.S 10 8.16 ± 0.486
*P＜0.01
By table as seen, compare with the blank group, the arginine Aescine of dosage 6.67,4.67,3.27mg/kg, 2.29mg all has significant differences, the arginine Aescine there was no significant difference of dosage 1.06mg/kg group.Test-results shows, the mice ear due to the arginine Aescine dimethylbenzene presents tangible anti-inflammatory action.
Embodiment 6 acute toxicity tests
According to pre-test result, arginine Aescine maximal dose group is set to 50mg/kg, and all the other each groups are successively decreased with 0.80 geometric progression, are followed successively by 40mg/kg, 32mg/kg, 25mg/kg, 20.5mg/kg.Intravenous administration, the administration volume is 0.5ml/20g, and the soup compound concentration is respectively 2mg/ml, 1.6mg/ml, 1.28mg/ml, 1.02mg/ml, 0.82mg/ml.
Choosing body weight is 50 of 19～21g mouse, is divided into 5 groups at random, and 10 every group, male and female half and half by set dosage intravenous administration, begin after the administration to observe immediately.Have animal to begin death in 5 minutes, animal dead is arranged in 1 day successively, each treated animal death toll of arginine Aescine sees the following form, and does not have animal dead in 2～14 days of observation later on.Dead animal becomes celestial, and major organs does not have obvious pathology through visual inspection, and surviving animals is observed to put to death after 14 days and dissected each organ no abnormality seen of visual inspection.
The single LD50 of mouse vein administration arginine Aescine LD50 measurement result animal subject dosage log10 dose number of animals dead animal mortality ratio probability and put (mg/kg) (X) (only) number (only) (%) believe and limit in position (Y)
50.0 1.7 10 9 90 6.28
40.0 1.6 10 8 80 5.84 29.7±
32.0 1.51 10 7 70 5.52 5.9mg/kg
25.0 1.4 10 3 30 4.48
20.5 1.31 10 1 10 3.72 (P＝0.95)
Test-results shows that mouse mainline arginine Aescine LD50 is 29.7 ± 5.9mg/kg.And aescine LD50 literature value is 4.8 ± 5.6mg/kg.
The test of embodiment 7 blood vessel irritations
Get 6 of healthy rabbits, be divided into 2 groups at random, 3 every group.The slow injection concentration of edge vein of picking up the ears first group of every day one is the arginine Aescine of 0.375mg/ml, 3.33ml/kg, and second group with method injection sodium chloride injection 3.33ml/kg, continuous three days.In injecting back 24 hours, the visual inspection rabbit ear vein has vacuum response, and with the animal sacrificed by exsanguination, cuts the ear edge, and ear edge blood vessel is done the pathology cut sections for microscopic examination, the reaction of obvious stimulation such as tissues observed sex change or necrosis.
Test-results shows, visual inspection injection site blood vessel there is no irritant reaction phenomenons such as obvious congestion and edema, pathology section examination result is similar to the sodium chloride injection control group, epidermis and each structure of corium of ear corridor skin are intact, do not see sex change, necrosis, disappearance and hyperkeratosis, auricular vein is not seen dilatation and congestion, is not seen the capable one-tenth of thrombus, hemorrhage, oedema that surrounding tissue is not seen.
The present invention brings out rat toes swelling test through egg white, the scorching method test of mouse ear caused by dimethylbenzene xylene, acute toxicity test, proofs such as blood vessel irritation test: the present invention is when keeping detumescence, anti-inflammatory and improving the blood circulation purposes, solved the solvability of Aescine in water, can reduce angiospastic generation, improve the security of medication.
Claims (6)
1, be applicable to the sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method, it is characterized in that: with arginine and Aescine reaction salify, and with the salt or the corresponding isomer of following structural (I) expression:
2, a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to according to claim 1, it is characterized in that: described preparation method is as follows:
(A) add Aescine, L-arginine and distilled water successively in reactor, stirring reaction is to clear liquor, and the evaporated under reduced pressure solvent adds ethanol or acetone in residue, grind to such an extent that off-white color precipitates, and filters, and drying under reduced pressure gets the off-white color solid;
Or (B) in reaction flask, add Aescine, L-arginine and distilled water successively, stirring reaction is to clear liquor, from-40 ℃ of temperature-gradient method vacuum lyophilizations, the off-white color solid.
3, a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to according to claim 1 and 2, it is characterized in that: the mole proportioning of described Aescine, L-arginine is: 1: 1.
4, a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to according to claim 1 and 2, it is characterized in that: described Aescine comprises aescine A, or aescine B.
5, a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to according to claim 1 and 2, it is characterized in that: described arginine comprises the L-arginine, or D-arginine, or D, L-arginine.
6, a kind of sanguimotor arginine Aescine of detumescence, anti-inflammatory and improvement and corresponding isomer and preparation method of being applicable to according to claim 1 and 2, it is characterized in that: described temperature-gradient method vacuum lyophilization is specific as follows :-40 ℃ of following pre-freezes are after 8 hours, continued to vacuumize freezing 2 hours, and under-30 ℃ ,-20 ℃ ,-10 ℃ ,-5 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃ temperature, vacuumized freezing 2 hours, 2 hours, 4 hours, 8 hours, 8 hours, 4 hours, 2 hours, 2 hours respectively again.
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100357312C (en) * | 2005-07-15 | 2007-12-26 | 武汉爱民制药有限公司 | Lysine aescin saponin, its preparation and use |
| CN102805750A (en) * | 2011-05-31 | 2012-12-05 | 天津药物研究院 | Composition of aescine derivative and salt thereof, preparation method and medical uses thereof |
| CN104288167A (en) * | 2014-10-29 | 2015-01-21 | 马应龙药业集团股份有限公司 | Sodium aescinate preparation curing haemorrhoids and preparation method for sodium aescinate preparation |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100428940C (en) * | 2005-07-15 | 2008-10-29 | 武汉爱民制药有限公司 | Notoginsenoside pharmaceutical composition and method for preparing the same and use thereof |
-
2002
- 2002-04-10 CN CNB021135916A patent/CN1158302C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100357312C (en) * | 2005-07-15 | 2007-12-26 | 武汉爱民制药有限公司 | Lysine aescin saponin, its preparation and use |
| CN102805750A (en) * | 2011-05-31 | 2012-12-05 | 天津药物研究院 | Composition of aescine derivative and salt thereof, preparation method and medical uses thereof |
| CN104288167A (en) * | 2014-10-29 | 2015-01-21 | 马应龙药业集团股份有限公司 | Sodium aescinate preparation curing haemorrhoids and preparation method for sodium aescinate preparation |
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| Publication number | Publication date |
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| CN1158302C (en) | 2004-07-21 |
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