CN102614234B - Anti-stroke medicinal composition, tablet and preparation methods thereof - Google Patents
Anti-stroke medicinal composition, tablet and preparation methods thereof Download PDFInfo
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Abstract
The invention discloses an anti-stroke medicinal composition, a tablet and preparation methods thereof. The method comprises the following steps of: adding 70 percent ethanol into szechuan lovage rhizome and Chinese angelica serving as raw medicinal materials in an amount of 10 times the total amount of the raw medicinal materials for the first time, putting into an extraction tank, extracting at the temperature of 70-100 DEG C for 2 hours, filtering an extracting solution out to obtain a first extracting solution, and filtering solid filter residues out for later use; adding 70 percent ethanol into the solid filter residues in an amount of 8 times the total amount of the solid filter residues, putting into the extraction tank, extracting at the temperature of 70-100 DEG C for 1.5 hours, filtering an extracting solution out to obtain a second extracting solution and solid residues; mixing the extracting solutions, concentrating the mixed solution under reduced pressure at the temperature of 60-70 DEG C till alcohol taste disappears to obtain an extracted concentrate, wherein the relative density of the concentrate is 1.10-1.30, and the density is measured at the temperature of 60 DEG C; and adding smashed natural borneol into the extracted concentrate for dissolving to obtain a medicinal composition, wherein the medicinal composition comprises the following medical materials in parts by weight: 10-50 parts of szechuan lovage rhizome, 50-10 parts of Chinese angelica and 1-10 parts of natural borneol. The obtained composition plays remarkable a role in repairing impairment of stroke and cranial nerve functions.
Description
Technical field
The invention belongs to Chinese medicine development field, relate to a kind of anti-stroke medicine combination and preparation, specifically formed by Chinese crude drug Rhizoma Chuanxiong, Radix Angelicae Sinensis and natural Broneolum Syntheticum compatible combination, by extract main effective ingredient Rhizoma Chuanxiong total alkaloids in the medical material, Rhizoma Chuanxiong total organic acids, the total lactone of Rhizoma Chuanxiong, Radix Angelicae Sinensis total organic acids, when summing up lactone etc., be aided with natural Broneolum Syntheticum as mainly going into explosive component, for the preparation for the treatment of and prevention of stroke, cure mainly ischemic cardio cerebrovascular diseases medicines such as suffering from acute stroke, convalescent period and sequela thereof, vascular senile dementia.
Background technology
Apoplexy claims cerebrovascular accident or apoplexy again, it be suddenly faint, syncope, the facial hemiparalysis that occurs together, dysphonia, hemiplegia or nothing are fainted and are occurred the class disease that hemiplegia is cardinal symptom suddenly.Apoplexy generally is divided into hemorrhagic cerebral apoplexy such as cerebral hemorrhage, subarachnoid hemorrhage and ischemia apoplexy such as cerebral artery thrombosis forms, cerebral embolism two big classes.Mostly by anxious state of mind, be worried angry, drink, factor such as spiritual hypertonicity brings out.Because the cerebrovascular wall is atherosis, cause the narrow or formation dissecting aneurysm of lumen of vessels stenosis, at various inducements such as excited, psychentonia, overexert, under the influence such as hypertension, cause angiorrhexis or obstruction, make the cerebral blood circulation obstacle, form pathological changes such as part cerebral tissue ischemia, edema, cause delayed ischemic neurological deficits, thus a series of apoplexy symptom of corresponding appearance.The high incidence of apoplexy disease, high disability rate, high mortality have caused that domestic and international the world of medicine pays much attention to.
At present, the Western medicine that is used for anti-stroke is mainly thrombolytic medicine and channel blocker, but sizable side effect is arranged mostly, and the patient should not take for a long time, so the long-term treatment effect is unsatisfactory.With the Chinese medical theory be the Chinese medicine that instructs not only have curative effect steadily, definite, the low characteristics of side effect, and a large amount of scientific experimentss also shows and can improve body's immunological function, repairs the cranial nerve cell function, plays the effect of Comprehensive Treatment; Though many Chinese patent medicines that are used for apoplexy are arranged at present on the market, general dose is bigger, the cost height, and mechanism of action is indeterminate.
Given this, the inventor is according to the cause of disease and the pathogenesis of this type of disease, with the Chinese medicine theoretical direction, researched and proposed the present invention by modern pharmacology, experimental result shows scientific and reasonable compatibility, can not only make medicine play the collaborative reinforced effects of drug effect, and can also significantly reduce the use amount of medicine.
Summary of the invention
The present invention's first purpose be to provide a kind of Aggrenox compositions with and preparation method thereof, the compositions that obtains has tangible repair to apoplexy, cranial nerve function impaired.
The present invention's second purpose be to provide a kind of Aggrenox compositions tablet with and preparation method thereof, the composition tablet that obtains has tangible repair to apoplexy, cranial nerve function impaired.
A kind of Aggrenox preparation method of composition provided by the invention comprises:
Extract for the first time: crude drug Rhizoma Chuanxiong and Radix Angelicae Sinensis are added 10 times of amount 70% ethanol for the first time, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 2 hours, leaches extracting solution, obtains first extracting solution, and the solid filtering residue is stand-by.
Extract for the second time: add 8 times of amount 70% ethanol in described solid filtering residue, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 1.5 hours, leaches extracting solution, leaches extracting solution, obtains second extracting solution and solid filtering residue.
Mix described first extracting solution and the extracting solution second time, be under the 60-70 ℃ of condition in temperature, mixed liquor is evaporated to does not have the alcohol flavor, obtains extracting concentrate, the relative density of described concentrate is 1.10～1.30, and wherein said relative density records in the time of 60 ℃;
In described extraction concentrate, add the natural Broneolum Syntheticum dissolving of pulverizing, namely get described Pharmaceutical composition;
The weight proportion of described Rhizoma Chuanxiong, Radix Angelicae Sinensis, natural Broneolum Syntheticum is: 32:32:1.
Alternatively, when extracting the described first time, specifically:
Described Rhizoma Chuanxiong and Radix Angelicae Sinensis are added described 10 times of amount 70% ethanol for the first time, place extraction pot, keep 80 ℃ of insulation normal pressures to soak and extracted 2 hours, leach extracting solution, obtain first extracting solution, the solid filtering residue is stand-by.
Alternatively, when extracting the described second time, specifically:
In described solid filtering residue, add described 8 times of amount 70% ethanol, place extraction pot, keep 80 ℃ of insulation normal pressures to soak and extracted 1.5 hours, leach extracting solution, leach extracting solution, obtain second extracting solution and solid filtering residue.
Alternatively, solution is evaporated to nothing alcohol flavor, obtains extracting concentrate, specifically:
The maintenance vacuum ranges is 0.06-0.08Mpa, and solution is evaporated to does not have the alcohol flavor, obtains described extraction concentrate.
A kind of anti-stroke Pharmaceutical composition provided by the invention, it is by above-mentioned arbitrary preparation method of composition system.
A kind of above-mentioned Aggrenox provided by the invention method of preparation of compositions Aggrenox tablet, it is utilizing above-mentioned arbitrary preparation method to obtain also comprising after the described Pharmaceutical composition:
Get described pharmaceutical composition 197g, add microcrystalline Cellulose 190g, stir, granulate with 20 mesh sieves, in 60-65 ℃ of drying, the granule water content is dropped to till 5%, 16 mesh sieve granulate,
Add carboxymethyl starch sodium 6g, magnesium stearate 1.5g, mixing is crossed 100 mesh sieves, is sieved in the above-mentioned dried granule, abundant mixing, and tabletting namely gets described Aggrenox tablet.
Aggrenox tablet provided by the invention, it adopts the method for the preparation of above-mentioned Aggrenox tablet to make.
Therefore Pharmaceutical composition of the present invention can be widely used in preparation treatment and prevention of stroke, apoplexy sequela, vascular senile dementia, improve the medicine of new generation that is undermined functions such as brain tissue impairment because of cranial nerve due to the ischemia.Compare with prior art, it has following novelty and advance:
At first, from the compatibility of drugs aspect, this product is under the guidance of theory of Chinese medical science, to carry out compatibility by three flavor Chinese crude drugs, selects the Rhizoma Chuanxiong blood-activating and qi-promoting for use in the side, wind-expelling pain-stopping, Chinese angelica blood supplementing is invigorated blood circulation, the have one's ideas straightened out effect of refreshment of natural Broneolum Syntheticum, and three medicine compatibilities have activating blood circulation to dissipate blood stasis, the refreshment of having one's ideas straightened out, the effect of promoting of the circulation of QI and removing the obstruction in the collaterals.This product has avoided big compound recipe to go into the various anxiety of flavour of a drug number, has not only kept the advantage of Chinese medicine, and has demonstrated fully scientific and reasonable compatibility and the complementary characteristics of effect of modern Chinese medicine;
The second, from the drug effect aspect, through a large amount of pharmacological experiments preferably with checking, with the ratio proportioning combination of three flavor medical materials according to the best, realized the effect of complementary short, the Synergistic mutually between medicine, drug effect significantly increases;
The 3rd, pharmacodynamic study shows that it not only has clear and definite action site, play activating blood circulation to dissipate blood stasis, the effect of channels sootheing and network vessel quickening is more because this product has significant protective effect and unique characteristics to cranial nerve is impaired, as the anti-early stage apoplexy Chinese patent medicine kind that is used for neuroprotective, it is an initiative;
The 4th, this product adopts and is the conventional Chinese medicine material, under scientific compatibility, with its remarkable role in synergy, very little (each dose amounts to medical material not enough 1.5g at dose, only be equivalent to four of positive control drug TONGMAI KELI/once) situation under can play excellent curative, relatively have significant advantage efficient, with low cost with the market similar drug, have quite high pharmacoeconomics meaning.
The analysis of experiments that concrete drug effect is seen below in detail.
The specific embodiment
The invention provides the Pharmaceutical composition that a kind of extract by Chinese crude drug Rhizoma Chuanxiong, Radix Angelicae Sinensis and natural Broneolum Syntheticum form through a large amount of pharmacodynamic experiment preferred compositions; it is a kind of Chinese medicine preparation that has protection cerebrovascular, resisting cerebrovascular thrombosis, anti-cardiac-cerebral ischemia, improves therapeutic effect such as cerebrovascular permeability, is used for curing mainly ischemic cardio cerebrovascular diseases medicines such as suffering from acute stroke, convalescent period and sequela thereof, vascular senile dementia.
The present embodiment Pharmaceutical composition not only has activating blood circulation to dissipate blood stasis, and the effect of channels sootheing and network vessel quickening more because this product has tangible repair and unique characteristics to the impaired of cranial nerve function, as the anti-early stage apoplexy kind that is used for neuroprotective, is undoubtedly an initiative.
Simultaneously, the present invention is pure Chinese medicinal preparation, and the raw materials used medicinal herbs most in use that are have no side effect and untoward reaction.Following detailed will help further to understand the present invention.
Unless otherwise indicated, the main terms of this description is defined as follows:
Rhizoma Chuanxiong: the dry root that refers to samphire Rhizoma Chuanxiong Ligustcum chuanxiong hort.Has blood-activating and qi-promoting, the effect of wind-expelling pain-stopping.
Radix Angelicae Sinensis: the dry root that refers to umbelliferae angelica Angelica sinensis (Oliv.) Diels.Having enriches blood invigorates blood circulation, menstruction regulating and pain relieving, the effect of loosening bowel to relieve constipation.Be used for blood deficiency and yellow complexion, dizzy cardiopalmus, menoxenia, asthenia cold abdominalgia, dryness of the intestine constipation, rheumatic arthralgia etc.
Natural Broneolum Syntheticum: this product is that the fresh branch of canella Camphor tree Cinnamomum camphora (L.) Presl, leaf extract the crystallization of being processed into.Has the refreshment of having one's ideas straightened out, the effect of clearing away heat to alleviate pain.Be used for the treatment of the calentura coma, convulsion is fainted, apoplexy syncope due to accumulation of phlegm, frightened pain expectorant fan, sore throat toothache, aphtha carbuncle and ulcer, conjunctival congestion.
Medical active component provided by the invention has protection cerebrovascular, resisting cerebrovascular thrombosis, anti-cardiac-cerebral ischemia, improves effect such as cerebrovascular permeability, and the present invention is that the medical active component is extracted its effective ingredient from natural Chinese medicine Rhizoma Chuanxiong, Radix Angelicae Sinensis and natural Broneolum Syntheticum combines.
The weight proportion of used medical material is: 32 parts of Rhizoma Chuanxiongs, 32 parts of Radix Angelicae Sinensis, 1 part of natural Broneolum Syntheticum.This Pharmaceutical composition is prepared from after wherein effective ingredient and natural Broneolum Syntheticum merge through ethanol extraction by Chinese crude drug Rhizoma Chuanxiong, Radix Angelicae Sinensis.
The processing step of this Pharmaceutical composition mainly comprises the following aspects:
Step1, extract for the first time: crude drug Rhizoma Chuanxiong and Radix Angelicae Sinensis are added 10 times of amount 70% ethanol for the first time, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 2 hours, leaches extracting solution, obtains first extracting solution, and the solid filtering residue is stand-by.
Step2, extract for the second time: add 8 times of amount 70% ethanol in described solid filtering residue, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 1.5 hours, leaches extracting solution, leaches extracting solution, obtains second extracting solution and solid filtering residue.
Step3 mixes described first extracting solution and the extracting solution second time, is under the 60-70 ℃ of condition in temperature, mixed liquor is evaporated to nothing alcohol flavor, obtain extracting concentrate, the relative density of described concentrate is 1.10～1.30, and wherein said relative density records in the time of 60 ℃;
Step4 adds the natural Broneolum Syntheticum dissolving of pulverizing in described extraction concentrate, namely get described Pharmaceutical composition;
When making tablet, continue to comprise following steps:
Aforementioned pharmaceutical compositions is added in an amount of excipient, and tabletting namely gets tablet.
For more concrete, the inventor provides following optional embodiment:
Embodiment 1
The preparation technology of Pharmaceutical composition:
Get Rhizoma Chuanxiong, Radix Angelicae Sinensis (each 320g) places extraction pot, adds for the first time 10 times of amount 70% ethanol, is heated to boiling back (about 70 ℃), insulation was extracted 2 hours, leached extracting solution, obtained extracting solution for the first time, the solid filtering residue is stand-by;
Add for the second time 8 times of amount 70% ethanol, continue under 70 ℃, insulation was extracted 1.5 hours, leached extracting solution;
Merge extracted twice liquid, 60 ℃ of temperature, under the vacuum 0.06Mpa, the solution that mixes is concentrated into nothing alcohol flavor obtains extracting concentrate, relative density is 1.10～1.30(60 ℃), standby;
Natural Broneolum Syntheticum (10g) namely gets Pharmaceutical composition after adding the dissolving of said extracted concentrate.
The preparation technology of Pharmaceutical composition:
Get Rhizoma Chuanxiong, Radix Angelicae Sinensis (each 320g) places extraction pot, adds for the first time 10 times of amount 70% ethanol, is heated to boiling back (about 80 ℃), insulation was extracted 2 hours, leached extracting solution, obtained extracting solution for the first time, the solid filtering residue is stand-by;
Add for the second time 8 times of amount 70% ethanol, continue under 80 ℃, insulation was extracted 1.5 hours, leached extracting solution;
Merge extracted twice liquid, 65 ℃ of temperature, under the vacuum 0.07Mpa, the solution that mixes is concentrated into nothing alcohol flavor obtains extracting concentrate, relative density is 1.10～1.30(60 ℃), standby;
Natural Broneolum Syntheticum (10g) namely gets Pharmaceutical composition after adding the dissolving of said extracted concentrate.
Embodiment 3
The preparation technology of Pharmaceutical composition:
Get Rhizoma Chuanxiong, Radix Angelicae Sinensis (each 320g) places extraction pot, adds for the first time 10 times of amount 70% ethanol, is heated to boiling back (about 100 ℃), insulation was extracted 2 hours, leached extracting solution, obtained extracting solution for the first time, the solid filtering residue is stand-by;
Add for the second time 8 times of amount 70% ethanol, continue under 100 ℃, insulation was extracted 1.5 hours, leached extracting solution;
Merge extracted twice liquid, 70 ℃ of temperature, under the vacuum 0.08Mpa, the solution that mixes is concentrated into nothing alcohol flavor obtains extracting concentrate, relative density is 1.10～1.30(60 ℃), standby;
Natural Broneolum Syntheticum (10g) namely gets Pharmaceutical composition after adding the dissolving of said extracted concentrate.
Embodiment 4
Get the pharmaceutical composition 197g of embodiment 1,2,3 systems respectively, carry out following tablet producing technology respectively, obtain 3 kinds of tablets respectively.Technology is as follows:
In each pharmaceutical composition 197g, add microcrystalline Cellulose 190g, stir, granulate with 20 mesh sieves, 60-65 ℃ of drying (making the granule water content is about 5%), 16 mesh sieve granulate add carboxymethyl starch sodium 6g, magnesium stearate 1.5g, mixing, cross 100 mesh sieves, be sieved in the above-mentioned dried granule, fully mixing, tabletting, namely.
Embodiment 5
The preparation technology of Pharmaceutical composition:
Step1, Rhizoma Chuanxiong 300g, Radix Angelicae Sinensis 200g place extraction pot, add 8 times of amount 80% ethanol for the first time, are heated to boiling back (about 90 ℃) in extraction pot, and insulation was extracted 2 hours, leached extracting solution, obtained extracting solution for the first time, and the solid filtering residue is stand-by;
Step2 adds 6 times of amount 80% ethanol for the second time, continues under 90 ℃, and insulation was extracted 1.5 hours, obtained extracting solution for the second time; Add 6 times of amount 80% ethanol for the third time, continue under 90 ℃, insulation was extracted 1.0 hours, leached extracting solution;
Step3 merges three times extracting solution, at temperature 60-70 ℃, under the vacuum 0.06-0.08Mpa, solution is concentrated into nothing alcohol flavor obtains extracting concentrate, and relative density is 1.05～1.20(60 ℃) standby;
Step4, natural Broneolum Syntheticum (5g) namely get Pharmaceutical composition after adding the dissolving of said extracted thing.
Embodiment 6
Get the pharmaceutical composition 180g that embodiment 5 obtains, add microcrystalline Cellulose 160g, stir, granulate with 20 mesh sieves, 60-65 ℃ of drying (making the granule water content is about 4%), 16 mesh sieve granulate add carboxymethyl starch sodium 5g, magnesium stearate 1.2g, mixing, cross 100 mesh sieves, be sieved in the above-mentioned dried granule, fully mixing, tabletting, namely.
For beneficial effect of the present invention is described, the inventor provides following test data respectively:
First: Rhizoma Chuanxiong, Radix Angelicae Sinensis ethanol extraction test relative analysis test
The inventor is in the process of the test of carrying out pharmaceutical composition of the present invention, active drug composition to Rhizoma Chuanxiong of the present invention, Radix Angelicae Sinensis: (ferulic acid and ligustilide all are the active drug branches in Radix Angelicae Sinensis, the Rhizoma Chuanxiong for ferulic acid and ligustilide, be the important parameter of weighing Radix Angelicae Sinensis, Rhizoma Chuanxiong quality) extraction process carried out deep research, extraction conditions (temperature, pressure) to ethanol secondary ethanol extraction has carried out nearly 2 years extraction analysis of experiments, specifically tests as follows:
Test apparatus:High performance liquid chromatograph (Tianjin, island LC-10ATvp, UV-detector SPD-10AVP), AE240 type electronic analytical balance, thermostat water bath.
Test operation:Get Rhizoma Chuanxiong, each 100g of Radix Angelicae Sinensis, add 2000ml70% ethanol and under different temperatures, carry out normal pressure extraction 2 hours respectively, filter after extracting, precision is measured 3ml from filtrate, be settled to 10ml with 70% ethanol, filter, as need testing solution, the content of ferulic acid and ligustilide in the mensuration extraction solution changes as shown in Figure 1 respectively;
The ferulic acid reference substance:Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides, lot number: 110773-200611, ligustilide (prepare in the supercritical extraction volatile oil, purity is more than 98%).Acetonitrile is chromatographically pure, and all the other reagent are analytical pure;
The ferulic acid testing conditions:Chromatographic condition is 150 * 4.6mmC18 post, mobile phase: methanol: water: acetic acid (35: 65: 1) mobile phase, 320nm wavelength, 1ml/min flow velocity, 30 ℃ of column temperatures;
The ligustilide testing conditions:Chromatographic condition is 150 * 4.6mmC18 post, mobile phase: methanol 20.1% trifluoroacetic acid aqueous solution (67: 33) adopts gradient elution; Detect wavelength: 284nm; Flow velocity: 1ml/min; Column temperature: 30 ℃.
As seen from Figure 1, discovery is in the ethanol extraction technology of Rhizoma Chuanxiong, Radix Angelicae Sinensis, the content of ferulic acid and ligustilide is along with the rising of extracting temperature in the extracting solution, but in the time of 80 ℃, unexpectedly present critical sudden change, the content of ligustilide reaches peak in the time of 80 ℃, and the content of ligustilide descends gradually after 80 ℃.
Second: compositions pharmacological evaluation compare of analysis:
Further specify drug effect of the present invention with pharmacological evaluation below:
Pharmaceutical composition: I(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=24:24:1)
Pharmaceutical composition: II(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=28:28:1)
Pharmaceutical composition: III(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=32:32:1)
Pharmaceutical composition: IV(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=36:36:1)
Pharmaceutical composition: V(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=40:40:1)
Pharmaceutical composition: VI(Rhizoma Chuanxiong: Radix Angelicae Sinensis: natural Broneolum Syntheticum=44:44:1)
Positive control drug: TONGMAI KELI
1, rat cerebral ischemia model test
Get 60 of Wistar rats, body weight 300～350g, male, take out 6 at random in contrast, other rats prepare cerebral ischemic model.The rat of preparation cerebral ischemic model, with 10% chloral hydrate 10ml/kg intraperitoneal injection of anesthesia, lie on the back and be fixed in the Mus platform, cervical region medisection, separate right carotid and external carotid artery and use the silk thread ligation, cut an osculum in the common carotid artery crotch, insert the nylon wire be fired into round end in advance and insert internal carotid artery, fixing nylon wire when meeting obstructions, insertion depth is about 18mm, suture muscles, skin successively then, lumbar injection penicillin 200,000 units, for three days on end; Control rats is operated by preparation cerebral ischemic model rat, but does not insert nylon wire.After treating that rat is clear-headed, get 54 of cerebral ischemic model rats, be divided into 9 groups by function of nervous system's scoring stratified random; Matched group and model group are given pure water, and other group rats are given this product different formulations ratio and positive control drug respectively, gastric infusion, and administration is 7 days altogether.
1.1 pharmaceutical composition is to the influence of rat cerebral ischemia model function of nervous system scoring
The dosage of pharmaceutical composition I, II, III, IV, V, VI: 0.76g/kg;
The dosage of positive control drug: 2.7g/kg
Table one: each pharmaceutical composition is to the influence of rat cerebral ischemia model function of nervous system scoring
N=6),
In Table 1,
Function of nervous system's scoring is compared before and after representing each medicine composite for curing, and n is rat number of each group rat test group.Compared respectively with matched group and model group by the medicine experimental group, calculate its P value, wherein parameter P is index parameter the most frequently used in the statistics, and both difference that the P value refers to mutual comparison is by the probability size due to the opportunity.
In Table 1, the group of mark (++), itself and matched group compare p＜0.05; Mark (
*) group, it is compared with model group, p＜0.05; Mark (
*) group, it is compared with model group, p＜0.01.
By table one as seen, before the administration, each organizes the cerebral ischemic model rat and control rats compares, and function of nervous system's scoring significantly increases; Each is organized does not relatively have significant difference between the cerebral ischemic model rat; After the administration 5 days, each organizes cerebral ischemic model rat function of nervous system scoring than significantly descending before the administration, and compares remarkable increase; Compare with model, pharmaceutical composition III significantly reduces the scoring of rats with cerebral ischemia function of nervous system, is better than positive control drug greatly; And significantly be better than other components, and it divides identical but different respectively the organizing in the pharmaceutical composition of each components contents at medicine, than higher IV-VI, its medication effect obtains beyond thought drug effect at pharmaceutical composition III place with respect to the lower pharmaceutical composition I-II of set of dispense and set of dispense for it.
1.2 pharmaceutical composition is to the influence of rat cerebral ischemia model cerebral tissue ischemic areas
The dosage of pharmaceutical composition I, II, III, IV, V, VI: 0.76g/kg;
The dosage of positive control drug: 2.7g/kg.
Table two: pharmaceutical composition is to the influence of rat cerebral ischemia model cerebral tissue ischemic areas
N=6)
Wherein,
Represent each medicine composite for curing hindbrain ischemic areas (%), n is the rat number of each group rat test group.Compared respectively with matched group and model group by the medicine experimental group, calculate its P value, wherein parameter P is index parameter the most frequently used in the statistics, and both difference that the P value refers to mutual comparison is by the probability size due to the opportunity.
In table two:
The group of mark (++), itself and matched group compare p＜0.05;
Mark (
*) group, it is compared with model group, p＜0.05;
Mark (
*) group, it is compared with model group, p＜0.01.
According to table two as seen: after the administration, and compare, the cerebral ischemia area of model group rat significantly increases; Compare with model group, pharmaceutical composition II, III, IV, V and positive control drug all obviously reduce the rat cerebral ischemia area, pharmaceutical composition III it divide identical but different respectively the organizing in the pharmaceutical composition of each components contents at medicine, than higher IV-VI, its medication effect (at the cerebral ischemia area that reduces rat) obtains beyond thought drug effect at pharmaceutical composition III place with respect to the lower pharmaceutical composition I-II of set of dispense and set of dispense for it.
Experimental result shows that pharmaceutical composition III has the most significant pharmacodynamics effect than other proportionings, be outstanding optimum formula combination, and its each composition weight proportioning is the desirable unexpected result's of getting proportioning.
Second: the test of anesthesia Beagle dog cerebral blood flow
Get 30 of Beagle dogs, body weight 8～10kg, female, hero half and half is divided into 5 groups by sex body weight stratified random.
Matched group is given pure water, and other groups give basic, normal, high dosage (0.11,0.23,0.45g/kg) and the TONGMAI KELI 2.7g/kg of pharmaceutical composition III, oral administration, common administration 7 days respectively.Before the last administration, with pentobarbital sodium 30mg/kg intravenous injection anesthesia, lie on the back in operating-table, separate femoral vein, the intubate transfusion; Separate femoral artery, insert the biological pressure transducer conduit of PT-100 type, insert ML224 bridge signal amplifier; Cervical region center skin is cut in the cervical region cropping, separates the flesh layer, finds out common carotid artery, upwards isolates internal carotid artery, puts FF030T type electromagnetic flowmeter probe, with MFV-1200 type electromagnetism blood flow instrumentation ICAF amount; Extremity thrust pin type electrode, with 6511 electrocardiographs record II lead electrocardiogram; Above-mentioned signal is all analyzed with PowerLab/8e polygraph record and with Chart4.2.3 software.After These parameters was stable, medicine diluted through the stomach tube administration with pure water.
Wherein above-mentioned dosage g/kg represents: every kilogram of administration body administered agents weight.
2.1 the influence of the Beagle dog of pharmaceutical composition III brain vessel blood amount
The pharmaceutical composition III that obtains and TONGMAI KELI influence contrast figure as shown in Figure 2 to Beagle dog brain vessel blood amount.
As seen from Figure 2, the brain vessel blood amount increases after the contrast dog administration, reaches peak value during about 30min, slowly descends subsequently, descends decline 32% when descending 19%, 180min during 120min to 60min fast.The brain vessel blood amount increases after the administration of the middle and high dosage group of pharmaceutical composition III, reaches peak value during about 15min, slowly descends subsequently, and blood flow keeps stable to the 60min, blood flow decline about 10%, and be maintained until 180min; With compare, middle dosage group (0.23g/kg), high dose group (0.45g/kg) and positive control drug (2.7g/kg) obviously reduce the variation of dog brain vessel blood amount, and pharmaceutical composition is better than positive control drug; Low dose group (0.11g/kg) does not have obvious influence (Fig. 2) to cerebrovascular flow.
In Fig. 2:
Curve
The influence of Beagle dog brain vessel blood amount in the expression matched group,
Curve
The influence of Beagle dog brain vessel blood amount in the expression pharmaceutical composition III low dose group,
Curve
The influence of Beagle dog brain vessel blood amount in the dosage group among the pharmaceutical composition III,
The influence of Beagle dog brain vessel blood amount in the pharmaceutical composition III high dose group,
Mark (
*) group, this group is compared with matched group, p＜0.05,
Mark (
*) group, this group is compared with matched group, p＜0.01.
2.2 the influence of the Beagle dog of pharmaceutical composition III cerebrovascular cerebral vascular resistance
The influence of the Beagle dog of the pharmaceutical composition III cerebral vascular resistance that obtains as shown in Figure 3.
As seen from Figure 3, cerebral vascular resistance descends slightly after the administration of contrast dog, and fast rise behind about 30min rises 61% when rising 28%, 180min during 120min.In after the dosage group (0.23g/kg), high dose group (0.45g/kg) administration cerebral vascular resistance descend earlier, slowly rising rises 19% and 15% respectively behind about 30min during to 120min, rises 14% and 24% respectively to 180min; With compare, 180min after the administration, middle dosage group (0.23g/kg), high dose group (0.45g/kg) and positive control drug (2.7g/kg) make the change of dog cerebral vascular resistance obviously reduce (Fig. 3).
In Fig. 3:
Curve
The influence of Beagle dog cerebral vascular resistance in the expression matched group;
Curve
The influence of Beagle dog cerebral vascular resistance in the pharmaceutical composition III low dose group;
Curve
The influence of Beagle dog cerebral vascular resistance in the dosage group among the pharmaceutical composition III;
Curve
The influence of Beagle dog cerebral vascular resistance in the pharmaceutical composition III high dose group;
Curve
The influence of Beagle dog cerebral vascular resistance in the positive control drug (TONGMAI KELI);
Mark (
*) group, this group compared with the control, p＜0.05,
Mark (
*) group, this group compared with the control, p＜0.01.
2.3 the influence of the Beagle dog of pharmaceutical composition III blood pressure
Obtain the experimental data shown in the table three, four, five respectively.
Table three: the influence of the Beagle dog of pharmaceutical composition III systolic arterial pressure
N=6)
In table three,
Represent each medicine composite for curing front and back dog systolic arterial pressure changing value, n is rat number of each group rat test group.
Table four: the influence that the Beagle dog of pharmaceutical composition III auterial diastole is pressed
N=6)
In table four,
Represent each medicine composite for curing hindbrain ischemic areas (%), n is the rat number of each group rat test group.Compared respectively with matched group and model group by the medicine experimental group, calculate its P value, wherein parameter P is index parameter the most frequently used in the statistics, and both difference that the P value refers to mutual comparison is by the probability size due to the opportunity.
In table four:
Mark (
*) group, this group compared with the control, p＜0.05;
Mark (
*) group, this group compared with the control, p＜0.01.
Table five: the easypro network sheet of refreshment is to the influence of Beagle dog mean arterial pressure
N=6)
In table five,
Represent each medicine composite for curing front and back dog mean arterial pressure changing value, n is rat number of each group rat test group.Compared with matched group by the medicine experimental group, calculate its P value.
In table five: mark (
*) group, this group compared with the control, p＜0.05;
Mark (
*) group, this group compared with the control, p＜0.01.
The comprehensive drug conclusion:
Show composition I by above-mentioned pharmacodynamic experiment result, II, III, IV, V, VI all can alleviate the rats with cerebral ischemia delayed ischemic neurological deficits, reduce rat cerebral tissue's damaged area, to with pharmaceutical composition III effect purpose less than the best, this proportioning drug synergism is the most outstanding, at consumption only under the situation of positive contrast medicine about 1/4, every treatment index all is better than or is equivalent to positive control drug, and the scoring of rats with cerebral ischemia function of nervous system is significantly reduced, increase cerebrovascular flow, reduce cerebral vascular resistance, have the tangible effect that improves cranial nerve disappearance function and anti-cerebral tissue ischemic injuries.
Claims (7)
1. an Aggrenox preparation method of composition is characterized in that, comprising:
Extract for the first time: crude drug Rhizoma Chuanxiong and Radix Angelicae Sinensis are added 10 times of amount 70% ethanol for the first time, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 2 hours, leaches extracting solution, obtains first extracting solution, and the solid filtering residue is stand-by;
Extract for the second time: add 8 times of amount 70% ethanol in described solid filtering residue, place extraction pot, keep arbitrary temperature of 70-100 ℃, insulation is soaked and was extracted 1.5 hours, leaches extracting solution, leaches extracting solution, obtains second extracting solution and solid filtering residue;
Mix described first extracting solution and the extracting solution second time, be under the 60-70 ℃ of condition in temperature, mixed liquor is evaporated to does not have the alcohol flavor, obtains extracting concentrate, the relative density of described concentrate is 1.10～1.30, and wherein said relative density records in the time of 60 ℃;
In described extraction concentrate, add the natural Broneolum Syntheticum dissolving of pulverizing, namely get described Pharmaceutical composition;
The weight proportion of described Rhizoma Chuanxiong, Radix Angelicae Sinensis, natural Broneolum Syntheticum is: 32:32:1.
2. Aggrenox preparation method of composition according to claim 1 is characterized in that,
When extracting the described first time, specifically:
Described Rhizoma Chuanxiong and Radix Angelicae Sinensis are added described 10 times of amount 70% ethanol for the first time, place extraction pot, keep 80 ℃ of insulation normal pressures to soak and extracted 2 hours, leach extracting solution, obtain first extracting solution, the solid filtering residue is stand-by.
3. Aggrenox preparation method of composition according to claim 1 is characterized in that,
When extracting the described second time, specifically:
In described solid filtering residue, add described 8 times of amount 70% ethanol, place extraction pot, keep 80 ℃ of insulation normal pressures to soak and extracted 1.5 hours, leach extracting solution, leach extracting solution, obtain second extracting solution and solid filtering residue.
4. Aggrenox preparation method of composition according to claim 1 and 2 is characterized in that,
Solution is evaporated to nothing alcohol flavor, obtains extracting concentrate, specifically:
The maintenance vacuum ranges is 0.06-0.08Mpa, and solution is evaporated to does not have the alcohol flavor, obtains described extraction concentrate.
5. anti-stroke Pharmaceutical composition that the arbitrary described method of utilizing claim 1 to 3 makes.
6. a method that adopts the described preparation of compositions Aggrenox of claim 5 tablet is characterized in that,
After obtaining described Pharmaceutical composition, also comprise:
Get described pharmaceutical composition 197g, add microcrystalline Cellulose 190g, stir, granulate with 20 mesh sieves, in 60-65 ℃ of drying, the granule water content is dropped to till 5%, 16 mesh sieve granulate,
Add carboxymethyl starch sodium 6g, magnesium stearate 1.5g, mixing is crossed 100 mesh sieves, is sieved in the above-mentioned dried granule, abundant mixing, and tabletting namely gets described Aggrenox tablet.
7. Aggrenox tablet that utilizes the described method of claim 6 to make.
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Address after: 410000 No. 7, Huan Lian Road, Changsha hi tech Zone, Changsha, Hunan Patentee after: Hunan 100041 cottage pharmaceutical Limited by Share Ltd Address before: Wantang Village, Laokou Town, Zhuzhou City, Hunan Province (Laokou Industrial Park) Patentee before: Hunan Tianjicaotang Pharmaceutical Co., Ltd. |