CN1823798A - Application of isobaicalin in preparation of medicine - Google Patents

Application of isobaicalin in preparation of medicine Download PDF

Info

Publication number
CN1823798A
CN1823798A CNA2005100074646A CN200510007464A CN1823798A CN 1823798 A CN1823798 A CN 1823798A CN A2005100074646 A CNA2005100074646 A CN A2005100074646A CN 200510007464 A CN200510007464 A CN 200510007464A CN 1823798 A CN1823798 A CN 1823798A
Authority
CN
China
Prior art keywords
isoscutellarin
medicine
scutellarin
preparation
blood
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2005100074646A
Other languages
Chinese (zh)
Inventor
史关正
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CNA2005100074646A priority Critical patent/CN1823798A/en
Priority to PCT/CN2006/000254 priority patent/WO2006089478A1/en
Publication of CN1823798A publication Critical patent/CN1823798A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An application of isoscutellarin 5,7,4'-trihydroxyflavone-6-0-glucuronicoside in preparing medicines for preventing and treating coronary heart disease, angina pectoris, myocardial ischema injury, cerebral thrombosis, cerebral infarction, etc.

Description

The application of Isoscutellarin in pharmacy
Technical field:
The present invention relates to the purposes of Isoscutellarin (ISOSCUTELLARIN 5,7,4 '-trihydroxyflavone-6-O-glucuronide), relate in particular to the purposes in pharmaceutical field.
Background technology:
Scutellarin (SCUTELLARIN 5,6,4 '-trihydroxyflavone-7--O-glucuronide) claims scutellarin again.Have effects [1] such as blood vessel dilating, cerebral blood flow increasing amount and heart coronary flow, blood viscosity lowering, microcirculation improvement.Be mainly used in diseases such as paralysis after treatment cerebral thrombosis, cerebral infarction, the apoplexy, coronary heart disease, angina pectoris clinically.Its existing preparation is conventional tablet, injection and injection powder pin.But the conventional tablet oral administration biaavailability is extremely low, has only 0.4 ± 0.19%[2].Normal injection and injectable powder injection administration half-life are short, eliminate [2-6] rapidly in the body.Research all contains chemical compound 5,6 with raising both at home and abroad at present, and the preparation bioavailability and the durative action preparation of 4 '-trihydroxyflavone-7-O-glucal thuja acid are main.Do not see that relevant Isoscutellarin preparation prevents and treats application and two kinds of isomers pharmacokinetic study in vivo of the medicine of cardiovascular and cerebrovascular vessel, thrombotic disease.Its Isoscutellarin structure is:
5,7,4 '-trihydroxyflavone-Isoscutellarin
(Isoscutellarin ISOSCUTELLARIN)
Its molecular formula of this chemical compound is C 21H 20O 12, yellow powder shape, molecular weight are 464.Be soluble in the ethanol of low concentration.Extract in can leaf according to document [7] and to make by Sterculiaceae plant palm leaf sterculia nobilis Sterculia foetida or sterculia nobilis Sterculia colorata.
Summary of the invention:
1, the object of the invention is to provide the new purposes of Isoscutellarin, i.e. new application in pharmacy.
2, the present invention relates to Isoscutellarin as the application in the medicine of cerebrovascular accident diseases such as preparation treatment and control cerebral thrombosis, cerebral embolism.
3, the present invention relates to Isoscutellarin as the application in the medicine of preparation treatment and control cerebrovascular disease.
4, the present invention has set up the determination of plasma concentration method (LC/MS/MS) of this chemical compound in the blood in human body in slurry of measuring; And Isoscutellarin carried out pharmacokinetic, and the present invention is by discovering the kinesiology of Isoscutellarin and scutellarin, plasma concentration＜5ng/ml behind the oral scutellarin, and eliminate irregular soon.And Isoscutellarin is kept higher blood drug level at the blood plasma of human body, and curative effect is better than scutellarin; Simultaneously, in clinical trial, do not observe the clinical adverse phenomenon.
Essence for a better understanding of the present invention will illustrate its new application in pharmaceutical field with the pharmacological testing and the result of Isoscutellarin below.
Adopt the leaf 100kg of Sterculiaceae plant palm leaf sterculia nobilis Sterculia foetida or sterculia nobilis Sterculia colorata, with 15 times 60% ethanol that is equivalent to leaf weight, reflux, extract, 40 minutes, reflux, extract, 2 times.Merge extractive liquid, behind the concentrating under reduced pressure ethanol, is used petroleum ether, chloroform, ethyl acetate, n-butanol extraction successively.N-butyl alcohol is partly used macroporous adsorption resin chromatography, water, 20%, 60%, 80% ethanol elution obtain 5 positions successively, its 20% alcohol layer silica gel column chromatography, use chloroform: methanol: water (1: 2: 2) eluting, reuse Sephadex LH220 chromatography, methanol: water (1: 2) eluting gets chemical compound Isoscutellarin (300mg).
The Isoscutellarin that above extraction separation is obtained, with polyethylene glycol 6000: (1: 2-6) mixed liquor is as substrate for Macrogol 4000, coolant is selected dimethicone: liquid paraffin (3: 2), different Radix Scutellariae acid glycosides 100g of raw material and substrate 500g proportioning, fluid temperature is that 60-90 ℃ testing program is best testing program; With chilling temperature is 0～5 ℃, and external diameter is the water dropper of 4.5/7.0mm in the drip, and drip is 2-6cm apart from the cooling liquid level, drips fast 20-45 and drips/the system condition of dripping of min, and makes the drop pill that every ball contains Isoscutellarin 10mg.
Get the 200mg that extraction separation obtains, add the injection water to 1000ml, behind the mix homogeneously, be distributed into injection that 1mg/5ml/ props up concentration and pack into and seal in the medicine bottle, it is standby that product is made in sterilization.
1, acute toxicity test in mice
The mensuration of A, intravenously administrable mice LD50:
Get 50 of healthy mices, body weight 18g～22g is divided into 5 groups at random by body weight.Every group 10, ♀ ♂ half and half tests fasting in preceding 12 hours.Than dilution method, preparation is subjected to the reagent thing by low, determines that through trial test maximum dose level is 2000mg/kg, and lowest dose level 1000mg/kg, common ratio r=0.84 between group, dosage are respectively 2000,1680,1411.2,1185.4,995.7mg/kg; I.v administration volume is the 0.2ml/10g body weight.
Behind the intravenously administrable, the dose dependent poisoning symptom appears in animal, and symptoms such as the spontaneous activity amount reduces, abdomen crouches, tic, struggle appear in visible mice.1185.4mg/kg dead animal appears in above dosage group, it is 1509.9 ± 142.7mg/kg that the Bliss method is calculated the LD50 value, 95% the credible 1399.9～1685.3mg/kg that is limited to.Animal was cutd open inspection when dead animal and observation finished, and showed no obvious abnormalities variation.The forward and backward body weight change of administration.
Intravenous injection mice LD50
Dosage (mg/kg) Log10 dose (xi) Number of animals (only) Death toll (only) Mortality rate (%) Probit (Y) LD 50And 95% fiducial limit (mg/kg)
2000 1680 1411.2 1185.4 995.7 3.301 3.225 3.150 3.074 2.998 10 10 10 10 10 10 7 3 1 0 100 70 30 10 0 6.78 5.68 4.57 3.46 2.36 1509.9±142.7 (1399.9～1685.3)
The forward and backward body weight change table of administration
Dosage (mg/kg) Size of animal (only) Body weight change (g)
Before the medicine Behind the medicine Before the administration Behind the medicine 7 days Behind the medicine 14 days
1680 1411.2 1185.4 995.7 10 10 10 10 3 7 9 10 20.49±0.92 20.45±0.90 20.53±0.85 20.52±0.60 21.40±0.43 21.57±1.14 22.37±1.14 23.00±0.78 29.13±0.58 29.27±1.09 29.90±0.71 30.58±0.89
The mensuration of B, oral administration mice LD50:
Pre-test result shows, observes continuously after trial drug 2500 and the 5000mg/kg administration and does not see dead animal in 3 days.Show that this product toxicity is lower, its LD50 is difficult to measure, so carry out mtd test.
After the administration, the test group mice does not see obvious poisoning symptom except that the spontaneous activity amount reduces to some extent, abdomen crouches, continue observation and also do not see animal dead in 7 days.The forward and backward body weight change of administration.
Sex Size of animal (only) Body weight change (g)
Before the administration Behind the medicine 7 days Behind the medicine 14 days
♀ ♂ 10 10 19.99±0.89 20.19±0.64 22.82±1.54 23.32±1.15 30.35±1.18 30.55±0.92
C, mtd test: get 20 of healthy mices, body weight 18 ∽ 22g, ♀ ♂ half and half tests fasting in preceding 12 hours, freely drinks water.Test is established the 5000mg/kg test group, administration concentration 12.5%, administration volume 0.4ml/10g body weight.
The result shows, poisoning symptoms such as the spontaneous activity amount reduces, abdomen crouches, tic, struggle appearred in visible mice after a vein gave the mouse experiment medicine, animal dead is dose dependent, calculate through the Bliss method, the LD50 value is 1509.9 ± 142.7mg/kg, 95% the credible 1399.9～1685.3mg/kg that is limited to.Per os is tested behind the medicine when dosage reaches 5000mg/kg, and animal generally in order, does not see dead animal except that abdomen crouches, spontaneous activity reduces to some extent.Show the oral LD50＞5000mg/kg of this product mice.
2, to the therapeutical effect of Focal Ischemia-Reperfusion in Rats
Rat separates the exposure bilateral carotid under the situation of anesthesia, add with bulldog clamp and close bilateral common carotid arteries, produces the bilateral cerebral ischemia.Can open bulldog clamp again by test requirements document behind the ischemia certain hour and carry out brain perfusion again.Get the healthy SD rat, male and female half and half, body weight 260-290 gram.Be divided into 3 groups at random, every group 15, irritate stomach respectively and give 5% sodium carboxymethyl cellulose (solvent group), scutellarin 20mg/kg (matched group) and different baicalin 20mg/kg (test group), every day 1 time, continuous 10 days, pentobarbital sodium (40mg/kg) ip. with 2% after 10 days anaesthetizes, and makes the cervical region median incision, closes bilateral common carotid arteries 20min with the bulldog clamp folder, pine folder back direct-view revascularization, the skin suture otch is put back to old terms and is raised, and adds up 24h mortality rate after each treated animal cerebral ischemia.The solvent group is dead 8 as a result, mortality rate 53.3%; Dead 3 of scutellarin group, mortality rate 20%; Dead 1 of different baicalin group, mortality rate 6.6%.Therefore baicalin, Isoscutellarin have stronger protective effect to focal brain ischemia-reperfusion injury in rats, but different baicalin has been compared the better protection effect with baicalin.
Its objective is the blood vessel of blocking-up domination cerebral tissue, can simulate and the akin pathological model of people's apoplexy, to estimate the effectiveness of medicine.
3, to the influence of blood coagulation system
(1) to the influence of clotting time of mice
Get 105 of Kunming mouses, male and female half and half, 20 ± 2g, be divided into 4 groups at random, give normal saline and scutellarin (matched group) respectively, Isoscutellarin (test group) is irritated stomach with the dosage of 20mg/kg, 40mg/kg, 60mg/kg respectively, one week of continuous irrigation stomach, 1h after the last administration, with the capillary glass-tube from childhood rathole endocanthion ball posterior vein from the interior blood of getting.Pick up counting in the autoblood inflow pipe, blood is filled with the back and is taken out capillary tube and lie against on the table, every the 10s about 0.5cm of capillary tube that fractures, till occurring to clotting strands, is the blood clotting time between institute lasts, and the meansigma methods of capillary tube two end datas is the blood clotting time of this Mus.
To the influence (capillary tube method) of clotting time of mice (X-± SD)
Figure A20051000746400051
Annotate: compare with the blank group, *P＜0.01
The mice thrombotest is shown: scutellarin group and Isoscutellarin group all have blood coagulation resisting function, and obvious with the effect of Isoscutellarin group especially.
(2) to the influence of rabbit prothrombin time
Get healthy rabbits venous blood, mix anticoagulant at 1: 9 with (38mg/ml) sodium citrate solution, the centrifugal 10min of 3000r/min, it is to be measured to get supernatant.Adopt blank scutellarin, Isoscutellarin medicinal liquid with variable concentrations to add the rabbit brain powder leachate respectively during mensuration, each 0.1ml of normal saline adds rabbit plasma 0.1ml again, puts incubation 30s in 37 ℃ of water-baths of people behind the mixing, adds 0.025mol/LCaCl 2Solution 0.1ml also picks up counting, and every 5s inclination test tube 1 time, the record fibrin solidifies (liquid level is motionless) required time.
Influence to the rabbit prothrombin time
Figure A20051000746400061
Annotate: compare with the blank group, *P＜0.05, *P＜0.01
Yellow different plain glycosides, Isoscutellarin can obviously prolong clotting time and prothrombin time, help preventing and treating thrombosis.
4, isoproterenol (ISO) is induced the effect of gerbil jird acute myocardial ischemia: get 48 of healthy gerbil jirds, body weight (54 ± 14) g, the male and female dual-purpose is divided into six groups at random, 8 every group, is respectively: (1) normal saline matched group (NS); (2) Isoscutellarin group (50mg/kg), more than each treated animal abdominal vein drug administration by injection respectively, continuous 2d, 3d shows the anesthesia pallasiomy, set up the intravenously administrable passage, by medicine of above-mentioned each group and measure respectively that vein is slow to push away administration, 5min gives ISO2.5ug/kg after the last administration, constant speed intravenous injection in 5min is observed and the II lead electrocardiogram ST section of the interior different time points of record 15min changes; (3) Isoscutellarin intravenously administrable group (50mg/kg); Behind the qualified 30min of screening, 5min vein constant speed injection ISO2.5ug again after the administration, observe and record 15min in the II lead electrocardiogram ST section of different time points change; It the results are shown in Table 1.
Result of the test shows, first lumbar injection Isoscutellarin preventive administration 2 days, the last intravenously administrable, with intravenous injection once, Isoscutellarin all has ofer short duration, the slight effect that alleviates the inductive acute myocardial ischemia of ISO.Its mechanism that resists myocardial ischemia may with its blood pressure lowering rapidly and enduringly, alleviated the heart burden, thereby it is relevant to have reduced myocardial oxygen consumption.Isoscutellarin can improve the SOD of heart tissue activity, reduces MDA, reduces free radical in the gathering of cardiac muscle, and has alleviated ISO to the induced myocardial injury effect, points out its function of resisting myocardial ischemia may be relevant with its lipoid peroxidization resistant.
5, the clinical research of Isoscutellarin:
Scutellarin has effects [] such as blood vessel dilating, enhancing arterial flow, blood viscosity lowering, reduction Peripheral resistance, minimizing platelet aggregation.Clinical treatment coronary heart disease, angina pectoris, treating myocardial ischemia damage and the cerebral thrombosis etc. of being mainly used in.Its existing preparation has conventional tablet, injection and injection powder pin.The conventional tablet oral administration biaavailability is extremely low, has only 0.4 ± 0.19%[1].Normal injection and injectable powder injection administration half-life are short, eliminate [2-5] rapidly in the body.And human pharmacokinetics research does not appear in the newspapers as yet.
According to two ones of Pharmacopoeias of People's Republic of China (version in 2000) regulation, measure the concentration of scutellarin, Isoscutellarin in 20 health volunteer's oral test preparation blood plasma respectively, draw blood drug level-time graph, ask the calculation pharmacokinetic parameter; And, provide the test data (seeing Table 2) of necessity for the research of Isoscutellarin drop pill human bioavailability respectively according to the amount of Isoscutellarin in the preparation:
Interpretation of result: 20 oral drop pill that contain Isoscutellarin 80mg of experimenter, the results are as follows: the T of Isoscutellarin in the blood plasma MaxBe respectively 7.7 ± 1.7h; C MaxBe respectively 178 ± 142ng/ml, t 1/2Be 3.26 ± 1.78h; Calculate AUC with trapezoidal method 0-tBe respectively 1195 ± 1136ngh/ml, AUC 0-∞Be respectively 1263 ± 1271ngh/ml.
And to the human body pharmacokinetic studies of scutellarin the time, find, the plasma concentration＜5ng/ml of main component scutellarin behind the oral scutellarin of experimenter, and eliminate fast, irregular.Be difficult to carry out the pharmacokinetics evaluation.Behind document [2] report beagle dog n of high dose oral scutellarin, between 1-3h, reach the blood drug level peak value, absolute bioavailability is between 0.2%-0.75%, and the prompting scutellarin is oral to be absorbed hardly; It is consistent that quiet notes are eliminated all short result of the test of half-life.
According to general pharmacokinetics rule, the relative scutellarin of Isoscutellarin has better drug effect; Simultaneously, in clinical trial, do not observe the clinical adverse phenomenon.
Can draw based on above result and the invention has the advantages that:
(1) the present invention has excavated new medical usage to the known compound Isoscutellarin, has opened up a new application.
(2) Isoscutellarin safety non-toxic of the present invention, pharmacological action is strong, good drug efficacy, indicating has good prospect in medicine.
(3) products material of the present invention source is abundant, inexpensive, simple as the abundant resource of extraction unit potential energy, preparation technology with leaf, does not see toxic and side effects.Both can make preparations such as oral formulations such as tablet, drop pill, capsule; Also can make intravenous formulations such as injectable powder, intravenous fluid etc.
(4) medicine made of product of the present invention has and can reduce brain water content and MDA content to some extent, improves SOD, CAT and GSH-Px activity, protection Na+, the K+-ATP enzymatic activity.The prompting Isoscutellarin can suppress lipid peroxidation, the infringement that alleviates the radical pair cerebral tissue by the activity of protection cerebral tissue antioxidase; Can reduce the water content of cerebral tissue, suppress cerebral tissue Na+, the active reduction of K+-ATPase and Ca2+-ATPase.Point out this medicine to produce protective effect to the ischemia-reperfusion cerebral tissue by protection ATPase activity.Its effect is better than scutellarin.
(5) medicine made of product of the present invention can obviously improve the variation that urine swashs the accumulative TXB2 of platelet behind the thrombolytic, and the concentration of tissue plasminogen activator, anticoagulin in the rising blood, reduce mortifier (PAI) concentration of activator of plasminogen, use the recanalization rate of urine hormone enzyme bolt treatment when improving acute coronary thrombosis.Can reduce platelet count, reduce platelet aggregation, promote fibrinolytic, anticoagulant, enzymatic activity etc. had anticoagulant and fibrinolytic effect.Its blood coagulation resisting function is better than scutellarin.
(6) the made medicine of product of the present invention has the effect that resists myocardial ischemia.Can improve the SOD of heart tissue activity, reduce MDA, reduce free radical, alleviate ISO, point out its function of resisting myocardial ischemia may be relevant with its lipoid peroxidization resistant to the induced myocardial injury effect in the gathering of cardiac muscle.
(7) product of the present invention has carried out clinical trial, adopts liquid chromatography-mass spectrography-mass spectrometry method to measure the blood drug level in the different blood plasma constantly behind 20 oral Isoscutellarins of experimenter, has drawn blood drug level-time graph.According to blood drug level-time data, adopt trapezoidal method to calculate the AUC value with the semilog graphing method, calculate t by eliminating terminal mutually concentration point 1/2, and obtain main pharmacokinetic parameter.Compare with its scutellarin, have the better medicament kinetic parameter.For the clinical efficacy of medicine has been established theoretical basis.Simultaneously, in clinical trial, do not observe the clinical adverse phenomenon.
The specific embodiment
Below will describe several embodiments of the present invention, but content of the present invention is not limited to this fully.
Embodiment 1:
Adopt the leaf 100kg of Sterculiaceae plant palm leaf sterculia nobilis Sterculia foetida or sterculia nobilis Sterculia colorata, with 15 times 60% ethanol that is equivalent to leaf weight, reflux, extract, 40 minutes, reflux, extract, 2 times.Merge extractive liquid, behind the concentrating under reduced pressure ethanol, is used petroleum ether, chloroform, ethyl acetate, n-butanol extraction successively.N-butyl alcohol is partly used macroporous adsorption resin chromatography, water, 20%, 60%, 80% ethanol elution obtain 5 positions successively, its 20% alcohol layer silica gel column chromatography, use chloroform: methanol: water (1: 2: 2) eluting, reuse Sephadex LH220 chromatography, methanol: water (1: 2) eluting gets the chemical compound Isoscutellarin.With polyethylene glycol 6000: (1: 2-4) mixed liquor is as substrate for Macrogol 4000, coolant is selected dimethicone: liquid paraffin (3: 2), different Radix Scutellariae anhydride of raw material and substrate were with 1: 4 proportioning, fluid temperature is 60-80 ℃, with chilling temperature is 0～5 ℃, and external diameter is the water dropper of 4.5/7.0mm in the drip, and drip is 3-6cm apart from the cooling liquid level, drip fast 25-35 and drip/the system condition of dripping of min, make the drop pill that every ball contains Isoscutellarin 10mg.
Embodiment 2:
Get Isoscutellarin 1000g, add proper amount of water for injection, transfer pH value to 7, stirring and dissolving with sodium carbonate by the method preparation of embodiment 1, add the mannitol that is equivalent to Isoscutellarin 10-15% amount injection again, degerming filters, and measures content, branch is filled to 10mg/ and props up, and seals, promptly.
Embodiment 3:
Get the Isoscutellarin of the method preparation of embodiment 1, take infusion solution preparation method well-known in the art, be prepared into the Isoscutellarin sodium chloride injection, its specification is 250ml: Isoscutellarin 20mg and sodium chloride 2.25g: be prepared into the Isoscutellarin glucose injection, its specification is 250ml: Isoscutellarin 20mg and glucose 12.5g.
Embodiment 4:
Get Isoscutellarin 260g, lactose 460g, starch 420g, the Pulvis Talci 148g of the preparation of embodiment 1 method.Take method for preparing tablet thereof well-known in the art, in appropriate vessel, mix all components, make granule, add magnesium stearate 2g again, mixing, with standard concave stamping in 9/32 o'clock, 10 weight were 1.3g, its specification is: the 20mg/ sheet.
Embodiment 5:
Get Isoscutellarin l00g, the 10% hydroxypropyl methylcellulose 32ml of the preparation of embodiment 1 method.Take capsule preparation method thereof well-known in the art, make 1000 capsules, its specification is: the 20mg/ grain.
Embodiment 6:
Consult domestic and international pertinent literature, find no the report of Isoscutellarin clinical trial.The present invention has carried out human pharmacokinetics research, and has measured Isoscutellarin plasma concentration in the human body with liquid chromatography-tandem mass spectrometry (LC/MS/MS) analytical method, and with the pharmacokinetics behavior of Isoscutellarin its preparation is carried out therapeutic evaluation.
The analytical method of plasma sample
Plasma sample is handled: add 100 μ l methanol respectively in 500 μ l blood plasma, 100 μ l inner mark solutions (baicalin 400ng/ml) and 200 μ l water, mixing; Add 3ml and extract solvent ethyl acetate, eddy current mixing 1min, reciprocating vibration 10min (240 times/minute), centrifugal 5min (3500rpm), divide and get upper organic phase in another test tube, dry up under 40 ℃ of nitrogen current, residue adds the dissolving of 150 μ l mobile phases, eddy current mixes, and gets 20 μ l and carries out the LC/MS/MS analysis.
Chromatographic condition: mobile phase is methanol: water: (70: 30: 0.5, v/v/v), flow velocity was 0.50ml/min to formic acid, column temperature: 25 ℃.
The mass spectrum condition: ion source is the ESI source; The source spray voltage is 4kV; The heated capillary temperature is 320 ℃; Sheath gas (N2) pressure 25Arb; Auxiliary gas (N2) flow 3Arb; Collision gas (Ar) pressure 1.0mTorr; Collision induced dissociation (CID) voltage is 25eV; The cation mode detects; Scan mode is selective response monitoring (SRM), and the ionic reaction that is used for quantitative analysis is respectively m/z463 → m/z287 (SCUTELLARIN and ISOSCUTELLARIN) and m/z447 → m/z271 (baicalin); Be 0.3s sweep time.Corresponding secondary full scan mass spectrum is seen Fig. 1.
Interpretation of result: 20 experimenters are oral contain Isoscutellarin 80mg be subjected to test preparation and reference preparation (scutellarin) after, the results are as follows: the T of Isoscutellarin in the blood plasma MaxBe respectively 7.7 ± 1.7h; C MaxBe respectively 178 ± 142ng/ml, t 1/2Be 3.26 ± 1.78h; Calculate AUC with trapezoidal method 0-tBe respectively 1195 ± 1136ng.h/ml, AUC 0-∞Be respectively 1263 ± 1271ng.h/ml.And the plasma concentration＜5ng/ml of scutellarin, and eliminate fast, irregular.
List of references
[1] Ding Guohua, Herba Erigerontis pharmacological research and Clinical advances, the time precious traditional Chinese medical science traditional Chinese medicines, 1999,10 (4), 303-306
[2] Ge Qinghua, Zhou Zhen, Zhi Xiaojin, etc. breviscapine is in intravital pharmacokinetics of dog and absolute bioavailability research [J]. Chinese Journal of Pharmaceuticals, 2003,34 (12): 618-620
[3] Jiang Xuehua, Li Suhua, Lan Ke, etc. breviscapine is in the intravital pharmacokinetics of domesticated dog [J]. Acta Pharmaceutica Sinica [J], 2003,38 (5): 371-373.
[4] Liu Yiming, the woods Aiwa, Chen Hui, wait .SCUTELLARIN at rabbit body giving drugs into nose for kinetics [J]. Acta Pharmaceutica Sinica, 2003,38 (10): 775-778.
[5] Li Suhua, Jiang Xuehua, Yang Qiang, etc. breviscapine is in the intravital pharmacokinetic studies of rabbit [J]. biomedical engineering's magazine, 2003,20 (4): 692～694.
[6]Zhong DF，Yang BH，Chen XY，et al.Determination of scutellarin in rat plasmaby high-performance liquid chromatography with ultraviolet detection[J].Journal of Chromatography B，2003，796(2)：439-444
[7]Current science.[periodical]46(1)14-15(English)1977

Claims (4)

1, the application of Isoscutellarin in the sequela medicine due to preparing treatment or prevention of brain thrombosis, cerebral infarction, cerebral hemorrhage etc.;
2, the application of Isoscutellarin in preparing treatment or prevention coronary heart disease, angina drug;
3, the application of Isoscutellarin in preparing the medicine for the treatment of or prevent and treat cardiovascular disease.
4, provide feasible research method for containing Isoscutellarin or scutellarin medicine at human or animal's drug disposition dynamics research.
CNA2005100074646A 2005-02-22 2005-02-22 Application of isobaicalin in preparation of medicine Pending CN1823798A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CNA2005100074646A CN1823798A (en) 2005-02-22 2005-02-22 Application of isobaicalin in preparation of medicine
PCT/CN2006/000254 WO2006089478A1 (en) 2005-02-22 2006-02-22 The use of isoscutellarin for the manufacture of medicine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNA2005100074646A CN1823798A (en) 2005-02-22 2005-02-22 Application of isobaicalin in preparation of medicine

Publications (1)

Publication Number Publication Date
CN1823798A true CN1823798A (en) 2006-08-30

Family

ID=36927029

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2005100074646A Pending CN1823798A (en) 2005-02-22 2005-02-22 Application of isobaicalin in preparation of medicine

Country Status (2)

Country Link
CN (1) CN1823798A (en)
WO (1) WO2006089478A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1147303C (en) * 2000-10-09 2004-04-28 朱邦豪 Application of Breviscapine in preparing medicine
CN1502337A (en) * 2002-11-20 2004-06-09 成都力思特制药股份有限公司 Oral medicine for treating cardio-cerebral vascular disease and preparation process thereof
RU2228673C1 (en) * 2003-06-20 2004-05-20 Московский государственный университет прикладной биотехнологии Antioxidant-containing food product from baikal scull-cap extract

Also Published As

Publication number Publication date
WO2006089478A1 (en) 2006-08-31

Similar Documents

Publication Publication Date Title
CN103880910B (en) A kind of preparation method and its usage of Cyclosiversigenin
CN101485666B (en) Application of Gamabufotalin and salt thereof in preparing medicament for treating gynaecologic tumor
CN101033245A (en) Preparation method and application of pedunculoside
CN1164264C (en) Dispersed general arasaponin tablet and its prepn and application
CN1216896C (en) Echinocystic acid preparation, medicinal preparation and new use as medicine
CN1768760A (en) Medicinal composition containing safflower total flavone and its preparation process and usage
CN101040891A (en) Preparation method and application of tripterygium hypoglaucum alkaloids
CN1823798A (en) Application of isobaicalin in preparation of medicine
CN1292750C (en) Total alkaloid composition from plant and its pharmaceutical preparation
CN1107501C (en) Albendazole emulsion
CN102688248A (en) Use of bufadienolide compound in preparing medicines for treating oral mucosal malignant tumors
CN1296089C (en) Zedoary injection preparation and its preparing method
CN101053587A (en) Medicinal composition for treating tumor and preparation method and quality control method thereof
CN1768753A (en) Medicinal composition containing bilobalide B and its preparation process and usage
CN101073598A (en) Medicinal composition for treating cardiovascular and cerebrovascular disease and its preparation
CN1636581A (en) Safflower medicine composition and its prepn process and use
CN101375954B (en) Medicament composition, preparation method thereof and use
CN1562313A (en) effervesce tablet of rheum and ground beetle, and preparation method
CN1813836A (en) Medicinal composition for treating cardio-cerebrovascular disease
CN1582946A (en) Use of centellosic acid derivative in preparation of medicines for diseases of cardio-cerebral blood vessels
CN1895298A (en) Medicinal preparation for treating and preventing coronary heart disease and thromboembolia disease and its preparation
CN1857255A (en) Bilobalide B emulsion for injection
CN1813885A (en) Compound red sage root spray and its preparing method
CN1768740A (en) Medicinal composition containing carthamin yellow and its preparation process and usage
CN1202839C (en) Chinese medicine prepn for treating hepatosis and its prepn process

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication