CN1857352A - Notoginseng medicine composition for treating cardiac and cerebral vascular diseases - Google Patents
Notoginseng medicine composition for treating cardiac and cerebral vascular diseases Download PDFInfo
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Abstract
The present invention relates to a kind of total arasaponin composition, which has the active component of total arasaponin comprising arasaponin R1, ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 not less than 55.0 wt% and ginsenoside Rd not more than 2.5 wt%. The total arasaponin composition is prepared into injection, powder for injection, enteric coated tablet, bolus, medicine powder and other preparation forms. The medicine of the present invention has the functions of promoting blood circulation to disperse blood clots and activating collateral flow, and is used in treating blood stasis to block collateral channels, apoplexy, hemiplegia and other cardiac and cerebral vascular diseases.
Description
Technical field
The present invention relates to a kind of Radix Notoginseng total arasaponins active ingredient by the Radix Notoginseng extraction for the treatment of cardiovascular and cerebrovascular disease, specifically, the invention provides a kind of Radix Notoginseng total arasaponins active ingredient compositions and application thereof with treatment cardio-cerebrovascular diseases.
Background technology
Cardiovascular and cerebrovascular disease is one of three big diseases, according to theory of Chinese medical science, and central retinal vein occlusion, interior ophthalmorrhagia disease, hyphema, cerebrovascular disease such as cerebral thrombosis and sequela thereof etc. belong to traditional Chinese medical science blood stasis and go out the blood disorder category.The Radix Notoginseng total arasaponins ejection preparation that is used for the treatment of cardiovascular and cerebrovascular disease at present has: panax notoginseng saponins for injection, XUESAITONG ZHUSHEYE, injection XUESHUANTONG, XUESHUANTONG ZHUSHEYE.
Radix Notoginseng is a kind of unique multi-functional Chinese crude drug, and these effects all have independence, collects some important biomolecule activity, can bring into play some kinds of clinical function in a medicine.In these all functions, the function that has is opposed, contradiction.Use Radix Notoginseng to extract the Radix Notoginseng total arasaponins ejection preparation of making as raw material, composition is also very complicated, still fail real clear and definite concrete what composition at present and play main therapeutical effect, the poisonous meeting of what composition causes untoward reaction, and the mechanism of action between the composition is also had no talent and done comprehensive research.Except that the composition of medicine own, the organic solvent that leaching process uses etc. all can cause untoward reaction, and impurity is difficult to eliminate in the preparation process in addition, also may be the reason that untoward reaction takes place.Many untoward reaction have taken place in Radix Notoginseng total arasaponins ejection preparation since clinical practice.The untoward reaction statistical result showed that Guangxi Zhuang Autonomous Region adverse drug reaction monitoring center of food and medicine Surveillance Authority provides: " Chinese biological medical science literary composition data base " (Institute of Medical Information of the Chinese Academy of Medical Sciences) 1978-2004 documents and materials in May by retrieval, there are 4 pieces of XUESHUANTONG ZHUSHEYE to cause anaphylactoid report, the report of 9 pieces of XUESAITONG ejection preparations untoward reaction, the injection XUESHUANTONG finds no untoward reaction.The untoward reaction result of above-mentioned retrieval only accounts for a few part in the actual generation untoward reaction, because domestic present untoward reaction monitoring system also is not very perfect, most untoward reaction are not reported or reported by the untoward reaction monitoring system.The applicant begins the production XUESHUANTONG ZHUSHEYE in nineteen eighty-three, and this kind adverse reaction rate was about 2% in nearly 3 years.
According to national drug untoward reaction centre retrieves result:
The main adverse reaction of using the XUESHUANTONG ZHUSHEYE appearance has: 1, whole skin pruritus, appearance redness or rose-colored maculopapule.2, feel cold, whole body shiver with cold, fervescence.3, redness appears in skin, pain is obvious, burn feeling is arranged, the skin color purpling.
Use XUESAITONG ZHUSHEYE and panax notoginseng saponins for injection and mainly contain following three kinds of untoward reaction: 1, severe allergic reaction, shiver with cold, heating, uncomfortable in chest, asthma etc. appear in the patient, and bring out acute left heart failure.2, hematuria appears.3, allergic rash occurs, the speckle that takes on a red color, pimple have dizzy symptom.4, occur cardiopalmus, breathe hard, uncomfortable in chest, pale complexion, dizziness, blurred vision, dry mouth and parching tongue.5, the prominent sense of patient numb limbs and tense tendons is unable, shiver with cold, pale complexion.6, severe headache appears in patient, dizziness, profuse sweating, symptom such as nervous.
Use the injection XUESHUANTONG untoward reaction similar also to occur to above-mentioned symptom.
Summary of the invention
Through the applicant to XUESHUANTONG ZHUSHEYE produce untoward reaction more batch carry out analysis-by-synthesis, find that the undue toxicity that untoward reaction and Radix Notoginseng total arasaponins ejection preparation take place has direct relation, the product batches that adverse reaction rate is high more, the undue toxicity is relatively large.XUESHUANTONG ZHUSHEYE undue toxicity is big more, and the number of times that the untoward reaction feedback occurs is also many more.Through analysis that Radix Notoginseng total arasaponins ejection preparation on the market is tested, the producer of more untoward reaction report is arranged, the undue toxicity is relatively large for this product.
The component that makes the Radix Notoginseng total arasaponins ejection preparation produce untoward reaction (undue toxicity) is screened,, found the component that mainly causes untoward reaction, at Panax Notoginseng saponin R through test for many years
1, the ginsenoside Rg
1, ginsenoside Re, ginsenoside Rb
1In the high-efficient liquid phase chromatogram of ginsenoside Rd's assay, these impurity appearance times that mainly cause untoward reaction are between 36 minutes-56 minutes, ginsenoside Rd's appearance time was about 46 minutes, because the physicochemical property and the ginsenoside Rd of these impurity are close, when removing this impurity composition, can remove in the lump together with the ginsenoside Rd, therefore, the ginsenoside Rd can be used as the above-mentioned impurity content index that causes untoward reaction, ginsenoside Rd's content height, represented impurity component content also higher, otherwise, then lower.(attached: high-efficient liquid phase chromatogram.See accompanying drawing 1,2,3)
According to present result of study, the ginsenoside Rd can anticancer growth, morely be used as a kind of Chinese medicine extract and use with antitumor action.Its pharmacological action is: improve the generation level of NK cytoactive and interferon gamma, the enhance immunity function strengthens the mice tumour inhibiting rate, and it is heavy to alleviate tumor; Can promote the T cell proliferation, improve the activity of natural killer cell (NK), thus human body immunity improving power, and have the effect of the adrenal cortex of promotion hormone secretion.Therefore, the ginsenoside Rd there is no obvious pharmacological action on the treatment cardiovascular and cerebrovascular disease, so remove the ginsenoside Rd to the not obviously influence of therapeutic effect of the present invention at treating cardiac and cerebral vascular diseases.
XUESAITONG ZHUSHEYE and panax notoginseng saponins for injection quality standard regulation are got this product, add the chlorination sodium injection and make the solution that contains Radix Notoginseng total arasaponins 5.0mg among every 1ml; XUESHUANTONG ZHUSHEYE quality standard regulation, it is an amount of to get this product, adds sterile saline and makes every 1ml and contain 7.0mg (with the ginsenoside Rg
1Meter) solution (conversion is about every 1ml and contains Radix Notoginseng total arasaponins 10.0mg by weight); Injection XUESHUANTONG quality standard regulation is got this product, adds the chlorination sodium injection and makes the solution that every 1ml contains Radix Notoginseng total arasaponins 8.0mg; Get above sample and carry out abnormal toxicity test.
By " 2005 editions undue toxicity's inspection techniques of Chinese pharmacopoeia are carried out abnormal toxicity test to the present invention, panax notoginseng saponins for injection, XUESHUANTONG ZHUSHEYE, XUESAITONG ZHUSHEYE.When above four kind concentration are every ml solution when containing Radix Notoginseng total arasaponins and being no more than 10mg, it is qualified that the abnormal toxicity test result is; Concentration is every ml solution when containing Radix Notoginseng total arasaponins 10mg to 15mg, and the abnormal toxicity test result is that part is qualified; When concentration is every ml solution when containing Radix Notoginseng total arasaponins and surpassing 15mg, abnormal toxicity test result only of the present invention is qualified, and abnormal toxicity test result of the present invention can reach 29mg.
Undue toxicity's index is more little, shows that to be subjected to reagent thing toxicity low more.As in above-mentioned test, when the result all guarantees when qualified, under the identical prerequisite of administration volume, the administration concentration that can bear is high more, the toxicity that shows medicine is low more, more than the toxicity of several Radix Notoginseng total arasaponins ejection preparations be arranged as from low to high: the present invention, injection XUESHUANTONG, panax notoginseng saponins for injection, XUESHUANTONG ZHUSHEYE, XUESAITONG ZHUSHEYE.
In conjunction with the experience of my company's production XUESHUANTONG ZHUSHEYE for many years, untoward reaction information and product practice examining result take place in statistics feedback, can know and see: take place untoward reaction batch, the undue toxicity is how below 12mg/ml.
The many more product batches of untoward reaction feedback number of times occur, correspondingly in preparation check out that ginsenoside Rd's content is higher relatively, and undue toxicity's index is also higher relatively.
We think, make Radix Notoginseng total arasaponins ejection preparation undue toxicity cause of increased with clinical in cause that the reason of untoward reaction is identical, and ginsenoside Rd's content relation in direct ratio in undue toxicity's (acute toxicity) and the arasaponin.Therefore, ginsenoside Rd's content and adverse reaction rate relation also in direct ratio in the Radix Notoginseng total arasaponins ejection preparation.When using high effective liquid chromatography for measuring arasaponin composition, find, in high-efficient liquid phase chromatogram, some not clear composition about the ginsenoside Rd peak, these compositions do not have in the pseudo-ginseng high-efficient liquid phase chromatogram.The ginsenoside Rd accounts for 4% of content of the total saponins in radix notoginseng at the content of pseudo-ginseng, accounts for the 0.2-0.4% of pseudo-ginseng weight.Pseudo-ginseng as not rigorous to some process control in the process of manufacture, can produce or bring into some by-products (being above-mentioned mentioned " not clear composition ") through production and processing, and the existence of these compositions is the main causes that cause untoward reaction.(attached: the pseudo-ginseng high-efficient liquid phase chromatogram.See accompanying drawing 4,5,6)
Prove through drug efficacy study, studies on acute toxicity and clinical statistics, remove this impurity composition after, compare with other Radix Notoginseng total arasaponins ejection preparations, drug effect of the present invention is suitable, but acute toxicity, undue toxicity significantly reduce, adverse reaction rate also greatly descends thereupon.
The composition of existing Radix Notoginseng total arasaponins injection has obviously differently on the present invention and the market, has kept Panax Notoginseng saponin R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1The isoreactivity composition, and remove operation at other impurity that with ginsenoside Rd are feature, controlled the toxicity of this Radix Notoginseng total arasaponins active ingredient compositions effectively, and drug effect keeps not reducing.Described Radix Notoginseng total arasaponins active ingredient compositions is to extract Radix Notoginseng total arasaponins in Radix Notoginseng, controls in the strict extract ginsenoside Rd's content less than 2.5%.
According to the national drug quality standard of existing Radix Notoginseng total arasaponins injection, different Radix Notoginseng total arasaponins injections are to Panax Notoginseng saponin R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1The requirement of isoreactivity composition is only slightly variant, and the injection XUESHUANTONG contains Panax Notoginseng saponin R
1Should be not less than 2.0%, the ginsenoside Rg
1Should be not less than 28.0%, ginsenoside Rb
1Should be not less than 25.0%, above three's addition should be not less than 55.0%, the ginsenoside Re is not made content requirement; Panax notoginseng saponins for injection contains Panax Notoginseng saponin R
1Should be 5.0-15.0%, the ginsenoside Rg
1Should be 25.0-45.0%, ginsenoside Rb
1Answer 30.0-40.0%, above three's addition should be not less than 65.0%, the ginsenoside Re is not made content requirement; XUESAITONG ZHUSHEYE contains Panax Notoginseng saponin R
1Should be not less than 5.0%, the ginsenoside Rg
1Should be not less than 20.0%, ginsenoside Rb
1Should be not less than 30.0%, above three's addition should be not less than 60.0%, the ginsenoside Re is not made content requirement; XUESHUANTONG ZHUSHEYE contains Radix Notoginseng total arasaponins with the ginsenoside Rg
1Meter must not be less than 60.0% (colorimetric method for determining).Measure with high-efficient liquid phase technique, contain the ginsenoside Rg approximately respectively
125%, ginsenoside Rb
121%, Panax Notoginseng saponin R
15%, the ginsenoside Re 4%, above addition about 55.0%).
By above-mentioned standard content regulation as can be known, Panax Notoginseng saponin R
1Minimum content is 2.0%, the ginsenoside Rg
1Minimum content is 20.0%, ginsenoside Rb
1Minimum content is 25.0%, and ginsenoside Re's actual measurement is about about 4.0%, and promptly above-mentioned several component total contents reach more than 51.0%, just meet the minimum requirements of Radix Notoginseng total arasaponins injection.The inventor is through concentrating on studies for many years, the technology of the notoginseng total saponin compounds of the preparation treatment cardio-cerebrovascular diseases that exploitation makes new advances, and the Radix Notoginseng total arasaponins active component for preparing not only meets above-mentioned requirements, and, Panax Notoginseng saponin R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Total amount be not less than 55%, and in this active ingredient compositions ginsenoside Rd's content less than 2.5%.
Therefore, the purpose of this invention is to provide a kind of Radix Notoginseng total arasaponins active ingredient compositions for the treatment of cardio-cerebrovascular diseases;
Another object of the present invention has provided this Radix Notoginseng total arasaponins active ingredient method for compositions of a kind of preparation.
Because the preparation technology of producer when actual production of each Radix Notoginseng total arasaponins ejection preparation has nothing in common with each other, so different Radix Notoginseng total arasaponins ejection preparations, containing with ginsenoside Rd is that the impurity content of feature is not quite similar, and makes the patient be prone to untoward reaction, serious even life that threaten the patient.Ginsenoside Rd's content is controlled at below 2.5% in the arasaponin injection among the present invention, can guarantee to remove the impurity that causes untoward reaction to greatest extent, has reduced the undue toxicity of medicine, alleviated incidence rate of adverse reaction, and drug effect remains unchanged.
The invention discloses a kind of Radix Notoginseng total arasaponins active ingredient composition and method of making the same that is used for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that active component is made up of Radix Notoginseng total arasaponins, wherein Panax Notoginseng saponin R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Gross weight be not less than 55% of active component gross weight, preferred 65%, more preferably 80%, and ginsenoside Rd's content must not surpass 2.5% of active component gross weight, preferably 2.0% of active component gross weight must not be surpassed, more preferably 1.0% of active component gross weight must not be surpassed.
The preferred embodiment of the invention is the ginsenoside R in the active component wherein
1Content is 8%～15%, the ginsenoside Rg
1Content is 35%～50%, ginsenoside Re's content is 3%～10%, ginsenoside Rb
1Content is 20%～35%, and ginsenoside R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1The content summation be not less than 55%, the ginsenoside Rd is less than 2.5%;
Preferably, the content of described active ingredient composition is: ginsenoside R
19%～14%, ginsenoside Rg
135%～50%, ginsenoside Re 4%～8%, ginsenoside Rb
125%～35%, and ginsenoside R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Summation be not less than 65%, the ginsenoside Rd is less than 2.0%:
More preferably, the content of described active ingredient composition is: ginsenoside R
110%～13%, ginsenoside Rg
136%～46%, ginsenoside Re 5%～8%, ginsenoside Rb
126%～33%, and ginsenoside R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Summation be not less than 80%, the ginsenoside Rd
1Less than 1.0%.
The dosage form of Radix Notoginseng total arasaponins active ingredient compositions of the present invention can be made various dosage forms, as make injection, powder ampoule agent for injection, freeze-dried powder injection, tablet, pill, powder, granule, mixture, syrup, capsule, drop pill preparation are preferably made injection, freeze-dried powder injection.
Below be the crude drug source of Chinese medicine preparation of the present invention:
Radix Notoginseng: be the dry root of Araliaceae Panax notoginseng (Burk.) F.H.Chen.
The invention also discloses the described Radix Notoginseng total arasaponins active ingredient of a kind of preparation method for compositions, it comprises the steps:
(1) get Radix Notoginseng powder and be broken into coarse powder 1000g, adding volume ratio is 5-30 times, the ethanol of preferred 8 times 45-95%, and preferred 60% ethanol 8000ml extracted 0.5～10 hour, and preferred 3 hours, collect extracting solution, filter.
(2) get filtrate recycling ethanol to there not being the alcohol flavor, add water and make the solution that every 1ml contains the 0.5g crude drug.
(3) solution is by the absorption of D type macroporous resin column, mixed liquor with ethanol-water carries out gradient elution, flow velocity, (4.5BV/h the per hour multiple of resin volume), concentration of alcohol progressively is adjusted to 95% by 5% in the eluent, collects to contain concentration of alcohol and (leading and containing Panax Notoginseng saponin R to the eluent below 70% 30% or more
1, the ginsenoside Rg
1With ginsenoside Rb
1, composition such as ginsenoside Re eluent), discard and contain the eluent (contain with ginsenoside Rd be other impurity component eluents of feature) of concentration of alcohol beyond 30% to 70%, decompression and solvent recovery below 65 ℃ also is concentrated into the clear paste that relative density is 1.10～1.20 (60 ℃), and cold drying gets Radix Notoginseng total arasaponins active ingredient compositions.
(4) with Radix Notoginseng total arasaponins active ingredient compositions according to the conventional method in the pharmaceutical field, make various preparations.
Each component content is about in the Radix Notoginseng total arasaponins active ingredient compositions that said process obtains: Panax Notoginseng saponin R
1Be 10.6%, the ginsenoside Rg
1Be 42.7%, the ginsenoside Re is 4.3%, ginsenoside Rb
1Be 26.5%, more than four composition total amounts be 84.1%; The ginsenoside Rd is 0.5%.
The present invention treats the Radix Notoginseng total arasaponins active ingredient compositions of cardiovascular and cerebrovascular disease and compares with other Radix Notoginseng total arasaponins ejection preparations, and drug effect is suitable, proves by following pharmacology or pharmacodynamic experiment.
Radix Notoginseng total arasaponins ejection preparation main pharmacodynamics effect comparative test research
One, to the influence of focal cerebral ischemia in rats
Summary application focal cerebral ischemia in rats model and myocardial infarction and ischemia model, comparative study the pharmacological action of the present invention and XUESHUANTONG ZHUSHEYE.PRELIMINARY RESULTS shows: two kinds of preparations all can obviously improve the cerebral infarction scope behind animal brain infraction back nervous symptoms, the focal cerebral ischemia, increase the SOD vigor, the experimental rat focal cerebral ischemia is had therapeutical effect, and the present invention is being better than two preparations in addition aspect the reduction Content of MDA; Simultaneously, two preparations also can obviously alleviate the myocardial infarction degree, dwindle infarction size, and myocardial ischemia is improved significantly, and the present invention and can reduce Serum LDH content is better than other Radix Notoginseng total arasaponins preparation to the protective effect of myocardial ischemia.
Purpose observation the present invention and other Radix Notoginseng total arasaponins ejection preparations are to the therapeutical effect of focal cerebral ischemia and myocardial ischemia, the effect characteristics of comparative drug.
Test material
The injectable powder of the medicine embodiment of the invention 1 preparation, the injection of 150mg/ bottle, the embodiment of the invention 2 preparations, the injectable powder of 50mg/ml, the embodiment of the invention 3 preparations, 150mg/ bottle; XUESHUANTONG ZHUSHEYE, 70mg/ props up (being equivalent to 50mg/ml approximately), is produced lot number: 0312018 by Yongkang, Guangdong pharmaceutcal corporation, Ltd; Panax notoginseng saponins for injection, 200mg/ props up, and is produced lot number: 20031002 by Zhenbao Island, Heilungkiang pharmaceutical Co. Ltd; 0.9% sodium chloride injection: the Beijing Double-Crane Pharmaceutical Co., Ltd produces, lot number: 050121612.
Test method
(280～320g) are divided into 14 groups to 1 grouping SD kind male rat at random: sham operated rats; Model group; The injectable powder 45.0mg/kg group of the embodiment of the invention 1 preparation; The injection 45.0mg/kg group of the embodiment of the invention 2 preparations; The injectable powder 45.0mg/kg group of the embodiment of the invention 3 preparations; XUESHUANTONG ZHUSHEYE 45.0mg/kg group; Panax notoginseng saponins for injection 45.0mg/kg group.
2 methods are pressed the TamuraShi method, animal is with 3.5% chloral hydrate intraperitoneal injection of anesthesia (35mg/100g body weight), through subtemporal approach, open the cranium window, the strip off pia mater encephali exposes the right side middle cerebral artery, and electricity coagulates the one section middle cerebral artery (it is 4W that electricity coagulates output) between tractus olfactorius and the inferior cerebral vein, sham operated rats is only opened the cranium window, the not electric middle cerebral artery that coagulates.After the operation at once tail vein injection be subjected to reagent thing (3ml/kg, sham operated rats and model group vein give the equivalent normal saline), steam again to raise behind the wound suture.Test and raising room temperature are 22.0 ± 1.0 ℃.
Postoperative 4 hours, list of references adopts single blind method by each treated animal nervous symptoms of following standard observation, carries out the behavior integration scoring.Standards of grading are: (1) mentions Mus tail built on stilts, observes two forelimb active situation, and receipts person is chosen as the 0-4 branch by degree in left fore flexing, the left side shoulder, and (normal rat) two forelimb symmetries are stretched to the place ahead person and are chosen as 0 fen; (2) gently carry the Mus tail, promote a left side and take on the 10cm that moves right, promote right shoulder again and be moved to the left 10cm,, be chosen as the 0-3 branch with left side resistance decline degree; (3) tractive two forelimbs are looked left side muscular strength decline degree and are chosen as the 0-3 branch.Three mark additions, and carry out classification, the I level with the mark sum: 0 minute; The II:1-3 branch; The III:4-6 branch; The IV:7-10 branch.The high more then animal behavior of rank obstacle is serious more.Postoperative 24 hours carries out the behavior integration scoring to each treated animal again by above-mentioned standard.The result carries out statistical procedures by grade preface value method.
After the last scoring, Animal Anesthesia, abdominal aortic blood, broken end takes out brain, and operating microscope affirmation medium-sized artery has down been blocked crown 4 cuttves of cutting in back, on average is cut into 5 brain sheets, TTC dyeing, 10% formalin keeps in Dark Place.Calculate the rat cerebral infarction scope with multi-media color pathology picture and text analytical systems (MPIAS-500) (the fixedly amplification of capture).Separation of serum is measured superoxide dismutase (SOD) vigor and malonaldehyde (MDA) content.The result carries out statistical procedures.
Result of the test:
1. to the influence of rat nervous symptoms
Table 1. Radix Notoginseng total arasaponins ejection preparation is to the influence (grade preface value method) of rat brain medium-sized artery blocking-up back nervous symptoms
| Behind the medicine | Group | Dosage (/kg) | Number of animals | Classification | The P value | |||
| I | II | III | IV | |||||
| 4 hours | The sham operated rats model group | 8 8 | 8 0 | 0 0 | 0 4 | 0 4 | ＜0.01 | |
| The embodiment of the invention 1 embodiment of the invention 2 embodiment of the invention 3 XUESHUANTONG ZHUSHEYE group panax notoginseng saponins for injection | 45.0mg 45.0mg 45.0mg 45.0mg 45.0mg | 8 8 8 8 8 | 0 0 0 1 1 | 3 3 2 3 4 | 4 4 4 4 3 | 1 1 2 0 0 | ＞0.05 ＞0.05 ＞0.05 ＜0.01 ＜0.01 | |
| 24 hours | The sham-operation group model group embodiment of the invention 1 embodiment of the invention 2 embodiment of the invention 3 XUESHUANTONG ZHUSHEYE group panax notoginseng saponins for injection | 45.0mg 45.0mg 45.0mg 45.0mg 45.0mg | 8 8 8 8 8 8 8 | 8 0 1 1 1 0 0 | 0 0 3 3 2 2 2 | 0 4 3 3 5 5 4 | 0 4 1 1 0 1 2 | ＜0.01 ＜0.05 ＜0.05 ＜0.05 ＞0.05 ＞0.05 |
By table 1 as seen, perform the operation back 4 hours, the behavior of 24 hours sham operated rats animal nerves are no abnormal, the visible significantly behavior disorder of model group animal, mainly show as in the shoulder of a left side receive, flexing, preceding myasthenia of limbs etc. are with sham operated rats comparing difference significantly (P＜0.01).4 hours animal nerve behavior disorders alleviate to some extent than model group after the preparation administration of the embodiment of the invention 1, embodiment 2, embodiment 3 preparations, but not statistically significant; The preparation animal behavior obstacle of the embodiment of the invention 1, embodiment 2, embodiment 3 preparations obviously improves after 24 hours, with model group notable difference (P＜0.05) is arranged relatively.4 hours neurobehavioral obstacles obviously improve after the administration of XUESHUANTONG ZHUSHEYE group, with model group notable difference (P＜0.01) are arranged relatively; But 24 hours neurobehavioral obstacles increase the weight of to some extent after the administration, compare no significant difference with model group.Compare no significant difference between two kinds of Radix Notoginseng total arasaponins ejection preparation groups.
2, to the influence of cerebral infarction scope
Table 2. Radix Notoginseng total arasaponins ejection preparation is to the influence of rat cerebral infarction scope (X ± SD)
| Group | Dosage (/kg) | n | Infarction size (%) |
| The sham-operation group model group embodiment of the invention 1 embodiment of the invention 2 embodiment of the invention 3 XUESHUANTONG ZHUSHEYE group panax notoginseng saponins for injection groups | 45.0mg 45.0mg 45.0mg 45.0mg 45.0mg | 8 8 8 8 8 8 8 | - 11.07±5.68 4.20±1.55 * 4.35±1.58 * 4.69±2.77 * 7.14±2.66 7.69±4.33 |
Annotate: compare with model group:
*P＜0.05
By table 2 as seen, performed the operation back 24 hours, model group rat art side ischemia is serious, forms tangible focus of infarct; Compare with model group, the preparation of the embodiment of the invention 1, embodiment 2, embodiment 3 preparations, the cerebral infarction scope is significantly dwindled (P＜0.05); XUESHUANTONG ZHUSHEYE group cerebral infarction scope is obviously dwindled (P＜0.05); Panax notoginseng saponins for injection group cerebral infarction scope is significantly dwindled (P＜0.01).
Two, to the influence of myocardial ischemia
The summary laboratory observation all can obviously alleviate the myocardial infarction degree to the present invention and XUESHUANTONG ZHUSHEYE; reduce myocardial infarction area and alleviate infarct weight; reduce infarct and account for ventricle and heart percentage ratio; the present invention can reduce Serum LDH content; analyze according to heart infarction area absolute value simultaneously, the present invention is better than XUESHUANTONG ZHUSHEYE to the protective effect of myocardial infarction due to the myocardial ischemia.
Purpose observation the present invention and other Radix Notoginseng total arasaponins injections are to the therapeutical effect of myocardial ischemia, the effect characteristics of comparative drug.
Test material
The injectable powder of the medicine embodiment of the invention 1 preparation, the injection of embodiment 2 preparations, the injectable powder of embodiment 3 preparations; XUESHUANTONG ZHUSHEYE, 2ml/ props up, and Yongkang, Guangdong pharmaceutcal corporation, Ltd produces, lot number: 0312018; Panax notoginseng saponins for injection (dry powder), 200mg/ props up, and the Heilongjiang Province Zhenbaodao Pharmaceutical Co., Ltd produces, lot number: 20031002.
Test method
1. (body weight 240～260g) is divided into 6 groups to grouping SD kind male rat at random: model group, the injectable powder 45mg/kg group of the embodiment of the invention 1 preparation, the injection 45mg/kg group of embodiment 2 preparations, the injectable powder 45mg/kg group of embodiment 3 preparations, XUESHUANTONG ZHUSHEYE 45mg/kg group, panax notoginseng saponins for injection 45mg/kg group.Medicine is assigned to desired concn with normal saline, and the administration volume is 3ml/kg, and route of administration is a left femoral vein.
2. the method animal faces upward the position and fixes with pentobarbital sodium intraperitoneal anesthesia (45mg/kg), and tracheostomize inserts tracheal intubation, meets respirator (SC-3 type, Shanghai Medical Equipment Factory) pedestrian worker and breathes (32 times/minute, breathed ratio 1: 3); Open breast, disconnected 3～4 ribs are opened pericardium, expose heart, in left anterior descending coronary artery root threading (No. 0 stitching thread), are equipped with ligation and use; Separate left femoral vein and prepare administration; Stablized behind the threading 10 minutes, ligation feeds and is subjected to sew up thoracic wall behind the reagent thing recovery autonomous respiration.
Behind the 150min, abdominal aortic blood is measured serum CK, LDH content; 5 of the following crosscuts of heart ligature, multi-media color pathology picture and text analytical systems (MPIAS-500) are adopted in N-BT dyeing, measure total myocardial area and infarcted myocardium area, observation myocardial infarction degree with fixing image distance; The result carries out statistical procedures (t check).
Result of the test
The Radix Notoginseng total arasaponins ejection preparation is to the influence of myocardial infarction degree
Each administration group of table 3 is to the influence of myocardial infarct size
| Grouping | Dosage/kg | n | Cardiac muscle gross area mm 2 | Infarcted myocardium area mm 2 | Infarct weight g | Infarct accounts for ventricle % | Infarct accounts for heart % |
| Model | 8 | 304.95±33.08 | 87.68±17.87 | 0.209±0.029 | 28.7±4.4 | 24.4±3.7 | |
| The present invention is real | 45.0mg | 8 | 312.31±26.86 | 53.97±19.05 ** | 0.123±0.046 ** | 17.0±5.5 ** | 14.6±4.8 * |
| Execute example 1 | |||||||
| The embodiment of the invention 2 | 45.0mg | 8 | 309.59±25.83 | 57.26±25.77 * | 0.133±0.065 ** | 18.2±7.3 ** | 15.4±6.1 * |
| The embodiment of the invention 3 | 45.0mg | 8 | 310.97±13.63 | 61.76±19.68 * | 0.143±0.043 ** | 19.8±6.2 ** | 16.8±5.0 * |
| XUESHUANTONG ZHUSHEYE | 45.0mg | 8 | 309.59±25.83 | 57.26±25.77 * | 0.133±0.065 ** | 18.2±7.3 ** | 15.4±6.1 * |
| Panax notoginseng saponins for injection | 45.0mg | 8 | 304.15±30.99 | 59.27±9.82 ** | 0.135±0.019 ** | 19.4±2.1 ** | 16.4±1.9 * |
Annotate: compare with model group,
*P＜0.01
Result of the test confirms that the model group infarct accounts for ventricle and heart percentage ratio is respectively 28.7 and 24.4%; Each three dosage groups effect of preparation, XUESHUANTONG ZHUSHEYE and panax notoginseng saponins for injection of the embodiment of the invention 1, embodiment 2, embodiment 3 preparations is similar, the myocardial infarction degree all has obviously and alleviates, infarct size reduces, infarct weight saving, infarct accounts for ventricle and heart percentage ratio reduces, with model group significant difference (P＜0.01) is arranged relatively, and basic visible its dose-effect relationship.
Conclusion
Coronary stenosis or obturation are interrupted blood flow due to the different causes of disease, the change of the early stage structure of ischemic myocardium still belongs to reversibility and changes, long coronary branches obturation, myocardial structural generation irreversibility changes, cause myocardial infarction, in the downright bad process of myocardial ischemia-anoxemia, the integrity of cell membrane is damaged, one of feature of cardiac muscle irreversible damage is that myocardium enzyme discharges increase, and content obviously raises.
This test is observed drug effect with myocardial infarction model due to the rat heart muscle ischemia.Experimental observation arrives, and myocardial ischemia causes myocardial infarction to take place, and N-BT dyeing back heart infarction speckle is obvious, accounts for 28.7% of the ventricle gross area; CK, LDH content increase simultaneously, have shown the feature of pathological model.
Three kinds of Radix Notoginseng total arasaponins ejection preparations all can obviously alleviate the myocardial infarction degree, and infarct size reduces, infarct weight saving, and infarct accounts for ventricle and heart percentage ratio reduces, and the present invention can reduce Serum LDH content, analyzes according to heart infarction area absolute value simultaneously.
Radix Notoginseng total arasaponins ejection preparation toxicity relatively
With reference to version in 2005 " Chinese pharmacopoeia undue toxicity's inspection technique and the present invention and relevant Radix Notoginseng total arasaponins injection are carried out toxicity test relatively with reference to the acute toxicity test method.
Be subjected to the reagent thing:
The injectable powder that the injection that the injectable powder that embodiment 1 makes, embodiment 2 make, embodiment 3 make, XUESHUANTONG ZHUSHEYE (production of Yongkang, Guangdong pharmaceutcal corporation, Ltd) panax notoginseng saponins for injection (Heilongjiang Province Zhenbaodao Pharmaceutical Co., Ltd) totally 5 be subjected to the reagent thing.
Respectively be subjected to reagent thing composition assay:
The acute toxicity tests (LD
50)
| Be subjected to the reagent thing | Embodiment 1 injectable powder | Embodiment 2 injection | Embodiment 3 injectable powder | XUESHUANTONG ZHUSHEYE | Panax notoginseng saponins for injection |
| LD 50 | 539mg/Kg | 516mg/Kg | 502mg/Kg | 355mg/Kg | 364mg/Kg |
The abnormal toxicity test result
| Be subjected to the reagent thing | Embodiment 1 injectable powder | Embodiment 2 injection | Embodiment 3 injectable powder | XUESHUANTONG ZHUSHEYE | Panax notoginseng saponins for injection |
| Drug level | 30.0mg/ml | 26.0mg/ml | 23.0mg/ml | 11.0mg/ml | 11.0mg/ml |
Annotate: abnormal toxicity test is by " 30.0mg/ml is meant the test medicinal liquid under this concentration, abnormal toxicity test requirement up to specification for Chinese pharmacopoeia version method test in 2005, the foregoing description 1 injectable powder.
The eluent abnormal toxicity test:
Embodiment eluent sample method for making: collect the ethanol elution (contain with ginsenoside Rd is the impurity of representative) in embodiment 1, embodiment 2, embodiment 3 preparation process respectively, decompression and solvent recovery below 65 ℃ also is concentrated into the clear paste that relative density is 1.05～1.15 (60 ℃), add the injection water and regulate every 1ml and contain solid content 100mg～150mg, add needle-use activated carbon an amount of (0.30%, weight ratio), 80 ℃ of following insulated and stirred 30 minutes, filter lyophilization, tamponade, gland is made sample.
Experimental technique:
Healthy mice (body weight 18-20g), male and female half and half, quarantine is 5 days before the test, according to the trial test result, random packet, every group each 10, male and female half and half.Adopt the tail vein injection administration, the disposable volume injection that waits, test solution concentration spacing is 0.5mg/ml.Injection capacity is every Mus 0.50ml.
Eluent composition assay:
| Embodiment 1 eluent | Embodiment 2 eluents | Embodiment 3 eluents |
| Panax Notoginseng saponin R 1 | ＜0.5％ | ＜0.5％ | ＜0.5％ |
| The ginsenoside Rg 1 | 5.0％ | 4.5％ | 4.2％ |
| The ginsenoside Re | 0.7％ | 0.8％ | 0.6％ |
| Ginsenoside Rb 1 | 15.0％ | 15.5％ | 14.6％ |
| The ginsenoside Rd | 38.0％ | 36.4％ | 34.8％ |
| Acute toxicity LD 50 | 105mg/Kg | 110mg/Kg | 115mg/Kg |
| Undue toxicity's drug level | 4.0mg/ml | 4.5mg/ml | 4.5mg/ml |
Brief summary as a result: ginsenoside Rd's content by low by high order is: injectable powder, panax notoginseng saponins for injection, XUESHUANTONG ZHUSHEYE that the injection that the injectable powder that embodiment 1 makes, embodiment 2 make, embodiment 3 make.Undue toxicity's (acute toxicity) by by little be the injectable powder made of embodiment 1, the injection that embodiment 2 makes, injectable powder, panax notoginseng saponins for injection, the XUESHUANTONG ZHUSHEYE that embodiment 3 makes to big ordering.
Above-mentioned experimental result shows: in the compound components of panax notoginseng compositions along with the increase that with ginsenoside Rd is relevant other compositions of feature, its unusual (acute) toxicity test result is obviously different, the difference highly significant, in the results suggest compound components of panax notoginseng compositions, relevant other composition total contents that with ginsenoside Rd are feature are low more, and unusual (acute) poison exponent is low more.
Description of drawings
Accompanying drawing 1: injection XUESHUANTONG high-efficient liquid phase chromatogram (high-efficient liquid phase chromatogram is measured under normal condition, down together)
Accompanying drawing 2: injection XUESHUANTONG high-efficient liquid phase chromatogram
Accompanying drawing 3: injection XUESHUANTONG high-efficient liquid phase chromatogram
Accompanying drawing 4: pseudo-ginseng high-efficient liquid phase chromatogram
Accompanying drawing 5: pseudo-ginseng high-efficient liquid phase chromatogram
Accompanying drawing 6: pseudo-ginseng high-efficient liquid phase chromatogram
Accompanying drawing 7: embodiment 1 total saponins active component high-efficient liquid phase chromatogram
Accompanying drawing 8: embodiment 2 total saponins active component high-efficient liquid phase chromatograms
Accompanying drawing 9: embodiment 3 total saponins active component high-efficient liquid phase chromatograms
The specific embodiment
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percent among the present invention is percetage by weight, and BV/h represents that in the resin volume be V, and solution elution volume hourly is resin volume B * V.
Embodiment 1: preparation of drug combination of the present invention
Get Radix Notoginseng powder and be broken into coarse powder 1000g, adding 60% ethanol 8000ml extracted 7 hours, collect extracting solution, filter, get filtrate recycling ethanol to there not being the alcohol flavor, add water and make the solution that every 1ml contains the 0.5g crude drug, with macroporous resin column (D class macroporous resin, resin volume 3000ml, the resin height of bed is about 8 with the diameter ratio) and alumina adsorption, carry out gradient elution with Different concentrations of alcohol liquid, concentration of alcohol was adjusted to 95% by 5% in 6 hours, flow velocity 4.5BV/h discards and contains the eluent of concentration of alcohol beyond 30% to 70%, collection contain concentration of alcohol more than 30% to the eluent below 70%, decompression and solvent recovery below 65 ℃ also is concentrated into the clear paste that relative density is 1.13 (60 ℃), the Radix Notoginseng total arasaponins active ingredient, add the injection water and regulate every 1ml and contain solid content 100mg, ultrafiltration, fill, powder ampoule agent for injection is made in lyophilization.
Assay: each component content in the said extracted thing: Panax Notoginseng saponin R
1Be 10.6%, the ginsenoside Rg
1Be 42.7%, the ginsenoside Re is 4.3%, ginsenoside Rb
1Be 26.5%, more than four composition total amounts be 84.1%; The ginsenoside Rd is 0.5%.
Embodiment 2: preparation of drug combination of the present invention
Get Radix Notoginseng powder and be broken into coarse powder 1000g, adding 50% ethanol 10000ml extracted 6 hours, collect extracting solution, filter, get filtrate recycling ethanol to there not being the alcohol flavor, add water and make the solution that every 1ml contains the 0.4g crude drug, with macroporous resin column (D class macroporous resin, resin volume 3000ml, the resin height of bed is about 8 with the diameter ratio) and alumina adsorption, carry out gradient elution (concentration of alcohol was adjusted to 95% by 5% in 5.5 hours) with Different concentrations of alcohol liquid, flow velocity 5.0BV/h, discard and contain the eluent of concentration of alcohol beyond 30% to 70%, collect contain concentration of alcohol more than 30% to the eluent below 70%, decompression and solvent recovery below 65 ℃ also is concentrated into the clear paste that relative density is 1.15 (60 ℃), dry, the Radix Notoginseng total arasaponins active ingredient, add the injection water and regulate every 1ml and contain solid content 50mg～55mg, ultrafiltration, injection is made in fill.
Assay: each component content in the said extracted thing: Panax Notoginseng saponin R
1Be 7.8%, the ginsenoside Rg
1Be 38.5%, the ginsenoside Re is 3.1%, ginsenoside Rb
1Be 24.5%, more than four composition total amounts be 73.9%; The ginsenoside Rd is 1.1%.
Embodiment 3: preparation of drug combination of the present invention
Get Radix Notoginseng powder and be broken into coarse powder 1000g, adding 75% ethanol 7500ml extracted 8 hours, collect extracting solution, filter, get filtrate recycling ethanol to there not being the alcohol flavor, add water and make the solution that every 1ml contains the 0.6g crude drug, with macroporous resin column (D class macroporous resin, resin volume 3000ml, the resin height of bed is about 8 with the diameter ratio) and alumina adsorption, carry out gradient elution (concentration of alcohol was adjusted to 95% by 5% in 6.5 hours) with Different concentrations of alcohol liquid, flow velocity 4.0BV/h discards and contains the eluent of concentration of alcohol beyond 30% to 70%, collection contain concentration of alcohol more than 30% to the eluent below 70%, decompression and solvent recovery below 65 ℃ also is concentrated into the clear paste that relative density is 1.16 (60 ℃), gets the Radix Notoginseng total arasaponins active ingredient, adds needle-use activated carbon 0.30% (weight ratio), 80 ℃ of following insulated and stirred 30 minutes, filter, add the injection water and regulate every 1ml and contain solid content 150mg, lyophilization, powder ampoule agent for injection is made in packing.
Assay: each component content in the said extracted thing: Panax Notoginseng saponin R
1Be 7.6%, the ginsenoside Rg
1Be 34.5%, the ginsenoside Re is 3.3%, ginsenoside Rb
1Be 25.1%, more than four composition total amounts be 70.5%; The ginsenoside Rd is 2.1%.
Embodiment 4: tablet
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into tablet according to the conventional formulation method.
Embodiment 5: capsule
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into capsule according to the conventional formulation method.
Embodiment 6: drop pill
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into drop pill according to the conventional formulation method.
Embodiment 7: pill
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into pill according to the conventional formulation method.
Embodiment 8: syrup
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into syrup according to the conventional formulation method.
Embodiment 9: mixture
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into mixture according to the conventional formulation method.
Embodiment 10: granule
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 1 makes, be prepared into granule according to the conventional formulation method.
Embodiment 11: capsule
Get the Radix Notoginseng total arasaponins active ingredient that embodiment 2 makes, be prepared into capsule according to the conventional formulation method.
Claims (5)
1, a kind of notoginseng total saponin compounds that is used for the treatment of cardiovascular and cerebrovascular disease is characterized in that the Radix Notoginseng total arasaponins active ingredient that active component is extracted by Radix Notoginseng forms, wherein Panax Notoginseng saponin R
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Gross weight be not less than 55% of active component gross weight, and ginsenoside Rd's content must not surpass 2.5% of active component gross weight.
2, according to the compositions of claim 1, Panax Notoginseng saponin R wherein
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Gross weight be not less than 80% of active component gross weight, and ginsenoside Rd's content must not surpass 1.0% of active component gross weight.
3, according to the compositions of claim 1, Panax Notoginseng saponin R wherein
1, the ginsenoside Rg
1, ginsenoside Re and ginsenoside Rb
1Gross weight be not less than 65% of active component gross weight, and ginsenoside Rd's content must not surpass 2.0% of active component gross weight.
4, according to the compositions of one of claim 1-3, it makes injection, powder ampoule agent for injection, freeze-dried powder injection, tablet, pill, powder, granule, mixture, syrup, capsule, drop pill preparation.
5, according to the compositions of claim 4, it makes injection, freeze-dried powder injection.
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Address after: 543002 No. 1, Industrial Avenue, Wuzhou Industrial Park, the Guangxi Zhuang Autonomous Region Patentee after: Guangxi Wuzhou Pharmaceutical (Group) Co., Ltd. Address before: 543002, No. 3, No. two, the Guangxi Zhuang Autonomous Region, Wuzhou Patentee before: Guangxi Wuzhou Pharmaceutical (Group) Co., Ltd. |