CN1241571A - Low-toxicity antiphlogistic exudation-resisting medicine composition - Google Patents

Low-toxicity antiphlogistic exudation-resisting medicine composition Download PDF

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CN1241571A
CN1241571A CN 99103226 CN99103226A CN1241571A CN 1241571 A CN1241571 A CN 1241571A CN 99103226 CN99103226 CN 99103226 CN 99103226 A CN99103226 A CN 99103226A CN 1241571 A CN1241571 A CN 1241571A
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aescin
pharmaceutical composition
exudation
toxicity
activeconstituents
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CN1073573C (en
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杨秀伟
苏卡加
朱发兵
刘淑艳
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Shandong Luye Pharmaceutical Co Ltd
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GREEN LEAF PHARMACEUTICAL CO Ltd YANTAI
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Abstract

The medicine composite contains one of two kinds of beta-Aesculus saponin or their mixture as active component, into which pharmacologically acceptable additive may be added. Compared with beta-Aesculus saponin sodium, the medicine composite has the same antiphlogistic and exudation-resisting activity whereas obviously lower toxicity and stimulation.

Description

A kind of anti-inflammatory and anti-exudation pharmaceutical composition of low toxicity
The present invention relates to the modified form anti-inflammatory and anti-exudation pharmaceutical composition that a kind of toxicity reduces, specifically, contain effective two kinds of single-activity compositions of the low toxicity that from β-Aescin, obtains or their mixture in this pharmaceutical composition and make activeconstituents.
β-Aescin is to extract anti-inflammatory, the exudation resistance activeconstituents that obtains a kind of seed of the drying and ripening from the Chinese medicine Wilsom Buckeye Seed, and the β of present clinical use-Sodium Aescinate injection (its activeconstituents mainly is β-seven total saponin from leaves) is widely used in the concurrent brain function imbalance of treatment cerebral edema, empyrosis, chronic venous insufficiency, wound, fracture and operation back oedema, hemotoncus.However, because β-Sodium Aescinate has big toxicity, LD 50Value is 3.99mg/kg only, and regular meeting produces than strong and stimulating and toxic side effects, so limited the use clinically of this medicine after the medication.Therefore, people seek the modified form anti-inflammatory and anti-exudation pharmaceutical composition that a kind of toxicity reduces always.The inventor has found the effective two kinds of simplification compounds of low toxicity through further investigation from β-Aescin, not only kept the anti-inflammatory exudation resistance activity of β-Sodium Aescinate, simultaneously, has also reduced the toxicity of β-Sodium Aescinate, thereby has finished the present invention.
The anti-inflammatory and anti-exudation pharmaceutical composition that the purpose of this invention is to provide a kind of low toxicity.
Activeconstituents contained in this anti-inflammatory and anti-exudation pharmaceutical composition is represented for following structural I
Figure A9910322600041
Figure A9910322600051
Or their mixture; Be preferably to contain β-Aescin (1) and β-Aescin (2) or only contain β-Aescin (1) and make activeconstituents; Best is only to contain β-Aescin (1) to make activeconstituents.When containing β-Aescin (1) and β-Aescin (2), β-Aescin (1) is 1-7: 3-9 with the weight ratio of β-Aescin (2), and preferred weight ratio is 2.5-4.5: 5.5-7.5, and optimum weight ratio is 4: 6.
Because the activeconstituents that contains in the pharmaceutical composition of the present invention is above-mentioned two kinds of simplification compounds or its mixture rather than existing β-seven total saponin from leaves, the activity of its anti-inflammatory exudation resistance activity and β-seven total saponin from leaves is substantially in same level, but its LD 50Value is far longer than the LD of β-seven total saponin from leaves 50Value 3.99mg/kg, or even its 10 times.
The significant quantity of the activeconstituents that pharmaceutical composition of the present invention is contained is 0.7-30.73mg/kg.
Pharmaceutical composition of the present invention can contain pharmaceutically acceptable various additives, and these additives comprise weighting agent, tackiness agent, wetting agent, disintegrating agent, tensio-active agent, lubricant, thinner etc.The formulation of pharmaceutical composition of the present invention is depended in the adding of additives.For example,, then can comprise the employed conventional additives of preparation tablet if pharmaceutical composition of the present invention is made tablet, as: wetting agent, lubricant, weighting agent etc.If pharmaceutical composition of the present invention is made liquid preparation, then can comprise thinner, as distilled water, G/W etc.Selected additives not with pharmaceutical composition of the present invention in activeconstituents react, in addition, will not be subjected to any restriction.
Because the toxicity of pharmaceutical composition of the present invention reduces, security increases, can adopt conventional pharmaceutical technology that pharmaceutical composition of the present invention is made various formulations, as gastrointestinal administration preparation and parenteral administration preparation, wherein comprise oral liquid, tablet, syrup, tincture, spirit, capsule, suppository, granule etc., non-ly comprise mucosa delivery preparation and external preparations such as gelifying agent, sprays such as injection and eye drops, vaginal suppository through the gastrointestinal administration preparation through the gastrointestinal administration preparation.
Further elaborate the present invention with the test example by the following examples.
Embodiment 1
Take by weighing Wilsom Buckeye Seed powder 1.0g, add water-saturated n-butanol 25ml, soaked overnight, sonic oscillation 10 minutes is got supernatant liquor 10.0ml, evaporate to dryness in the water-bath, residue 95% dissolve with ethanol, decolouring gets β-Aescin always.Boil off behind the ethanol with methanol constant volume to 1ml, sample introduction 5 μ l, carry out the high performance liquid chromatography analysis, obtain β-Aescin (2) that β-Aescin that structural formula is I (1) and structural formula are II, wherein β-Aescin (2) is isolated Aescin I (b) and two kinds of mixture of isomers of I (a) from the horse-chestnut of Europe, β-Aescin (1) only is that terminal bonded sugar is different with the difference of β-Aescin (2), and glucuronic acid C-2 ' position bonded sugar is semi-lactosi in β-Aescin (1) sugar chain.
Embodiment 2
β-Aescin (2) 10mg
Water for injection is an amount of
β-Aescin (2) with the water for injection dissolving, is made lyophilized injectable powder according to the lyophilized injectable powder technology of routine.
Embodiment 3
β-Aescin (1) 10mg
Water for injection is an amount of
Adopt the method for embodiment 1 to make lyophilized injectable powder.
Embodiment 4
β-Aescin (1) 7mg
β-Aescin (2) 3mg
Water for injection is an amount of
Adopt the method for embodiment 1 to make lyophilized injectable powder.
Embodiment 5
β-Aescin (1) 1mg
β-Aescin (2) 9mg
0.9% physiological saline 1000ml
β-Aescin (1) and β-Aescin (2) dissolving, adopt the technology of conventional injection liquid to make injection liquid with physiological saline.
Embodiment 6
β-Aescin (1) 4mg
β-Aescin (2) 6mg
Starch 20mg
Magnesium Stearate 5mg
Adopt conventional tablet preparation technology to make tablet.
Embodiment 7
β-Aescin (1) 6mg
β-Aescin (2) 4mg
0.9% physiological saline 1000ml
Said components is mixed with eye drop.
Embodiment 8
β-Aescin (1) 4.5mg
β-Aescin (2) 5.5mg
Said components as activeconstituents, is added the used excipient commonly used of gelifying agent, adopt conventional gelifying agent preparation technology to make gelifying agent.
Embodiment 9
β-Aescin (1) 2.5mg
β-Aescin (2) 7.5mg
Said components as activeconstituents, is added the used excipient commonly used of sprays, adopt conventional sprays preparation technology to make sprays.
Test example 1: anti-inflammatory test
The healthy male mouse of kunming of experimental animal: 25-30g.
Route of administration: intraperitoneal administration
Dosage: 0.7mg/kg
Test method: every group of 10 mouse, respectively medicine β-Sodium Aescinate, β-Aescin (1), β-Aescin (2) or β-Aescin (1)+(2) intraperitoneal administration, every mouse auris dextra melted paraxylene 30 μ l (tow sides) after 30 minutes, after 30 minutes, put to death mouse successively, lay the ears disk with 7.0mm macropore device, weigh, obtain the swelling degree (it is heavy that auris dextra heavily deducts left ear) of each mouse.
Result such as following table:
Group Contrast β-Sodium Aescinate β-Aescin (2) β-Aescin (1) β-Aescin (1)+(2)
Number of animals ????10 ????10 ????9 ????10 ????10
The swelling degree 12.31±1.24 ?8.33±2.82 *** 8.79±3.59 ** 8.25±2.64 *** 8.73±2.64 **
Press down swollen rate (%) ????- ????32.33 ????28.59 ????32.98 ????29.08
Compare with control group, *P＜0.01, * *P＜0.001 this shows, the anti-inflammatory action of the contained activeconstituents of pharmaceutical composition of the present invention and the anti-inflammatory action of existing β-Sodium Aescinate be substantially in same level, to each other the difference not statistically significant.
Test example 2: exudation resistance test
The healthy kunming mice of experimental animal: 18-24g, male and female half and half.
Route of administration: subcutaneous injection
Dosage: 1.4mg/kg
Test method: subcutaneous injection medicine or physiological saline, posterior vein was injected 0.5% ivens dye liquor 0.1mg/kg in 40 minutes, peritoneal injection 0.2%HAc 0.3ml/ only puts to death mouse after 20 minutes successively at random, cuts off the abdominal cavity, wash with physiological saline, to the 10ml centrifuge tube, supernatant liquor is got in centrifugal 3000rpm * 15 minute with the washings sucking-off, measure absorbance at the 590nm place, compare between organizing.The result is as follows:
Group Contrast β-Sodium Aescinate β-Aescin (2) β-Aescin (1) β-Aescin (1)+(2) (4: 6)
Number of animals ????10 ????9 ????10 ????10 ????10
The swelling degree 0.480±0.038 ?0.287±0.126 *** 0.323±0.061*** 0.302±0.087 *** 0.338±0.058 ***
Press down swollen rate (%) ????- ????40.2 ????32.7 ????37.1 ????29.6
Compare with control group, *P＜0.01, * *P＜0.001
As seen, the exudation resistance effect of the contained activeconstituents of pharmaceutical composition of the present invention and the effect of existing β-Sodium Aescinate be substantially in same level, to each other the difference not statistically significant.
Test example 3: acute toxicity test test dose: select 6 dosage groups for use, the group spacing determines via the trial test result.Route of administration: intravenous administration test method: animal is divided into 6 groups at random by body weight, 10 every group (male and female half and half),
Observe the reaction of animals situation after the administration, write down dead animal distribution in 7 days.The result is as follows: 1. the LD of β-Aescin (1)+(2) 50
Number of animals Body weight (g) Dosage (mg/kg) Death toll Mortality ratio (%)
????10 ????19.7±1.3 ????15.00 ????10 ????100
????10 ????19.5±1.6 ????11.70 ????10 ????100
????10 ????19.6±2.0 ????9.12 ????8 ????80
????10 ????19.2±1.8 ????7.12 ????6 ????60
????10 ????19.4±1.8 ????5.55 ????5 ????50
????10 ????19.6±1.9 ????4.33 ????2 ????20
(1∶K＝1∶0.78)
????LD 5 ????LD 50 ????LD 95 Regression equation
????3.12 ????5.99 ????11.51 ??E＝0.487+5.803log(D)
????1.80-4.54 ????4.56-7.08 ????8.51-17.80
2. the LD of β-Sodium Aescinate 50
Number of animals Body weight (g) Dosage (mg/kg) Death toll Mortality ratio (%)
????10 ????19.8±1.8 ????15.00 ????10 ????100
????10 ????19.7±1.6 ????10.50 ????10 ????100
????10 ????19.6±1.8 ????7.35 ????9 ????90
????10 ????19.7±1.4 ????5.14 ????5 ????50
????10 ????19.1±1.7 ????3.60 ????4 ????40
????10 ????19.3±1.5 ????2.52 ????3 ????30
(1∶K＝1∶0.75)
????LD 5 ????LD 50 ????LD 95 Regression equation
????1.57 ????3.99 ????10.13 ?E＝2.56+4.06log(D)
????0.54-2.47 ????2.91-5.06 ????7.03-23.20
3. the LD of β-Aescin (2) 50
Number of animals Body weight (g) Dosage (mg/kg) Death toll Mortality ratio (%)
????10 ????18.8±1.0 ????7.00 ????8 ????80
????10 ????19.0±0.7 ????5.25 ????8 ????80
????10 ????19.0±0.9 ????3.94 ????5 ????50
????10 ????19.2±0.4 ????2.95 ????2 ????20
????10 ????19.0±0.0 ????2.21 ????1 ????10
????10 ????19.2±0.4 ????1.66 ????0 ????0
(1∶K＝1∶0.75)
????LD 5 ????LD 50 ????LD 95 Regression equation
????1.96 ????4.12 ????8.65 ??E＝1.86+5.11log(D)
????1.21-3.18 ????3.20-5.30 ????4.96-15.10
4. the LD of β-Aescin (1) 50
Number of animals Body weight (g) Dosage (mg/kg) Death toll Mortality ratio (%)
????10 ????18.3±1.2 ????48.00 ????9 ????90
????10 ????18.3±1.2 ????38.40 ????9 ????90
????10 ????18.3±1.0 ????30.72 ????5 ????50
????10 ????18.3±0.9 ????24.58 ????2 ????20
????24 ????20.0±1.3 ????20.00 ????1 ????10
????10 ????18.2±1.3 ????15.73 ????0 ????0
(annotate: 24 of 20mg/kg dosage groups are the comprehensive of twice revision test)
????LD 5 ????LD 50 ????LD 95 Regression equation
????20.10 ????30.73 ????46.97 ?E＝8.28+8.92log(D)
????15.99-25.45 ????26.40-35.75 ????34.97-63.09
The result:
The LD of the contained activeconstituents of pharmaceutical composition of the present invention 50The LD of value and the quiet notes of β-Sodium Aescinate 50The comparison of value
Classification ????LD 50Value (mg/kg)
β-Sodium Aescinate ????3.99
β-Aescin (1)+(2) ????5.99
β-Aescin (2) ????4.12
β-Aescin (1) ????30.73
This shows the LD of the contained activeconstituents of pharmaceutical composition of the present invention 50Value is less than the LD of β-Sodium Aescinate 50Value that is to say that the toxicity of the contained activeconstituents of pharmaceutical composition of the present invention obviously reduces.

Claims (5)

1. the anti-inflammatory and anti-exudation pharmaceutical composition of a low toxicity, it contains β-Aescin (1) that useful following structural I represents or β-Aescin (2) of representing with following structural II or their mixture and makes activeconstituents and/or pharmaceutically acceptable additives, and wherein the structural formula I of β-Aescin (1) is:
Figure A9910322600021
The structural formula II of β-Aescin (2) is:
Figure A9910322600031
2. pharmaceutical composition according to claim 1, when wherein the mixture of β-Aescin (1) and β-Aescin (2) was made activeconstituents, β-Aescin (1) was 1-7: 3-9 with the weight ratio of β-Aescin (2).
3. pharmaceutical composition according to claim 2, wherein β-Aescin (1) is 2.5-4.5: 5.5-7.5 with the weight ratio of β-Aescin (2).
4. pharmaceutical composition according to claim 3, wherein β-Aescin (1) is 4: 6 with the weight ratio of β-Aescin (2).
5. according to arbitrary described pharmaceutical composition among the claim 1-4, its formulation is a lyophilized injectable powder.
CN99103226A 1998-07-15 1999-03-29 Low-toxicity antiphlogistic exudation-resisting medicine composition Expired - Lifetime CN1073573C (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
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
CN102755297A (en) * 2011-04-29 2012-10-31 天津药物研究院 Escin B freeze-dried powder injection and preparation method and application thereof
CN103655644A (en) * 2012-09-17 2014-03-26 南京星银药业集团有限公司 Aescine oral preparation and preparation method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1017591A (en) * 1996-06-27 1998-01-20 Jintan Dorufu:Kk Antiinflammatory agent

Cited By (3)

* Cited by examiner, † Cited by third party
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
CN102755297A (en) * 2011-04-29 2012-10-31 天津药物研究院 Escin B freeze-dried powder injection and preparation method and application thereof
CN103655644A (en) * 2012-09-17 2014-03-26 南京星银药业集团有限公司 Aescine oral preparation and preparation method thereof

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Address after: 264003, No. 11, Po Yuen Road, Laishan District, Shandong, Yantai

Applicant after: Luye Pharmaceutical Co., Ltd., Shandong

Applicant before: Green Leaf Pharmaceutical Co. Ltd., Yantai

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