CN101062088A - Cardiac and cerebral vascular disease treating medicine, the preparing method, the quality control method and the function thereof - Google Patents
Cardiac and cerebral vascular disease treating medicine, the preparing method, the quality control method and the function thereof Download PDFInfo
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Abstract
The invention discloses a compound medicine with salvia miltiorrhizae extract, notoginseng root extract and nature left-handed baras camphor (Ai slice with 1-borneol (l-Borneol)) as effective element, preparing method and application to cure heart and brain ischemia disease medicine, which is characterized by the following: incorporating all active element of salvia miltiorrhizae liposolubility and water-solubility of the medicinal preparation; possessing high content; coming from activate blood circulation and remove stasis effective position of notoginseng for Notoginsen triterpenes; possessing high purity and strong activator for 1-borneol. This invention adopts three grade quality control mode, which keeps high grade and uniform of product.
Description
Technical field
The present invention relates to a kind of Chinese medicine compound and preparation thereof, its preparation method and application; More specifically, the present invention relates to a kind of medicine, its preparation method and application in preparation treatment cardiac-cerebral ischemia diseases medicine thereof that contains Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and natural left-handed Borneolum Syntheticum (mainly contain 1-Borneolum Syntheticum (Borneol), claim Blumeae preparatum Tabellae again) as active ingredient.
Background technology
Radix Salviae Miltiorrhizae, the root of Labiatae salvia Salviamiltiorrhiza Bge., the Chinese crude drug that a kind of tradition is commonly used records in the People's Republic of China (PRC) and goes through in edition pharmacopeia, and relevant Chinese medicine universities and colleges teaching material, monograph and dictionary class Chinese medicine books all record introduction as the emphasis medicine.For a long time, Radix Salviae Miltiorrhizae is widely used as multiple treatment of diseases medicine, is the representative medical material of blood-activating and stasis-removing.Radix Salviae Miltiorrhizae mainly contains diterpene quinones, phenolic acid compound, also contains tannin, polysaccharide etc. in addition.Wherein, diterpenoid tanshinone mainly comprises Tanshinone I I A (Tanshinone II A), cryptotanshinone (Cryptotanshinone), Tanshinone I (Tanshinone I), dihydrotanshinone (Dihydrotanshinone), methyltanshinone (Methyltashinone) etc.; Phenolic acid compound mainly comprises salvianolic acid B (Salvianolic acid B), salvianolic acid A (Salvianolic acid A), danshensu (Danshensu), rosmarinic acid (Rosmarinic acid), protocatechualdehyde (Protocatechualdehyde), protocatechuic acid (Protocatechuic acid), caffeic acid (Coffeic acid) and salvianolic acid C, D, E etc.This two compounds of the water-soluble phenolic acid compounds of Radix Salviae Miltiorrhizae and fat-soluble diterpene quinone all is main effective ingredient of Radix Salviae Miltiorrhizae, it also is the main effective ingredient of Treated with Radix Salviae Miltiorrhizae cardiovascular disease, because this two constituents character is all very unstable, the improper of extraction process can greatly influence product quality.In containing the existing preparation of Radix Salviae Miltiorrhizae, usually make water or Different concentrations of alcohol extract Radix Salviae Miltiorrhizae as solvent, but obtain the water-soluble phenolic acid compounds and the fat-soluble diterpene quinone of low yield, and contain relatively large impurity, be unfavorable for controlling product quality, and reduced bioavailability.
Radix Notoginseng, the dry root of panax araliaceae plant Panax notoginseng (Burk.) F.H.Chen divides main root, supporting root and stem foot, belongs to valuable medicinal, also is a kind of tradition Chinese crude drug commonly used, records in the People's Republic of China (PRC) and goes through in edition pharmacopeia.A large amount of research datas show that the main effective ingredient of Radix Notoginseng is its contained Saponin constituents, and arasaponin also is the main effective ingredient of Radix Notoginseng treatment cardiovascular and cerebrovascular disease.Arasaponin is all easily molten in water, alcohol.But Radix Notoginseng is a root class medical material, contains a large amount of starch simultaneously.Because Radix Notoginseng crude drug matter is hard, in often must brokenly being, fine powder side proposes its effective ingredient easily, thereby select as solvent improper, when extracting the Saponin constituents thing followed be in the Radix Notoginseng composition such as starch with a large amount of strippings, give extract, process for refining brings certain difficulty.
Natural left-handed Borneolum Syntheticum claims Blumeae preparatum Tabellae again, is the crystal from the blade distillation extraction acquisition of feverfew Herba Blumeae Balsamiferae Blumea balsamifera (Linn.) DC..Feverfew Herba Blumeae Balsamiferae main product in Guizhou, ground such as Guangdong, Guangxi, Yunnan, extract the crystalline solid that distillation processes from the leaf of Herba Blumeae Balsamiferae, claim Blumeae preparatum Tabellae again, mainly contain left-handed Borneolum Syntheticum.GUIXIN, spleen, lung meridian have the refreshment of having one's ideas straightened out, clearing away heat to alleviate pain, and the effect of improving acuity of vision and removing nebula can be used for treating the calentura coma, and convulsion is fainted, apoplexy syncope due to accumulation of phlegm, stagnation of QI sudden syncope, diseases such as attacked by pestiferous factors stupor.On pharmacopedics, also usually use synthetic borneol now, synthetic borneol has been sneaked into plurality of impurities in preparation process, and very difficult purification, make the content of Borneolum Syntheticum in the synthetic borneol only greater than 55%, and natural left-handed Borneolum Syntheticum can reach about 85%, and the multiple reaction impurities that contains in the synthetic borneol (for example isoborneol and unknown foreign body) bring the problem of safety may for the preparation make, and has increased dose reaching under the situation of same effect, is unfavorable for absorption of human body.
Red sage compound is one of Chinese patent medicine that China is most widely used, sales volume is maximum, relevant modern study is maximum.It starts from nineteen seventies, and preparation the earliest is FUFANG DANSHEN PIAN, records in 2000 editions first one 518 pages of Pharmacopoeias of People's Republic of China.But because there is some serious problem in said preparation at aspects such as extraction process, quality standards, even to a certain degree seriously influenced the quality of FUFANG DANSHEN PIAN.We are by systematic research, adjust original formulation and change the method that tradition feeds intake with crude drug into effective site (composition) and feed intake, the stability and the homogeneity of the quality standard and the product of compound red sage root preparation have been increased substantially, increased substantially main content of effective in the preparation, make it have significant anti-cardiac-cerebral ischemia effect and activating blood circulation to dissipate blood stasis effect, higher than compound red sage root formula preparation efficacy strength, and guaranteeing that under the prerequisite of its clinical efficacy, the preparation dose greatly reduces.。
Summary of the invention
The object of the invention is to provide a kind of compound medicine for the treatment of cardiovascular and cerebrovascular disease, its preparation method, method of quality control and uses thereof.
A kind of medicine for the treatment of cardiovascular and cerebrovascular disease of the present invention is that the Radix Salviae Miltiorrhizae extract that contains molten and water solublity two effective constituents of Radix Salviae Miltiorrhizae ester is Radix Salviae Miltiorrhizae extract, the Radix Notoginseng extract Radix Notoginseng total arasaponins of main component, the compound formulation and the medicine thereof of natural left-handed Borneolum Syntheticum with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae promptly.By understanding to the drug action of forming medicine and effective ingredient thereof, and on the basis of effective ingredient-technology-pharmacodynamics correlational study, improve conventional formulation and original crude drug fed intake and change effective site (composition) into and feed intake, obtain the effective site of crude drug in whole by the technology of optimizing, the active component and the effect that keep crude drug, guarantee stable, the homogeneous of product with the quality standard of science, this pharmaceutical preparation has and resists myocardial ischemia significantly and the effect of activating blood circulation to dissipate blood stasis, contains Radix Salviae Miltiorrhizae active component height, efficacy strength increases substantially.Pharmacodynamic study shows, medicine of the present invention has and resists myocardial ischemia significantly and blood circulation invigorating efficacies, and toxicologic study shows that its safety is good.
The present invention has taked three grades of Quality Control patterns in preparation technology, and formulated more comprehensive quality control standard, crude drug raw material, extract and finished product have been formulated strict and relevant main effective ingredient (position) quality index, this system of quality control of following " from the metastable product of the metastable medicinal raw material preparation quality of quality " principle is known quality and the homogeneity thereof of surveying composition (position) the may command product not only, also can to a certain degree control in the product the not quality of principal component and homogeneity thereof, guarantee the high-quality and the homogeneous of product.The present invention is achieved by the following technical solution:
The invention discloses a kind of medicine for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that this medicine is to be made for active ingredient by Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and natural left-handed Borneolum Syntheticum (Blumeae preparatum Tabellae).
Wherein, Radix Salviae Miltiorrhizae extract extracts aqueous soluble active constituent Radix Salviae Miltiorrhizae total phenolic acids or the total ketone preparation of the fat-soluble effective ingredient Radix Salviae Miltiorrhizae of Radix Salviae Miltiorrhizae by Radix Salviae Miltiorrhizae; The Radix Notoginseng extract extracts the preparation of Radix Notoginseng total saponins by Radix Notoginseng main root or clip; Natural left-handed Borneolum Syntheticum (Blumeae preparatum Tabellae) is extracted and is got by Herba Blumeae Balsamiferae.
Preferably, the active ingredient of this medicine and consumption are by weight:
Radix Salviae Miltiorrhizae extract 50-95%, Radix Notoginseng extract 20-50%, natural left-handed Borneolum Syntheticum 2-25%, more than the summation of three kinds of compositions be 100%.
Preferably, the consumption of Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and natural left-handed Borneolum Syntheticum is 61.3%: 22.7%: 16% by weight, l-Borneolum Syntheticum 〉=85% in the described natural left-handed Borneolum Syntheticum,
Wherein, described Radix Salviae Miltiorrhizae extract makes like this: get red rooted salvia, clean system back is broken to be coarse powder, carries out CO in the SFE device
2-SFE extracts, and extraction conditions is: pressure: 15MPa, and 40 ℃ of temperature are entrainer with 95% ethanol, the entrainer consumption is 8 times of doses, extraction time 10h; Get above-mentioned Radix Salviae Miltiorrhizae CO
2Residue behind the-SFE extraction step adopts conventional water decocting process to extract the water solublity salvianolic acid, and the water yield of adding is 10 times of medical material amount, extracts 2-3 time, and each 1 hour, amount of water was 12 times of inventory; With the above-mentioned Radix Salviae Miltiorrhizae water extract for preparing of ethyl acetate purification, extraction conditions is: pH value is 2.5 then, and adding the ethyl acetate number of times is 4 times, and extraction time is 20 minutes, and the amount that at every turn adds ethyl acetate is 2 times of extractum amount; Get Radix Salviae Miltiorrhizae SFE extract at last and adopt vacuum dehydrating at lower temperature, water intaking-ethyl acetate extract adopts spray drying, after obtaining two kinds of pressed powders, mix according to the red rooted salvia mixed in equal amounts of this extract equity or in following ratio respectively: Radix Salviae Miltiorrhizae SFE extract 1-2 part: water-ethyl acetate extract 4-8 part is Radix Salviae Miltiorrhizae extract;
Described Radix Notoginseng extract makes like this: get the Radix Notoginseng medical material, broken is coarse powder, twice of 75% alcohol reflux with 10 times of amount medical materials, each 1 hour, extracting solution was used water dissolution after reclaiming ethanol, filtered, use the macroporous resin separation and purification, with 70% ethanol elutions of 10 times of amount crude drugs, eluent reclaims the ethanol after drying, promptly gets the Radix Notoginseng extract after the absorption;
Described natural left-handed Borneolum Syntheticum, be with the Herba Blumeae Balsamiferae be feedstock production be the Blumeae preparatum Tabellae of effective ingredient with l-Borneolum Syntheticum, can from Herba Blumeae Balsamiferae leaf distillation, distillation carry or commercially available acquisition,
Get the above Radix Salviae Miltiorrhizae extract that makes, Radix Notoginseng extract, natural left-handed Borneolum Syntheticum and mix in proportion, drug formulation process is made the medicine of the dosage form that can be suitable for by oral administering mode, coelenteron administering mode, spray delivery mode, drug administration by injection mode, transfusion administering mode and Transdermal absorption administering mode routinely.
Wherein, in this medicine, contain the total ketone of 40-51.34% Radix Salviae Miltiorrhizae in the described Radix Salviae Miltiorrhizae SFE extract, wherein tanshinone content is 10.39-16.22%; Described water-ethyl acetate extract contains 62.32-82.28% Radix Salviae Miltiorrhizae total phenols, and wherein content of danshinolic acid B is 35.98-48.42%; Described Radix Notoginseng extract contains the 65.76-82.95% Radix Notoginseng total arasaponins, and wherein Rg1 content is 28.80-35.20%, and Rb1 content is 21.70-26.53%, and R1 content is 4.58-6.83%.
Preferably, in the said medicine, contain the total ketone of 46.68% Radix Salviae Miltiorrhizae in the wherein said Radix Salviae Miltiorrhizae SFE extract, wherein tanshinone content is 13.39%; Described water-ethyl acetate extract contains 74.80% Radix Salviae Miltiorrhizae total phenols, and wherein content of danshinolic acid B is 42.20%; Wherein said Radix Notoginseng extract contains 75.41% Radix Notoginseng total arasaponins; Wherein Rg1 content is 32%, and Rb1 content is 24.12%, and R1 content is 6.21%.
The present invention also discloses a kind of method for preparing this medicine: Radix Salviae Miltiorrhizae extract is by CO
2-SFE technology is extracted the total ketone of Radix Salviae Miltiorrhizae, is extracted Radix Salviae Miltiorrhizae total phenolic acids by decocting, ethyl acetate extraction technology; The Radix Notoginseng extract is with the ethanol extraction of polar solvent water or 40～95%, the preparation of macroporous resin adsorption isolation technics; Natural left-handed Borneolum Syntheticum from Herba Blumeae Balsamiferae leaf distillation, distillation carry or commercially available acquisition.
Preferably, this method comprises the steps:
1) get red rooted salvia, clean system back is broken to be coarse powder, carries out CO in the SFE device
2-SFE extracts, and extraction conditions is: pressure: 15MPa, and 40 ℃ of temperature are entrainer with 95% ethanol, the entrainer consumption is 8 times of doses, extraction time 10h; Get above-mentioned Radix Salviae Miltiorrhizae CO
2Residue behind the-SFE extraction step adopts conventional water decocting process to extract the water solublity salvianolic acid, and the water yield of adding is 10 times of medical material amount, extracts 2-3 time, and each 1 hour, amount of water was 12 times of inventory; With the above-mentioned Radix Salviae Miltiorrhizae water extract for preparing of ethyl acetate purification, extraction conditions is: pH value is 2.5 then, and adding the ethyl acetate number of times is 4 times, and extraction time is 20 minutes, and the amount that at every turn adds ethyl acetate is 2 times of extractum amount; Get Radix Salviae Miltiorrhizae SFE extract at last and adopt vacuum dehydrating at lower temperature, water intaking-ethyl acetate extract adopts spray drying, after obtaining two kinds of pressed powders, mix according to the red rooted salvia mixed in equal amounts of this extract equity or in following ratio respectively: Radix Salviae Miltiorrhizae SFE extract 1-2 part: water-ethyl acetate extract 4-8 part promptly gets Radix Salviae Miltiorrhizae extract;
2) get the Radix Notoginseng medical material, broken is coarse powder, twice of 75% alcohol reflux with 10 times of amount medical materials, each 1 hour, extracting solution was used water dissolution after reclaiming ethanol, filtered, use the macroporous resin separation and purification, with 70% ethanol elutions of 10 times of amount crude drugs, eluent reclaims the ethanol after drying, promptly gets the Radix Notoginseng extract after the absorption;
3) get with the Herba Blumeae Balsamiferae be raw material from the distillation of Herba Blumeae Balsamiferae leaf, sublimation production or commercially available be the natural left-handed Borneolum Syntheticum of effective ingredient with l-Borneolum Syntheticum;
4) get the above Radix Salviae Miltiorrhizae extract that makes, Radix Notoginseng extract, natural left-handed Borneolum Syntheticum and mix in proportion, drug formulation process is made the dosage form that is fit to clinically routinely.
Above-mentioned preparation method is characterized in that in the 4th step, gets the above Radix Salviae Miltiorrhizae extract that makes, Radix Notoginseng extract, natural left-handed Borneolum Syntheticum and mixes in proportion, and takes by weighing mixed powder; Get pregelatinized Starch, carboxymethyl starch sodium, be mixed to evenly with above-mentioned mixed powder behind 60 mesh sieves excessively; Add dehydrated alcohol again and make suitable soft material, cross 18 mesh sieves, granulate drying, granulate; Get the magnesium stearate mix homogeneously, wrap film-coat after the shallow arc stamping of employing Φ 9.0mm, the coating pan rotating speed is 20 rev/mins, and leaving air temp is 35 ℃～40 ℃, and the sheet bed tempertaure is 40 ℃～45 ℃, makes the medicine that dosage form is a tablet.
Above-mentioned preparation method, wherein the dosage form that is fit to clinically described in the 4th step is the dosage form of the pharmaceutical preparation of oral administration, coelenteron administration, spray delivery, ejection preparation, infusion preparation and Transdermal absorption.
Above-mentioned preparation method, the dosage form of wherein said oral administration are tablet, capsule, powder, granule, crystal, solution, suspension, syrup, elixir, medicinal tea and masticatory.
The invention provides the application of said medicine in the medicine of preparation treatment cardiovascular and cerebrovascular disease.Wherein, described cardiovascular and cerebrovascular disease is ischemic heart desease and ischemia apoplexy.
The present invention also provides the method for quality control of said medicine, and this method comprises:
1) salvia miltiorrhiza raw material quality control standard
In Radix Salviae Miltiorrhizae, the content of the total ketone of Radix Salviae Miltiorrhizae 〉=0.45%; Tanshinone 〉=0.2%; Radix Salviae Miltiorrhizae total phenols 〉=4.5%; Salvianolic acid 〉=3.0%;
2) quality control of Radix Notoginseng raw material
2 years storage lifves are with interior Radix Notoginseng; Primary colors is not answered dyed processing; 80～120 statures; Crude drug arasaponin content conformance with standard, promptly ginsenoside Rg1, Rb1 and arasaponin R1 are not less than 3.0%, 2.5% and 0.6% respectively; Contained persticide residue and content of beary metal meet the GAP standard;
3) quality control of Radix Salviae Miltiorrhizae extract
Radix Salviae Miltiorrhizae total phenolic acids, salvianolic acid B, the total ketone of Radix Salviae Miltiorrhizae, tanshinone are used spectrophotography respectively and the HPLC method is measured; Choosing salvianolic acid B is reference substance, and its standard curve equation is: C (μ g/ml)=27.26A-0.472 (r=0.9999,4.136～24.816); In the Radix Salviae Miltiorrhizae extract, the total ketone of Radix Salviae Miltiorrhizae 〉=8.0%, tanshinone 〉=2.5%, Radix Salviae Miltiorrhizae total phenols 〉=50%; Salvianolic acid B 〉=30%;
4) quality control of Radix Notoginseng extract
With ginsenoside Rg1, Rb1 and arasaponin R1 is reference substance, the content of using each saponin monomer of Radix Notoginseng that the HPLC method records is respectively 〉=and 28%, 22% and 5%;
5) quality control of natural left-handed Borneolum Syntheticum
Use gas chromatogram and carry out l-Borneolum Syntheticum mensuration.
6) standard of each composition is in medicine day of the present invention dose:
Total ketone 〉=the 15mg/d of Radix Salviae Miltiorrhizae, tanshinone 〉=6mg/d, total phenols 〉=120mg/d, red phenol B 〉=70mg/d, Radix Notoginseng R
1〉=5mg/d, Radix Notoginseng Rg
1〉=26mg/d, Radix Notoginseng Rb
1〉=20mg/d, left-handed Borneolum Syntheticum 〉=60mg/d in the Borneolum Syntheticum.
The advantage of technical solution of the present invention mainly shows:
1. according to the physicochemical property of forming effective ingredient, taked " individuation " principle of extracts active ingredients purification, promptly adopt the extraction and purification process that is suitable for this component (composition) most respectively to forming each medicine, the yield and the purity of extract effective site (composition) have been improved significantly, be that main effectively definite ingredients, amount are high, stable, thereby quality is outstanding and its controllability and homogeneity all increase substantially real " pure Chinese medicinal preparation ".
2. change the traditional alcohol-water backflow of Radix Salviae Miltiorrhizae and be carbon dioxide supercritical fluid extraction-water (SFE-H
2O) extract, compare with red sage formulation commercially available in the prior art, medicine of the present invention is higher than content of effective such as the contained Radix Salviae Miltiorrhizae total phenols of commensurability crude drug, the total ketone of Radix Salviae Miltiorrhizae, salvianolic acid B, tanshinones, and therefore medicine of the present invention can be obtained more significant curative effect in the scope that keeps former Radix Salviae Miltiorrhizae and red sage formulation consumption per day.And the rate of transform of this two constituents in preparation increases substantially than current technology, have extraction time short, operator are few, high product quality advantages.
3. being different from traditional Radix Notoginseng is used as medicine with fine powder, medicine of the present invention is used as medicine Radix Notoginseng with ethanol-macroporous resin extraction purification thing, this extract is based on Radix Notoginseng cardiac vascular activity main component arasaponin, the rate of transform of Radix Notoginseng total arasaponins 〉=95%, not only reduce dose, and more helped the performance of compound components of panax notoginseng bioavailability.
4. by pharmacodynamics comparative study than system, be that the natural left-handed Borneolum Syntheticum (Blumeae preparatum Tabellae) that the master of feedstock production contains l-Borneolum Syntheticum is used as medicine with the Herba Blumeae Balsamiferae, increase substantially the content (〉=85%) of Borneolum Syntheticum, and avoided the safety issue that synthetic reaction impurity (as isoborneol and unknown foreign body) may bring in the composite preparation.The Blumeae preparatum Tabellae medicinal history is remote, and its effect is relatively for more obvious, and to meet native compound be the universal law of active component with left-handed product.
5. drug efficacy study shows, obeying crude drug daily dose reduced value with the people of Radix Salviae Miltiorrhizae Tabellae commercially available in the prior art, red sage formulation compares, medicine of the present invention has tangible function of resisting myocardial ischemia and function of promoting blood circulation to disperse blood clots, and toxicologic study shows that the toxicity of medicine of the present invention is very little.
6. taked three grades of Quality Control patterns among the preparation technology, and formulated more comprehensive quality control standard, this has strided forward major step for high-quality and the homogeneous that guarantees product.In medicine of the present invention, each can measure summation 〉=60% of composition, more can guarantee the effectiveness that it is clinical and the stability of curative effect.Acute toxicity test by rat, mice, show that its safety is good, rat single administration maximum tolerated dose reaches 8g/kg, 6 months rat long term toxications reach 1.25g/kg dosage and do not see obvious drug toxicity, and 0.4g/kg dosage only causes that also the liver zymetology changes (ALP rising) in the long poison of Beagle dog JIUYUE.
To preparation of the present invention and preparation technology's substantive distinguishing features and beneficial effect be described further below.
1. to the improvement of Radix Salviae Miltiorrhizae extraction process
Existing pharmaceutical research result and secular Clinical Experience show that all contained phenolic acid compound of Radix Salviae Miltiorrhizae and diterpene quinone all are the main effective ingredient of Radix Salviae Miltiorrhizae cardiac vascular activity, thereby the target of the extraction and purification process of preparation of the present invention research is to propose as far as possible and keep this element of the second species in preparation.Salvianolic acid and diterpene quinone are all very unstable, diterpene quinones substance particularly, extract, in the refining and preparation process easily because of the improper considerable damage loss of condition.In technical study, we are according to the physicochemical property of this two effective constituents, with Radix Salviae Miltiorrhizae total phenols and main component salvianolic acid B thereof and the total ketone of Radix Salviae Miltiorrhizae and main representative composition Tanshinone I I A thereof is index, by repetition test, has selected a comparatively reasonably process route; By multi-level condition optimizing test, determined comparatively reasonable process conditions; And, verified the reasonability and the feasibility of technology by many batches of pilot scales.The main points of Radix Salviae Miltiorrhizae extraction process of the present invention are by carbon dioxide supercritical fluid extraction (CO
2-SFE), under low temperature, oxygen barrier condition, fully to extract and keep the diterpenoid tanshinone compounds, its rate of transform is more than 85%; Radix Salviae Miltiorrhizae residue behind the extraction ester soluble components obtains the salvianolic acid compounds with the ethyl acetate purification again with hot water extraction water solublity salvianolic acid after acidify, its rate of transform is about 70%.The abundant mix homogeneously of above-mentioned two parts extract promptly gets Radix Salviae Miltiorrhizae extract---and with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae is the Radix Salviae Miltiorrhizae extract raw material midbody of main component.The results are shown in Table 1 according to 5 batches of pilot scales of above-mentioned technology.
Table 1 Radix Salviae Miltiorrhizae extract (is the Radix Salviae Miltiorrhizae extract of main component with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae) 5 batches of pilot-scale experiment and the main effective ingredient rates of transform
| Pilot scale batch | Material quantity (kg) | Radix Salviae Miltiorrhizae extract powder (kg) | Radix Salviae Miltiorrhizae extract powder component and percentage composition (%) | The component rate of transform (%) | ||||||
| Total phenols | Red B | Total ketone | IIA | Total phenols | Red B | Total ketone | IIA | |||
| 1 | 80.0 | 5.70 | 59.93 | 32.05 | 9.93 | 2.72 | 76.00 | 65.62 | 92.39 | 86.78 |
| 2 | 80.0 | 5.68 | 58.28 | 30.03 | 9.46 | 2.90 | 73.89 | 61.26 | 87.67 | 92.18 |
| 3 | 80.0 | 5.30 | 57.83 | 33.42 | 10.56 | 2.85 | 68.41 | 63.62 | 91.32 | 84.66 |
| 4 | 80.0 | 5.53 | 59.73 | 31.95 | 9.19 | 2.73 | 73.73 | 63.47 | 83.00 | 84.56 |
| 5 | 80.0 | 5.71 | 60.91 | 31.44 | 9.31 | 2.77 | 77.63 | 64.47 | 86.75 | 88.70 |
| Meansigma methods | 80.0 | 5.58 | 59.34 | 31.78 | 9.69 | 2.79 | 73.93 | 63.69 | 88.23 | 87.38 |
Show by pharmacodynamic study, the present invention with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae be the Radix Salviae Miltiorrhizae extract of main component in the test of dog and rat all performance have significantly resist myocardial ischemia, function of promoting blood circulation to disperse blood clots, the more commercially available red sage formulation of its effect is evident as by force, shows that with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae be the main effective site that the Radix Salviae Miltiorrhizae extract of main component can be represented the Radix Salviae Miltiorrhizae cardiac vascular activity substantially.
In addition, we discover with different reference substances (protocatechualdehyde, danshensu, salvianolic acid B) when doing the total phenols acidity test its slope big difference is arranged; Secondly, the salvianolic acid constituents is how unstable and can promptly wait to determine as the good and bad evaluation index of determining of technology because of heat transform in solution.For this reason, we use with the salvianolic acid B, and to be reference substance measure the two with the HPLC of total phenolic acid ultraviolet determination and salvianolic acid B itself is the investigation that index has been carried out technology, obtained comparatively more rational process route and condition result of study.
2. to the improvement of Radix Notoginseng extraction process
The Radix Notoginseng master contains Saponin, and arasaponin is the main effective site of Radix Notoginseng, and big quantity research shows that all arasaponin is the active main effective ingredient of Radix Notoginseng cardiovascular and cerebrovascular vessel.The absorption with macroporous adsorbent resin isolation technics is rather useful as the separation and purification of Saponin constituents, by systematically examining or check the technical conditions of each operating unit of arasaponin extraction separation; And carried out on this basis with the research of the macroporous resin of two kinds of brands, result such as table 2 to the pilot scale of Radix Notoginseng total arasaponins extraction and separation process.
The total Saponin pilot scale yield and the rate of transform (%) in the table 2 Radix Notoginseng extract
| The resin model | Radix Notoginseng inventory (kg) | Radix Notoginseng total glucosides content (%) | Arasaponin must be measured (g) | The rate of transform (%) |
| WLD | 9.5 9.5 9.0 | 8.62 8.62 8.52 | 677.19 736.14 565.88 | 82.76 89.89 85.67 |
| D101 | 10 10 10 | 8.52 8.52 8.52 | 635.71 625.17 698.13 | 74.61 73.38 81.94 |
By table 2 as seen, the macroporous adsorbent resin of two kinds of models all has the higher rate of transform, and products obtained therefrom purity is all good.
3. about Borneolum Syntheticum
Former red sage compound preparation uses synthetic borneol more, by 2000 editions Chinese Pharmacopoeia standards, wherein Borneolum Syntheticum content only 〉=55%, no matter all have certain problem to guarantee the drug safety aspect, and the safety known, unknown impuritie that brings because of synthetic reaction is troubling from its source angle or from the quality control of medicine material.In fact, it is with a long history that China uses natural Borneolum Syntheticum, and the contained Borneolum Syntheticum purity of the homemade natural Broneolum Syntheticum of China very high (〉=85%) far surpasses synthetic borneol at present, does not contain the impurity that synthetic reaction is brought, and therefore replaces synthetic borneol more reasonable with natural Broneolum Syntheticum.We are by finding the drug effect toxicity comparative study of synthetic borneol and two kinds of natural Broneolum Syntheticums (from the dextro Borneolum Syntheticum of canella Borneolum Syntheticum Camphor tree preparation and the left-handed Borneolum Syntheticum for preparing from Herba Blumeae Balsamiferae), the natural left-handed Borneolum Syntheticum effect of anti-acute myocardial ischemia is stronger in three kinds of Borneolum Syntheticums, so medicine of the present invention is used as medicine with natural left-handed ice (Blumeae preparatum Tabellae, l-Borneolum Syntheticum).
4. at the preparations shaping process aspect
The physicochemical property of compound medicine constitutive material thing according to the present invention, wherein in the Radix Salviae Miltiorrhizae extract diterpenoid tanshinone compounds as far as possible lucifuge, keep away oxygen, the salvianolic acid compounds also should be kept away oxygen, arasaponin is stable, Borneolum Syntheticum is then airtight because of being easy to wave the palpus that looses.For this reason; we attach most importance to by stablize, avoid Borneolum Syntheticum to wave diffusing loss with the protection effective component in red sage in preparations shaping technology; and with guarantee the quality of the pharmaceutical preparations evenly, disintegration etc. meets the requirements is that purpose has been carried out preparation prescription screening and technical study, has prepared Film coated tablets.Dark film-coat not only is convenient to take, and in can preventing to store the variation of tanshinone and Borneolum Syntheticum wave the loss of loosing.
5. the composition measurement of medicine of the present invention and quality control
In the red sage root water soluble ingredient, salvianolic acid B, rosmarinic acid, salvianolic acid A, danshensu and protocatechualdehyde etc., tanshinone, cryptotanshinone, Tanshinone I etc. in the Radix Salviae Miltiorrhizae ester soluble components, the Panax Notoginseng saponin R in the Radix Notoginseng
1, ginsenoside R
G1, R
B1Deng and Blumeae preparatum Tabellae all have tangible pharmacologically active, and all may in the treatment of cardiovascular disease, play a role, be control of quality effectively, effective part extract and medicine are analyzed.Main quality control index is: Radix Salviae Miltiorrhizae total phenolic acids, salvianolic acid B, the total ketone of Radix Salviae Miltiorrhizae, tanshinone, and Rg1, Rb1, three main representative Saponins of R1 in the Radix Notoginseng, l-Borneolum Syntheticum is used UV, HPLC respectively and gas chromatography is measured to mentioned component.Concrete testing result sees the following form.
Table 3: main effective ingredient (position) assay result (per diem dosing calculating)
6. the comparison of the same veriety of compound medicinal formulation of the present invention and existing national standard class
We have carried out parallel assay to the content of effective ingredient (component) in the red sage compound preparation that can collect, the results are shown in following table.
Table 4. compound medicine of the present invention and the main effective ingredient of commercially available red sage compound preparation (position) assay result (calculating) by the same preparation amount
By table as seen, the red sage compound quality of the pharmaceutical preparations that different manufacturers is produced has than big-difference, and obviously as can be seen, the amount of effective ingredient that preparation of the present invention contains (position) is maximum, and the preparation technology who also verifies out preparation of the present invention is effective really.
7. for controlling the inherent quality of medicine of the present invention well, we follow three stage models of modern Chinese medicine quality control, promptly all formulate tighter and relevant quality standard for three grades at medicinal raw material, extract and finished product, to guarantee the quality of finished product:
1) salvia miltiorrhiza raw material quality control
The salvia miltiorrhiza raw material quality is uneven, and multiple reason can influence the content of effective component in red sage in the raw material.According to the requirement that the Radix Salviae Miltiorrhizae phenolic ketone is produced, in conjunction with the practical situation of salvia miltiorrhiza raw material, the present invention has formulated the red rooted salvia quality standard on the basis of state-promulgated pharmacopoeia Radix Salviae Miltiorrhizae standard, and its main standard is as follows:
Table 5 Radix Salviae Miltiorrhizae phenolic ketone production red rooted salvia main standard
| The total ketone of Radix Salviae Miltiorrhizae (%) tanshinone (%) Radix Salviae Miltiorrhizae total phenols (%) salvianolic acid B (%) | ≥0.45 ≥0.2 ≥4.5 ≥3.0 |
2) Radix Notoginseng raw material quality control
Radix Notoginseng crude drug raw material is standard, neat comparatively, for guaranteeing the stable and controllable for quality of Radix Notoginseng crude drug raw material.By research, determine that the quality control standard of Radix Notoginseng crude drug raw material is: 2 years storage lifves are with interior Radix Notoginseng; Primary colors is not answered dyed processing; 80～120 statures; Crude drug arasaponin content conformance with standard, promptly ginsenoside Rg1, Rb1 and arasaponin R1 are not less than 3.0%, 2.5% and 0.6% respectively; Contained persticide residue and content of beary metal meet the GAP standard.
3) quality control of Radix Salviae Miltiorrhizae extract
The main Quality Control of Radix Salviae Miltiorrhizae extract contains the survey index: Radix Salviae Miltiorrhizae total phenolic acids, salvianolic acid B, the total ketone of Radix Salviae Miltiorrhizae, tanshinone, use spectrophotography respectively and the HPLC method is measured.Show through methodological study, with the salvianolic acid B is reference substance, measure salvianolic acid B, tanshinone with spectrophotometry Radix Salviae Miltiorrhizae total phenolic acids, the total ketone of Radix Salviae Miltiorrhizae with the HPLC method, crude drug raw material, extract semi-finished product and medicine of the present invention are carried out quality testing, also as the guiding index of technical study.
The half-finished quality of Radix Salviae Miltiorrhizae extract (Radix Salviae Miltiorrhizae phenolic ketone) is one of most important basis of preparation medicine of the present invention, for guaranteeing that it is quality controllable and evenly meet the requirements that it is as follows that it contains the main standard of surveying quality control standard:
The index (%) of table 6 Radix Salviae Miltiorrhizae extract main component
| Project | Index (%) | Measured value (%) | ||
| 1 batch | 2 batches | 3 batches | ||
| The total ketone tanshinone of Radix Salviae Miltiorrhizae Radix Salviae Miltiorrhizae total phenols salvianolic acid B | ≥8.0 ≥2.5 ≥50 ≥30 | 9.46 2.90 58.28 30.03 | 9.93 2.72 59.93 32.05 | 9.31 2.77 60.91 31.44 |
4) quality control of Radix Notoginseng extract (Radix Notoginseng total arasaponins)
Comparatively ripe about the content assaying method of Radix Notoginseng total arasaponins and each saponin monomer of Radix Notoginseng, we continue to use, and GB, the standard laid down by the ministries or commissions of the Central Government are contained to contain containing the survey method and all can easily carrying out assay to Radix Notoginseng crude drug, extract (total Saponin) and each principal monomer Saponin of Radix Notoginseng kind.With ginsenoside Rg1, Rb1 and arasaponin R1 is reference substance, the content of using each saponin monomer of Radix Notoginseng that the HPLC method records is respectively 〉=and 28%, 22% and 5%.
5) quality control of natural left-handed Borneolum Syntheticum
Use gas chromatogram and carry out l-Borneolum Syntheticum and measure, no matter raw material or finished product are feasible, and the result is good.
8. the pharmacodynamic experiment of medicine of the present invention
Medicine of the present invention causes on the dog acute myocardial ischemia model in the ligation anterior descending coronary, 50,100,200mg/kg can obviously improve the degree of myocardial ischemia of epicardial electrogram mapping, wherein middle and high dosage group descend respectively 44.5 ± 18% (P＜0.01), 45.9 ± 18.7% (P＜0.01); The ischemia scope also has in various degree dwindles; Little, in, heavy dose of myocardial infarct size then dwindled 17.6% (P＞0.05), 27.2% (P＜0.01), 50.3% (P＜0.01) respectively; High dose can also obviously suppress the rising of Serum LDH, CK-MB cardiac muscle isozyme level; Reduce myocardial oxygen consumption.
Rats gavaged is made with extra care medicine 110,220 of the present invention, 440mg/kg every day 1 time, and continuous 5 days, can suppress in various degree because of the anterior descending coronary ligation causes raising of II lead electrocardiogram ST section, 5～30min onset is kept more than the 180min; Can obviously dwindle myocardial infarct size, infarcted region/hazardous area has reduced by 34.9% (P＜0.05), 52.2% (P＜0.01), 57.8% (P＜0.01) respectively; Can obviously suppress the rising of serum myocardium enzyme level, AST has suppressed 17.5% (P＜0.05), 26.1% (P＜0.05), 39.8% (P＜0.01) respectively; LDH has suppressed 12.1% (P＜0.05), 20.4% (P＜0.05), 32.0% (P＜0.01) respectively; CK-MB has suppressed 19.8% (P＞0.05), 31.0% (P＜0.01), 44.3% (P＜0.01) respectively.
Rat every day 1 time, gavaged medicine 110,220 of the present invention, 440mg/kg in continuous 5 days, can suppress the platelet aggregation that multiple derivant causes, the inductive gathering suppression ratio of adenosine diphosphate (ADP) (ADP) is respectively 21.9% (P＜0.05), 31.9% (P＜0.01), 53.5% (P＜0.01), ED
50Be 404.8mg/kg; The inductive gathering suppression ratio of arachidonic acid (AA) is respectively 20.4% (P＜0.05), 50.5% (P＜0.01), 56.2% (P＜0.01), ED
50Be 196.2mg/kg; The inductive gathering suppression ratio of collagen (CG) is respectively 13.1% (P＞0.05), 25.5% (P＜0.01), 45.6% (P＜0.01), ED
50Be 481.7mg/kg.The experimental artery thrombosis time due to the electricity irritation carotid artery intima damage is prolonged 3.5% (P＞0.05), 19.4% (P＜0.05), 38.6% (P＜0.01) respectively.The conclusion of pharmacodynamic study is: medicine of the present invention has tangible function of resisting myocardial ischemia and function of promoting blood circulation to disperse blood clots.
9. the toxicological experiment of medicine of the present invention
Medicine of the present invention has been taked to give the disposable LD that gavages of white mice by " maximum admissible dosage " and " the longest administration time " dispensing principle
50Be 6.84g/kg.The disposable 8g/kg that gavages of rat there is no and causes obvious toxic reaction, observes for 2 weeks and does not have dead the generation, does not also see the weight of animals increased to have a significant effect, and expires to put to death that to dissect main organs no abnormal.By the most secular long term toxication heavy dose rat up to 1.25g/kg, Beagle reaches the long term toxicity test that 0.4g/kg has carried out rat June and recovered January, not seeing has definite overt toxicity to rat; The long poison of JIUYUE Beagle dog determines that heavy dose does not have definite overt toxicity to dog.The acute and chronic toxicity and the general pharmacology result of the test of medicine of the present invention are not seen overt toxicity, have reliable safety.
The specific embodiment
The following examples are only in order to illustrate the present invention, rather than in order to limit protection scope of the present invention.
Embodiment 1: the method for extracting the effective active position from raw material
Radix Salviae Miltiorrhizae, Radix Notoginseng, Blumeae preparatum Tabellae medical material used in the inventive method are purchased in the GAP production base, and other raw materials all are commercially available, and device therefor is field of traditional Chinese medicine pharmacy extraction process equipment commonly used.
(1) acquisition of Radix Salviae Miltiorrhizae extract (is the Radix Salviae Miltiorrhizae extract of main component with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae)
Of the present invention is that the Radix Salviae Miltiorrhizae extract extracting method of main component is with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae: use CO
2-SFE technology is extracted tanshinone compound, gets red rooted salvia, and clean system back is broken to be coarse powder, carries out CO in the SFE device
2-SFE extracts, and extraction conditions is: pressure: 15MPa, and 40 ℃ of temperature are entrainer with 95% ethanol, the entrainer consumption is 8 times of doses, extraction time 10h.Get the residue behind the above-mentioned fat soluble ingredient of red sage root extraction step, adopt conventional water decocting process to extract water solublity salvianolic acid class, the water yield of adding is 10 times of medical material amount, extracts 2-3 time, and each 1 hour, amount of water was 12 times of inventory.Last extraction conditions is: pH value is 2.5 with the above-mentioned Radix Salviae Miltiorrhizae water extract for preparing of ethyl acetate purification, and adding the ester number of times is 4 times, and extraction time is 20 minutes, and the amount that at every turn adds ethyl acetate is 2 times of extractum amount.Get Radix Salviae Miltiorrhizae SFE extract at last and adopt vacuum dehydrating at lower temperature, water intaking-ethyl acetate extract adopts spray drying, after obtaining two kinds of pressed powders, mix according to the red rooted salvia mixed in equal amounts of this extract equity or in following ratio respectively: Radix Salviae Miltiorrhizae SFE extract 1-2 part: water-ethyl acetate extract 4-8 part is Radix Salviae Miltiorrhizae extract---and with Radix Salviae Miltiorrhizae total phenols and the total ketone of Radix Salviae Miltiorrhizae is the Radix Salviae Miltiorrhizae extract of main component.This technology makes the rate of transform of two constituents in preparation increase substantially than current technology, and the yield of the total ketone of Radix Salviae Miltiorrhizae is 1.46%, and content is 46.68%, and wherein tanshinone content is 13.39%.The rate of transform of Radix Salviae Miltiorrhizae total phenols is 73.75%, and content is 74.80%; The salvianolic acid B rate of transform 66.90%, content 42.20%.
(2) acquisition of Radix Notoginseng extract
With Radix Notoginseng broken be coarse powder.Every batch fed intake about 10kg, with 75% alcohol reflux twice of 10 times of amount crude drugs, each 1 hour, extracting solution is used water dissolution after reclaiming ethanol, filters, with WLD or D101 resin separation purification, with 70% ethanol elutions of 10 times of amount crude drugs, eluent reclaims the ethanol after drying, promptly after the absorption.The Radix Notoginseng total arasaponins and the saponin monomer rate of transform be all more than 80%, Radix Notoginseng total arasaponins yield 8.34%, content 75.41%; Wherein Rg1 content is 32%, and Rb1 content is 24.12%, and R1 content is 6.21%.
Embodiment 2: the preparation method of medicinal tablet of the present invention
It is even by the mixed of 50-95%: 20-50%: 2-25% to get Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract, natural Broneolum Syntheticum, takes by weighing mixed powder; Get pregelatinized Starch, carboxymethyl starch sodium, be mixed to evenly with above-mentioned mixed powder behind 60 mesh sieves excessively; Add dehydrated alcohol again and make suitable soft material, cross 18 mesh sieves, granulate drying, granulate; Get the magnesium stearate mix homogeneously, wrap film-coat after the shallow arc stamping of employing Φ 9.0mm, the coating pan rotating speed is 20 rev/mins, and leaving air temp is 35 ℃～40 ℃, and the sheet bed tempertaure is 40 ℃～45 ℃, makes medicine of the present invention.
Embodiment 3: be equipped with conventional adjuvant with medicine effect composition of the present invention and make capsule according to the conventional medicine formulation method.
Embodiment 4: be equipped with conventional adjuvant with medicine effect composition of the present invention and make powder according to the conventional medicine formulation method.
Embodiment 5: be equipped with conventional adjuvant with medicine effect composition of the present invention and make granule according to the conventional medicine formulation method.
Embodiment 6: be equipped with conventional adjuvant with medicine effect composition of the present invention and make oral liquid according to the conventional medicine formulation method.
Embodiment 7: be equipped with conventional adjuvant with medicine effect composition of the present invention and make syrup according to the conventional medicine formulation method.
Embodiment 8: be equipped with conventional adjuvant is made the coelenteron administration according to the conventional medicine formulation method dosage form with medicine effect composition of the present invention.
Embodiment 9: be equipped with conventional adjuvant with medicine effect composition of the present invention and make injection according to the conventional medicine formulation method.
Embodiment 10: be equipped with conventional adjuvant with medicine effect composition of the present invention and make transdermal agent according to the conventional medicine formulation method.
Embodiment 11: be equipped with conventional adjuvant with medicine effect composition of the present invention and make masticatory according to the conventional medicine formulation method.
Embodiment 12: be equipped with conventional adjuvant with medicine effect composition of the present invention and make medicinal tea according to the conventional medicine formulation method.
Embodiment 13: be equipped with conventional adjuvant with medicine effect composition of the present invention and make elixir etc. according to the conventional medicine formulation method.
Claims (11)
1, a kind of medicine for the treatment of cardiovascular and cerebrovascular disease is characterized in that this medicine is to be made for active ingredient by Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and natural left-handed Borneolum Syntheticum (Blumeae preparatum Tabellae).
2, the described medicine of claim 1, Radix Salviae Miltiorrhizae extract extracts aqueous soluble active constituent Radix Salviae Miltiorrhizae total phenolic acids or the total ketone preparation of the fat-soluble effective ingredient Radix Salviae Miltiorrhizae of Radix Salviae Miltiorrhizae by Radix Salviae Miltiorrhizae; The Radix Notoginseng extract extracts the preparation of Radix Notoginseng total saponins by Radix Notoginseng main root or clip; Natural left-handed Borneolum Syntheticum (Blumeae preparatum Tabellae) is extracted and is got by Herba Blumeae Balsamiferae.
3, medicine as claimed in claim 1 is characterized in that the active ingredient of this medicine and consumption are by weight:
Radix Salviae Miltiorrhizae extract 50-95%, Radix Notoginseng extract 20-50%, natural left-handed Borneolum Syntheticum 2-25%, more than the summation of three kinds of compositions be 100%.
4, as claim 1 or 3 described medicines, the consumption that it is characterized in that Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and natural left-handed Borneolum Syntheticum is 61.3%: 22.7%: 16% by weight, 1-Borneolum Syntheticum 〉=85% in the described natural left-handed Borneolum Syntheticum,
Wherein, described Radix Salviae Miltiorrhizae extract makes like this: get red rooted salvia, clean system back is broken to be coarse powder, carries out CO in the SFE device
2-SFE extracts, and extraction conditions is: pressure: 15MPa, and 40 ℃ of temperature are entrainer with 95% ethanol, the entrainer consumption is 8 times of doses, extraction time 10h; Get above-mentioned Radix Salviae Miltiorrhizae CO
2Residue behind the-SFE extraction step adopts conventional water decocting process to extract the water solublity salvianolic acid, and the water yield of adding is 10 times of medical material amount, extracts 2-3 time, and each 1 hour, amount of water was 12 times of inventory; With the above-mentioned Radix Salviae Miltiorrhizae water extract for preparing of ethyl acetate purification, extraction conditions is: pH value is 2.5 then, and adding the ethyl acetate number of times is 4 times, and extraction time is 20 minutes, and the amount that at every turn adds ethyl acetate is 2 times of extractum amount; Get Radix Salviae Miltiorrhizae SFE extract at last and adopt vacuum dehydrating at lower temperature, water intaking-ethyl acetate extract adopts spray drying, after obtaining two kinds of pressed powders, mix according to the red rooted salvia mixed in equal amounts of this extract equity or in following ratio respectively: Radix Salviae Miltiorrhizae SFE extract 1-2 part:: water-ethyl acetate extract 4-8 part is Radix Salviae Miltiorrhizae extract;
Described Radix Notoginseng extract makes like this: get the Radix Notoginseng medical material, broken is coarse powder, twice of 75% alcohol reflux with 10 times of amount medical materials, each 1 hour, extracting solution was used water dissolution after reclaiming ethanol, filtered, use the macroporous resin separation and purification, with 70% ethanol elutions of 10 times of amount crude drugs, eluent reclaims the ethanol after drying, promptly gets the Radix Notoginseng extract after the absorption;
Described natural left-handed Borneolum Syntheticum, be with the Herba Blumeae Balsamiferae be feedstock production be the Blumeae preparatum Tabellae of effective ingredient with 1-Borneolum Syntheticum, can from Herba Blumeae Balsamiferae leaf distillation, distillation carry or commercially available acquisition,
Get the above Radix Salviae Miltiorrhizae extract that makes, Radix Notoginseng extract, natural left-handed Borneolum Syntheticum and mix in proportion, drug formulation process is made the medicine of the dosage form that can be suitable for by oral administering mode, coelenteron administering mode, spray delivery mode, drug administration by injection mode, transfusion administering mode and Transdermal absorption administering mode routinely.
5, as claim 3 or 4 described medicines, it is characterized in that containing the total ketone of 40-51.34% Radix Salviae Miltiorrhizae in the described Radix Salviae Miltiorrhizae SFE extract, wherein tanshinone content is 10.39-16.22%; Described water-ethyl acetate extract contains 62.32-82.28% Radix Salviae Miltiorrhizae total phenols, and wherein content of danshinolic acid B is 35.98-48.42%; Described Radix Notoginseng extract contains the 65.76-82.95% Radix Notoginseng total arasaponins, and wherein Rg1 content is 28.80-35.20%, and Rb1 content is 21.70-26.53%, and R1 content is 4.58-6.83%.
6,, it is characterized in that this medicine can be the medicine of the dosage form of suitable oral administration, coelenteron administration, spray delivery, drug administration by injection, transfusion administration and Transdermal absorption administration as claim 1,3,4 each described medicines.
7, medicine as claimed in claim 7 is characterized in that the dosage form of the pharmaceutical preparation that described oral administration mode is suitable for can be selected from: tablet, capsule, powder, granule, crystal, solution, suspension, syrup, elixir, medicinal tea and masticatory.
8, a kind of method for preparing claim 1 or 3 described medicines: Radix Salviae Miltiorrhizae extract is to be extracted the total ketone of Radix Salviae Miltiorrhizae, extracted Radix Salviae Miltiorrhizae total phenolic acids by decocting, ethyl acetate extraction technology by the carbon dioxide supercritical fluid extraction technology; The Radix Notoginseng extract is with the ethanol extraction of polar solvent water or 40～95%, the preparation of macroporous resin adsorption isolation technics; Natural left-handed Borneolum Syntheticum from Herba Blumeae Balsamiferae leaf distillation, distillation carry or commercially available acquisition.
9, as the application of each described medicine of claim 1-8 in the medicine of preparation treatment cardiovascular and cerebrovascular disease.
10, application as claimed in claim 9 is characterized in that described cardiovascular and cerebrovascular disease is ischemic heart desease and ischemia apoplexy.
11, as the method for quality control of each described medicine of claim 1-5, this method comprises the steps:
1) salvia miltiorrhiza raw material quality control standard
In Radix Salviae Miltiorrhizae, the content of the total ketone of Radix Salviae Miltiorrhizae 〉=0.45%; Tanshinone 〉=0.2%; Radix Salviae Miltiorrhizae total phenols 〉=4.5%; Salvianolic acid 〉=3.0%;
2) quality control of Radix Notoginseng raw material
Radix Notoginseng, crude drug arasaponin content conformance with standard: ginsenoside Rg1, Rb1 and arasaponin R1 are not less than 3.0%, 2.5% and 0.6% respectively;
3) quality control of Radix Salviae Miltiorrhizae extract
Radix Salviae Miltiorrhizae total phenolic acids, salvianolic acid B, the total ketone of Radix Salviae Miltiorrhizae, tanshinone are used spectrophotography respectively and the HPLC method is measured; Choosing salvianolic acid B is reference substance, and its standard curve equation is: C (μ g/ml)=27.26A-0.472 (r=0.9999,4.136～24.816); In the Radix Salviae Miltiorrhizae extract, the total ketone of Radix Salviae Miltiorrhizae 〉=8.0%, tanshinone 〉=2.5%, Radix Salviae Miltiorrhizae total phenols 〉=50%; Salvianolic acid B 〉=30%;
4) quality control of Radix Notoginseng extract
With ginsenoside Rg1, Rb1 and arasaponin R1 is reference substance, use the content that the HPLC method records ginsenoside Rg1 in the Radix Notoginseng, Rb1 and arasaponin R1 to be respectively 〉=28%, 22% and 5%;
5) quality control of natural left-handed Borneolum Syntheticum
Use gas chromatogram and carry out 1-Borneolum Syntheticum mensuration.
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Cited By (5)
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| EP2286819A1 (en) * | 2008-05-09 | 2011-02-23 | Kunming Pharmaceutical Corp. | Pharmceuttical composition for treating cardio-cerebro vascular diseases and preparative method and kit thereof |
| CN102526380A (en) * | 2010-12-28 | 2012-07-04 | 天津同仁堂集团股份有限公司 | Quality control method of coronary artery dredging tablet |
| CN106176781A (en) * | 2016-07-01 | 2016-12-07 | 南京大学 | A kind of compound Salviae Miltiorrhizae active ingredient composition and its preparation method and application |
| CN106474139A (en) * | 2016-08-28 | 2017-03-08 | 张金凤 | One kind is for paracmastic tablet of pulmonary heart disease and preparation method thereof |
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| CN1296063C (en) * | 2002-12-23 | 2007-01-24 | 北京采瑞医药有限公司 | Compound red sage prepn for treating cardiac and cerebral vascular diseases and its prepn process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2286819A1 (en) * | 2008-05-09 | 2011-02-23 | Kunming Pharmaceutical Corp. | Pharmceuttical composition for treating cardio-cerebro vascular diseases and preparative method and kit thereof |
| EP2286819A4 (en) * | 2008-05-09 | 2011-06-08 | Kunming Pharmaceutical Corp | Pharmceuttical composition for treating cardio-cerebro vascular diseases and preparative method and kit thereof |
| CN102526380A (en) * | 2010-12-28 | 2012-07-04 | 天津同仁堂集团股份有限公司 | Quality control method of coronary artery dredging tablet |
| CN106176781A (en) * | 2016-07-01 | 2016-12-07 | 南京大学 | A kind of compound Salviae Miltiorrhizae active ingredient composition and its preparation method and application |
| CN106474139A (en) * | 2016-08-28 | 2017-03-08 | 张金凤 | One kind is for paracmastic tablet of pulmonary heart disease and preparation method thereof |
| CN108096318A (en) * | 2017-12-29 | 2018-06-01 | 北京中医药大学 | Treat pharmaceutical composition of cardiovascular and cerebrovascular disease and its preparation method and application |
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| CN101062088B (en) | 2011-06-08 |
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