CN104095840A - Application of Euparin in preparing medicine for treating ischemic cardiovascular and cerebrovascular diseases - Google Patents
Application of Euparin in preparing medicine for treating ischemic cardiovascular and cerebrovascular diseases Download PDFInfo
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Abstract
The invention provides an application of Euparin in preparing a medicine for treating ischemic cardiovascular and cerebrovascular diseases. According to the pharmacological experiments, the mouth open breathing time of a mouse after decapitation can be prolonged obviously by Euparin, the moisture content of brain tissue after cerebral ischemia can be reduced remarkably; MDA (methylene dioxyamphetamine) content of brain tissue of a forebrain ischemia mouse can be reduced and the SOD (superoxide dismutase) content can be elevated; the unfavorable mouse memory acquisition due to scopolamine can be alleviated; the raw materials for preparing Euparin are easy to get, the Euparin can be prepared into various normal dosage forms such as tablets, capsules and injections through normal methods and the preparing method is simple.
Description
Technical field
The invention belongs to biological medicine technology field, be specifically related to the application of Euparin in preparation treatment ischemic cardio cerebrovascular diseases medicine.
Background technology
Ischemic cerebrocardiac disease, is due to body abnormalities of sugar/lipid metabolism, and the dysequilibrium of blood, and blood flow rate is slack-off, and blood fat is deposited in blood vessel wall and metabolite is detained in vivo, causes due to heart coronary artery and brain blood circulation obstacle.At present, ischemic cardio cerebrovascular diseases clinically sickness rate is higher, old man's physical and mental health in serious harm.
Comparatively serious with cerebral infarction and myocardial infarction in ischemic cerebrocardiac disease, case fatality rate and complication are higher.Clinically to this type of disease except operative treatment, its base therapy mainly depends on various anti-cerebral ischemia drugs, as anticoagulant, expand blood vessel medicine and Thrombolytic Drugs etc.Known at present, during acute onset, thrombolytic therapy has sure curative effect and positive prospect, but the reperfusion injury of following for thromboembolism treatment and miss the patient of thrombolytic time window, satisfied medicine is also very rare.
Euparin (euparin, euparin) be a kind of monomeric compound, can be from the rhizome of narrow Farfugium kaemferi of Ligularia From Sichuan, China (Ligularia Cass) plant and Huang Liang Farfugium kaemferi separation and Extraction, also can from the rhizome of feverwort, obtain, its structure is as follows:
Plant origin, separation method and antitumor and the bactericidal action etc. of Euparin have more report, but its research to ischemic cardio cerebrovascular diseases and apply nobody and relate to.
Summary of the invention
The object of the present invention is to provide the application of Euparin in preparation treatment ischemic cardio cerebrovascular diseases medicine.
The present invention is achieved through the following technical solutions:
The invention provides the application of the application, particularly Euparin of Euparin in preparation treatment ischemic cardio cerebrovascular diseases medicine in the medicine of the memory impairment due to preparation treatment ischemic cardio cerebrovascular diseases.
Medicine of the present invention is taking Euparin as active component, and acceptable preparation in the medical treatment made from pharmaceutically suitable carrier, as tablet, capsule and injection etc.
Wherein, described tablet formula is by weight: 200～400 parts of Euparin, 10～150 parts of disintegrating agents, 10～20 parts of lubricants; Described disintegrating agent is microcrystalline Cellulose (MCC), low-substituted hydroxypropyl cellulose or carboxymethyl starch sodium; Described lubricant is magnesium stearate, micropowder silica gel or Polyethylene Glycol.
In addition, can also comprise 150～300 parts of correctivess in the formula of described tablet, described correctives is lactose.
Preparation method: by the raw material mix homogeneously except lubricant, with water-wet, sieve (16～20 order), dry, and then sieve (18～22 order), add lubricant, tabletting after mix homogeneously.
Described capsule formula is by weight: 200～400 parts of Euparin, 10～20 parts of lubricants; Described lubricant is magnesium stearate, micropowder silica gel or Polyethylene Glycol.In addition, can also comprise 100～250 parts of correctivess, described correctives is lactose.
Preparation method: by the various raw material mix homogeneously except lubricant, with water-wet, sieve (18～22 order), dry, and then sieve (20～24 order), add lubricant, after mix homogeneously, incapsulate.
Described injection formula is by weight: 200～800 parts of Euparin, 150～360 parts, sodium chloride, 100～200 parts of suspending agents, 50～100 parts of emulsifying agents, 500～1500 parts of waters for injection.
Described suspending agent is tween 80 or carboxymethyl cellulose; Described emulsifying agent is lecithin, fabaceous lecithin, pluronic F-68, oxygen ethylene propylene polymerization thing etc.
Preparation method: Euparin and sodium chloride are dissolved in water for injection, add suspending agent and emulsifier for mixing and dissolve, pack in ampulla under aseptic condition.
The present invention, by pharmacodynamics test, further illustrates the application of Euparin of the present invention at preparation treatment ischemic cardio cerebrovascular diseases, particularly remembers the application in declining in preparation cerebral ischemia and ischemic.
Compared with prior art, the present invention has following useful technique effect:
1, the invention provides the medical usage that Euparin monomer is new, opened up new application; Euparin monomer has good therapeutic effect to ischemic cardio cerebrovascular diseases, can effectively be applied to the preparation of ischemic cardio cerebrovascular diseases medicine.
2, the pharmacological action of Euparin is obvious, main manifestations is: the broken end that can obviously the extend mice breathing time of dehiscing, can significantly reduce the water content of cerebral ischemia tissues following MCAO in rats, can reduce Forebrain Ischemia mouse brain and organize the content of MDA, the content of increased SOD, and can improve the bad effect of scopolamine induced mice memory acquisition.
3, Euparin raw material is easy to get, and can make various common formulations by conventional method, and as tablet, capsule, injection etc., preparation method is simple.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
Embodiment 1
The preparation (1000) of Euparin tablet
200 parts of formula: Euparin (pharmaceutical college of Xinxiang College of Medical Science experimental teaching of medicinal chemistry chamber provides, purity > 96%, following examples are all identical), 150 parts of MCC (microcrystalline Cellulose), 10 parts of magnesium stearate.
Preparation method: by Euparin, MCC mix homogeneously, with water-wet, then cross 18 mesh sieves, dry, again cross 22 mesh sieves, then add magnesium stearate, mix homogeneously, tabletting.
Embodiment 2
The preparation (1000) of Euparin tablet
Formula: 300 parts of Euparin, 150 parts of lactose, 100 parts of sodium carboxymethyl cellulose, 20 parts of magnesium stearate.
Preparation method: by Euparin, lactose and sodium carboxymethyl cellulose mix homogeneously, with water-wet, then cross 18 mesh sieves, dry, again cross 24 mesh sieves, then add magnesium stearate, mix homogeneously, tabletting.
Embodiment 3
The preparation (1000) of Euparin tablet
Formula: 300 parts of Euparin, 200 parts of lactose, 10 parts of carboxymethyl starch sodium, 15 parts of micropowder silica gels.
Preparation method: by Euparin, lactose and carboxymethyl starch sodium mix homogeneously, with water-wet, then cross 18 mesh sieves, dry, again cross 24 mesh sieves, then add micropowder silica gel, mix homogeneously, tabletting.
Embodiment 4
The preparation (1000) of Euparin tablet
Formula: 400 parts of Euparin, 300 parts of lactose, 80 parts of carboxymethyl starch sodium, 10 parts of Polyethylene Glycol.
Preparation method: by Euparin, lactose and carboxymethyl starch sodium mix homogeneously, with water-wet, then cross 18 mesh sieves, dry, again cross 24 mesh sieves, then add Polyethylene Glycol, mix homogeneously, tabletting.
Embodiment 5
The preparation (1000) of Euparin capsule
Formula: 400 parts of Euparin, 100 parts of lactose, 10 parts of magnesium stearate.
Preparation method: by Euparin, lactose mix homogeneously, with water-wet, then cross 20 mesh sieves, dry, again cross 22 mesh sieves, then add magnesium stearate, mix homogeneously, incapsulates.
Embodiment 6
The preparation (1000) of Euparin capsule
Formula: 200 parts of Euparin, 100 parts of lactose, 20 parts of micropowder silica gels.
Preparation method: by Euparin, lactose mix homogeneously, with water-wet, then cross 20 mesh sieves, dry, again cross 22 mesh sieves, then add micropowder silica gel, mix homogeneously, incapsulates.
Embodiment 7
The preparation (1000) of Euparin capsule
Formula: 300 parts of Euparin, 250 parts of lactose, 15 parts of Polyethylene Glycol.
Preparation method: by Euparin, lactose mix homogeneously, with water-wet, then cross 20 mesh sieves, dry, again cross 22 mesh sieves, then add Polyethylene Glycol, mix homogeneously, incapsulates.
Embodiment 8
The preparation (100 bottles) of Euparin injection
Formula: 200 parts of Euparin, 300 parts, sodium chloride, 100 parts of carboxymethyl celluloses, 100 parts of fabaceous lecithins, 500 parts of waters for injection.
Preparation method: Euparin, sodium chloride are dissolved in water for injection, then carry out sterilization treatment after adding carboxymethyl cellulose and fabaceous lecithin stirring and evenly mixing, and pack in ampulla under aseptic condition.
Embodiment 9
The preparation (100 bottles) of Euparin injection
Formula: 500 parts of Euparin, 150 parts, sodium chloride, 150 parts of tween 80s, 50 parts, lecithin, 800 parts of waters for injection.
Preparation method: Euparin, sodium chloride are dissolved in water for injection, then carry out sterilization treatment after adding tween 80 and lecithin stirring and evenly mixing, and pack in ampulla under aseptic condition.
Embodiment 10
The preparation (100 bottles) of Euparin injection
Formula: 1500 parts of 800 parts of Euparin, 360 parts, sodium chloride, 200 parts of carboxymethyl celluloses, pluronic F-68100 part, water for injection.
Preparation method: Euparin, sodium chloride are dissolved in water for injection, then carry out sterilization treatment after adding carboxymethyl cellulose and pluronic F-68 stirring and evenly mixing, and pack in ampulla under aseptic condition.
Below, by relevant pharmacological evaluation, further illustrate the present invention.
One, the impact of Euparin on mice broken end breathing time
1. experimental technique
48 of ICR male mices, male and female half and half, body weight 18-22g, is divided into 4 groups at random, that is: compound 8mg/kg group, 16mg/kg group, 32mg/kg group described in solvent matched group, embodiment 1,12 every group.Solvent matched group gives dimethyl sulfoxide+0.125% Tween 80 of normal saline+0.625%, and other each group gives the described compound of corresponding dosage, all by 0.2mL/10g lumbar injection, injects broken end after 30 minutes, with stopwatch numeration mice breathing time.
2. experimental result
The each dosage group of Euparin and the comparison of solvent matched group, all can obviously extend the mice broken end breathing time of dehiscing, and its pharmacodynamic action exists dose dependent, points out this medicine to have good anti-mouse brain hypoxic-ischemic effect (in table 1).
The impact of table 1 Euparin on mice broken end breathing time
With relatively * P<0.05 of solvent matched group, * * P<0.01.
Two, the impact of Euparin on mouse forebrain ischemia-reperfusion
1 experiment material and method
1.1 animal grouping and administrations
40 of ICR male mices, are divided into 4 groups at random, i.e. compound 8mg/kg group, 16mg/kg group, 32mg/kg group described in solvent matched group, embodiment 2,10 every group.Solvent matched group gives dimethyl sulfoxide+0.125% Tween 80 of normal saline+0.625%, and other each group gives the described compound of corresponding dosage, all by 0.2ml/10g lumbar injection.
1.2 main experimental drugs, reagent, test kit
Described compound provides (purity > 96% by pharmaceutical chemistry research department of Xinxiang College of Medical Science for Euparin, for yellow crystal powder), 5ml glass homogenizer, MDA, SOD and Coomassie brilliant blue test kit build up Bioengineering Research Institute by Nanjing and provide.
1.3 key instrument
FA2004 type electronic balance (above the flat instrument and meter of current chart company limited produces), 101-3 type electric heating air blast thermostatic drying chamber (production of instrument plant of Jiamei of Community of Jin Tan County city), T6 type spectrophotometer (production of Beijing Pu Xi all purpose instrument Co., Ltd), TG16-W high speed centrifugal machine for minim (production of Hunan, Changsha instrument centrifuge instrument company limited), the quick swirl mixing device of SK-1 type (production of Community of Jin Tan County Medical Instruments factory), electric-heated thermostatic water bath (Shanghai Medical Apparatus and Instruments Factory's production).
1.4 Forebrain Ischemia modelling and tissue treatment methods
10% chloral hydrate anesthesia (400mg/kg) for mice, cervical region median incision, isolates bilateral common carotid arteries, closes bilateral common carotid arteries pour into for 2 hours again with noinvasive bulldog clamp folder, mouse peritoneal drug administration by injection between flush phase again, 2 times/day (all lumbar injections).After administration 48h, put to death animal and take out cerebral tissue, left brain claims dry weight in wet base, and right brain is made 10% brain tissue homogenate DEG C preservation of centrifuging and taking supernatant-20.
The assay method of 1.5 brain water contents
After the left side cerebral tissue of taking-up is weighed with analytical balance, put into 110 DEG C of baking box baking 15h and again weigh, then calculating the water content of cerebral tissue according to formula.Formula is as follows:
Tissue water content (%)=(weight in wet base-dry weight)/weight in wet base × 100%
The mensuration of 1.6 cerebral tissue MDA and SOD
1.6.1 MDA (malonaldehyde) assay method: after Coomassie brilliant blue protein quantification, take best sampling amount, required each test tube of preparation experiment in order, wortex device mixes, 95 DEG C of water-baths 40 minutes, after taking out, flowing water is cooling, and centrifugal 10 minutes (3500-4000 rev/min), gets supernatant appropriate, 532nm place, 1cm optical path, distilled water zeroing, measures each pipe absorbance.Calculate the MDA value of each group of each animal according to following computing formula.
Wherein, nmoL/mgprot is sodium mole of/milligram of albumen.
1.6.2 SOD (total superoxide dismutase) assay method in cerebral tissue:
After Coomassie brilliant blue protein quantification, adopt best sampling amount strictly by required each test tube of test kit description preparation experiment, wortex device fully mixes, put 37 DEG C of waters bath with thermostatic control 40 minutes, then each pipe add developer again room temperature place 10 minutes, in wavelength 550nm place, 1cm optical path cuvette, distilled water zeroing, numerical value is respectively organized in colorimetric determination.Then calculate the SOD value of each group of each animal according to formula.
1.7 statistical method
Adopt SPSS17.0 to carry out statistical procedures, all use ± s of measurement data represents, adopts variance analysis, compares between two, and the neat person of variance adopts LSD method, and heterogeneity of variance person adopts Dunnett's T3 method, and P ﹤ has significant difference.
2 experimental results
The impact of 2.1 Euparin on Forebrain Ischemia mouse brain tissue water content
Described in embodiment 2, the each dosage group of compound and model group more all can significantly reduce the water content of cerebral ischemia tissues following MCAO in rats, have good dose dependent.(in table 2)
The comparison of table 2 Euparin on the impact of Forebrain Ischemia brain water content
With relatively * P<0.05 of model group, * * P<0.01.
2.2 Euparin organize the impact of MDA and SOD on Forebrain Ischemia mouse brain
The each dosage group of Euparin and model group more all can reduce the content of cerebral ischemia tissues following MCAO in rats MDA, the content of increased SOD, and along with the rising of dosage, the effect of described compound is stronger, has good dose dependent.
The comparison of table 3 Euparin on Forebrain Ischemia MDA, SOD and the impact of NO value
With relatively * P<0.05 of model group, * * P<0.01.
Three, the impact of Euparin on myocardial ischemia in rats experiment
1 experiment material and method
1.1 laboratory animal grouping and medications
40 of SD male rats, body weight 180-220g, is divided into 5 groups, 8 every group.That is: model group (isoproterenol 30mg/kg), blank group (equal-volume water for injection), Euparin8mg/kg group, 16mg/kg group, 32mg/kg group, all by the volume administration of 20ml/kg, B.i.d, lumbar injection 1 day.
The making of 1.2 treating myocardial ischemia damage models and organized processing
10% chloral hydrate for animal (300mg/kg) anesthesia, tracheostomy tube, separate external jugular vein to be on the waiting list blood, connection electrocardiograph records limbs II and leads, isoproterenol (isoproterenol, ISO) (30mg/kg), slowly subcutaneous injection, observe ECG change, injection ISO10min is that visible heart rate and ST-T ripple obviously change.Matched group injecting normal saline, each medication group is being injected equal lumbar injection after ISO15 minute, after 2 hours, put to death animal and take out heart, wash down bloodstain with normal saline, get 20-30mg cardiac muscular tissue, under 1-4 DEG C of condition, make 10% normal saline cardiac muscular tissue homogenate, then centrifugal (3000r/min, 10min), get appropriate supernatant and detect myocardial cell MDA and SOD level.
1.3 statistical method
Adopt SPSS17.0 to carry out statistical procedures, measurement data is all used
represent, adopt variance analysis, compare between two, the neat person of variance adopts LSD method, and heterogeneity of variance person adopts Duttet method, and P ﹤ has significant difference.
2 results
The impact of 2.1 Euparin on acute myocardial ischemia MDA, SOD
The each dosage group of Euparin and model group more all can reduce the content for the treatment of myocardial ischemia damage tissues following MCAO in rats MDA, and the content of increased SOD has good dose dependent (in table 4).
The comparison of table 4 Euparin on acute myocardial ischemia MDA, the impact of SOD value
With relatively * P<0.05 of model group, * * P<0.01
Four, Euparin is to the improvement effect to memory deficits in mice
1 experiment material and method
1.1 laboratory animal grouping and medications
60 of ICR kind mices, male and female half and half, body weight 18-22g, be divided at random 5 groups, be blank group (giving equivalent solvent), pathological model group (scopolamine 5mg/kg), positive drug matched group (1% aniracetam), Euparin8mg/kg group, 16mg/kg group, 32mg/kg group, 12 every group.All by 10ml/kg administration, q.d., continuous 10 days lumbar injections.
1.2 main agents, medicine and instrument
Euparin (is provided by pharmaceutical chemistry research department of Xinxiang College of Medical Science, purity > 96%, for yellow crystal powder), scopolamine hydrobromide injection (is purchased from Third Affiliated Hospital of Xinxiang Medical Coll, specification: 0.3mg/ml, lot number: 5A18002, Shanghai Hefeng Pharmaceutical Co., Ltd. produces), STT-Z mice diving tower instrument (institute of Materia Medica,Chinese Academy of Medical Sciences production)
1.3 experimental technique
After the disposable training of animal via, choose qualified animal, test and the achievement of misregistration number of times and SDL (time of staying on mice platform) with mice diving tower instrument, experimental result with
represent, statistical method is the same.
2. result
To scopolamine induced mice, memory obtains dysgenic comparative analysis to 2.1 Euparin
The paramnesia number of times of the each dosage group of Euparin and model group comparison mice obviously reduces, and the SDL time obviously increases (P<0.05 or P<0.01); Obviously be better than positive control drug aniracetam with the middle and high dosage group of positive control drug comparison Euparin, point out this medicine to have and improve the bad effect of scopolamine induced mice memory acquisition, in table 5.
On scopolamine induced mice, memory obtains bad impact to table 5 Euparin
With relatively * P<0.05 of model group, * * P<0.01; With relatively #P<0.05 of 1% aniracetam group, ##P<0.01
More than experiment shows, compd E uparin can be applied to following field:
1. be used for the treatment of cerebral ischemia and thrombotic disease due to cerebral vasospasm disease and other reason.
2. be used for the treatment of the myocardial ischemia disease due to a variety of causes.
3. for the memory impairment due to treatment of vascular senile dementia and other cerebrovascular disease.
Treatment for above disease can be made monomeric compound described in embodiment the peroral dosage forms such as tablet, capsule or oral liquid for patient, also injectable administration.
Claims (10)
- The application of 1.Euparin in preparation treatment ischemic cardio cerebrovascular diseases medicine.
- 2. application according to claim 1, is characterized in that, described medicine is the medicine of the memory impairment that causes for the treatment of ischemic cerebrovascular.
- 3. application according to claim 1 and 2, is characterized in that, described medicine refers to tablet, capsule and the injection that Euparin and pharmaceutically suitable carrier are made.
- 4. application according to claim 3, is characterized in that, the formula that described tablet is counted by weight comprises: 200～400 parts of Euparin, 10～150 parts of disintegrating agents, 10～20 parts of lubricants.
- 5. application according to claim 4, is characterized in that, described disintegrating agent is microcrystalline Cellulose, low-substituted hydroxypropyl cellulose or carboxymethyl starch sodium; Described lubricant is magnesium stearate, micropowder silica gel or Polyethylene Glycol.
- 6. according to the application described in claim 4 or 5, it is characterized in that, the formula of described tablet also comprises 150～300 parts of correctivess; Described correctives is lactose.
- 7. application according to claim 3, is characterized in that, the formula that described capsule is counted by weight comprises: 200～400 parts of Euparin, 10～20 parts of lubricants; Described lubricant is magnesium stearate, micropowder silica gel or Polyethylene Glycol.
- 8. application according to claim 7, is characterized in that, the formula of described capsule also comprises 100～250 parts of correctivess; Described correctives is lactose.
- 9. application according to claim 3, it is characterized in that, the formula that described injection is counted by weight comprises: 200～800 parts of Euparin, 150～360 parts, sodium chloride, 100～200 parts of suspending agents, 50～100 parts of emulsifying agents, 500～1500 parts of waters for injection.
- 10. application according to claim 9, is characterized in that, described suspending agent is tween 80 or carboxymethyl cellulose; Described emulsifying agent is lecithin, fabaceous lecithin, pluronic F-68, oxygen ethylene propylene polymerization thing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919991A (en) * | 2016-05-18 | 2016-09-07 | 西安交通大学 | Application of euparin to preparation of medicine for treating depression |
| CN112716939A (en) * | 2021-01-08 | 2021-04-30 | 贵州中医药大学 | Application of scopoletin in preparation of preparation for treating ischemic cardiovascular and cerebrovascular diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000002874A2 (en) * | 1998-07-09 | 2000-01-20 | University Of Strathclyde | Integrin dependent cell adhesion inhibitors |
| CN1935800A (en) * | 2006-10-16 | 2007-03-28 | 闫福林 | Compound with anti cerebralischemia, myo cardialischemia and memory-improving functions, and its preparing method and use |
-
2014
- 2014-06-23 CN CN201410283733.0A patent/CN104095840B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000002874A2 (en) * | 1998-07-09 | 2000-01-20 | University Of Strathclyde | Integrin dependent cell adhesion inhibitors |
| CN1935800A (en) * | 2006-10-16 | 2007-03-28 | 闫福林 | Compound with anti cerebralischemia, myo cardialischemia and memory-improving functions, and its preparing method and use |
Non-Patent Citations (2)
| Title |
|---|
| MEHDI MOHAMMADI ET AL: "Chemical composition and antioxidant activity of the essential oil of aerial parts of Petasites albus from Iran: a good natural source of euparin", 《NATURAL PRODUCT RESEARCH》 * |
| 李炜等: "《临床实用急症手册》", 31 August 1996 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919991A (en) * | 2016-05-18 | 2016-09-07 | 西安交通大学 | Application of euparin to preparation of medicine for treating depression |
| CN105919991B (en) * | 2016-05-18 | 2019-01-15 | 西安交通大学 | Application of the euparin in preparation medicament for treatment of depression |
| CN112716939A (en) * | 2021-01-08 | 2021-04-30 | 贵州中医药大学 | Application of scopoletin in preparation of preparation for treating ischemic cardiovascular and cerebrovascular diseases |
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| CN104095840B (en) | 2016-04-27 |
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