CN100563662C - Chinese medicine active ingredient composition of treatment cardiovascular disease and preparation method thereof - Google Patents
Chinese medicine active ingredient composition of treatment cardiovascular disease and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
- A61K36/258—Panax (ginseng)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses a kind of red seven compositionss, it contains following composition: (a) ginsenoside Rg of 0.7-4.3 weight portion
1(b) salvianolic acid B of 1.0 weight portions; (c) the ginsenoside Rb of 0.7-4.3 weight portion
1The invention also discloses a kind of method of quality control of red seven preparations, described method comprises: control ginsenoside Rg in red seven preparations
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3.The present invention has found in the necessary component Radix Salviae Miltiorrhizae of red seven preparations and the Radix Notoginseng first for treatment effective main component of cardiovascular disease and optimum ratio thereof.Ratio range of the present invention is convenient to when red seven preparations of preparation the control components contents to obtain preferable therapeutic effect, has overcome in the past when red seven preparations of preparation owing to learning wherein to bring into play active main component and content causes the not good difficult problem of therapeutic effect.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of Chinese medicine active ingredient composition of cardiovascular disease and a kind of method of quality control of red seven preparations for the treatment of.
Background technology
Along with the variation of aspects such as people's living environment, life style and dietary habit, cardiovascular diseases's sickness rate rises year by year, and at present, cardiovascular and cerebrovascular disease has become the topmost disease that influences the residents ' health level.More than 40 years old among the crowd, Incidence of CHD is 3-5% in China, and indivedual areas are 8-10%, and are in rising trend in recent years.China has entered aging society, and the percentage ratio that accounts for total population to the population of over-65s in 2004 is greater than 10%, and the patients with coronary heart disease group also will enlarge thereupon.In China, annual nearly 2,600,000 people, every day, nearly 7000 people died from cardiovascular and cerebrovascular disease.Along with the ill crowd's of cardiovascular and cerebrovascular disease increase, the cardiovascular and cerebrovascular vessel medication has become the first quasi drugs of world's medical market, adds up according to IMS, 2003, painstaking effort tubing medicine ranks the first at global drug market, and the market share is 16.09%, and market scale is 75,000,000,000 dollars.Estimate that according to SFDA south medication economics institute CDCC model 2003, China's cardiovascular and cerebrovascular vessel medication was number two at Chinese drug market, is only second to the infection medication, the market share is 14.36%.The cardiovascular and cerebrovascular disease pathogeny is comparatively complicated, still is difficult to bring into play effectively therapeutical effect in some field based on the modern medicines therapeutics of molecular biology.
The cardiovascular and cerebrovascular vessel Chinese patent medicine is meant treatment coronary heart disease, apoplexy, myocardial infarction and merges the Chinese patent medicine of various cardiovascular and cerebrovascular diseases such as shock, arrhythmia, angina pectoris and hypertension, comprises the product of oral Chinese patent medicine, Chinese medicine and other dosage form.Chinese patent medicine has occupied considerable position as the traditional disease treatment means of China on China cardiovascular and cerebrovascular vessel medication market.Market scale is to weigh the topmost index of market economy feature.Estimate according to southern medication economics institute CDCC model, 2003, the retail total scale in domestic cardiovascular and cerebrovascular vessel Chinese patent medicine market is about 82.10 hundred million yuan (± 10%), accounts for 25.41% of cardiovascular and cerebrovascular vessel medication (comprising Chinese patent medicine and chemical medicine) overall market, accounts for 3.64% of China's drug market.
Radix Salviae Miltiorrhizae is the dry root and the stem of labiate Radix Salviae Miltiorrhizae, has blood circulation promoting and blood stasis dispelling, an effect of the relieving restlessness that clears away heart-fire.Radix Notoginseng is the dry root of panax araliaceae plant, has the dissipating blood stasis hemostasis, reducing swelling and alleviating pain, the effect of benefiting qi and nourishing blood.Pellet seven compound preparations that Radix Salviae Miltiorrhizae, Radix Notoginseng compatibility are formed are used for cardiovascular system diseases such as clinical treatment coronary heart disease, angina pectoris.The function of DANQI PIAN is blood circulation promoting and blood stasis dispelling with curing mainly, and is used for stagnation of QI and blood, cardiodynia, dizziness and headache, abdominal pain in menstruation.Because its determined curative effect, untoward reaction is few, is clinical treatment coronary heart disease, uncomfortable in chest, anginal Chinese patent medicine commonly used.But, pellet seven products that existing explained hereafter goes out, effective ingredient differs greatly, the proportioning instability, and dose is big, disintegration is relatively poor, the existence of no perfect problems such as quality control standard also can not be ignored.
Therefore, be necessary further to improve extraction process, maximum possible obtains effective site, finds the most effective active component and ratio range thereof, to reduce the drug administration amount, to improve the effectiveness of taking.
Summary of the invention
The object of the present invention is to provide a kind of compositions for the treatment of cardiovascular disease.
The present invention also aims to provide a kind of method of quality control of red seven preparations.
In a first aspect of the present invention, a kind of compositions is provided, it contains following composition:
(a) ginsenoside Rg of 0.7-4.3 weight portion
1
(b) salvianolic acid B of 1.0 weight portions;
(c) the ginsenoside Rb of 0.7-4.3 weight portion
1And
(d) acceptable carrier on the pharmacy of 6-100 weight portion or the bromatology;
Wherein, the total content of component (a)+(b)+(c) is the 1-50% of composition total weight.
In another preference of the present invention, described compositions contains:
The ginsenoside Rg
1Content be the 1.5-3.5 weight portion;
The content of salvianolic acid B is 1.0 weight portions; Or
Ginsenoside Rb
1Content be the 1.5-3.5 weight portion.
In another preference of the present invention, the dosage form of described compositions is selected from (including but not limited to): tablet, oral cavity disintegration tablet, injection, lyophilized injectable powder, granule, capsule, drop pill, pill or oral liquid.
In another preference of the present invention, acceptable carrier is selected from described pharmacy or the bromatology: filler, disintegrating agent, lubricant, fluidizer, effervescent, correctives, coating material or other adjuvant or excipient.
In another preference of the present invention, described compositions contains: Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins.
In another preference of the present invention, described compositions contains Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, and ginsenoside Rg wherein
1, salvianolic acid B and ginsenoside Rb
1Weight ratio satisfy 0.7-4.3: 1.0: 0.7-4.3.
In a second aspect of the present invention, the purposes of described compositions is provided, be used to prepare the medicine of prevention or treatment cardiovascular disease.
In a third aspect of the present invention, a kind of method of quality control of red seven preparations is provided, described method comprises step:
Control ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Content, make three's weight ratio be:
The ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3.
In another preference of the present invention, control ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Weight ratio be:
The ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=1.5-3.5: 1.0: 1.5-3.5.
In another preference of the present invention, described quality control may further comprise the steps:
Measure the ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Content is if three's content satisfies the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 does not then adjust the preparation composition; If three's content does not satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 then regulates the wherein consumption of respective components according to measurement result, thereby makes three's content satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3;
Perhaps described control may further comprise the steps:
Measure ginsenoside Rg in Radix Salviae Miltiorrhizae and the Radix Notoginseng raw material
1, salvianolic acid B and ginsenoside Rb
1Content is determined the proportioning of medicinal raw material according to measurement result.
In another preference of the present invention, measure ginsenoside Rg1, salvianolic acid B or ginsenoside Rb1's content in red seven preparations by chromatograph (as liquid chromatograph).
In another preference of the present invention, the following mensuration of the content of salvianolic acid B:
With the octadecylsilane chemically bonded silica is filler; With acetonitrile-0.1% phosphoric acid (21: 79) is mobile phase; The detection wavelength is 286nm, and number of theoretical plate calculates by the salvianolic acid B peak should be not less than 4000;
In the salvianolic acid B reference substance, add 40% ethanol and make the solution of 80 μ g salvianolic acid B/ml, obtain reference substance solution;
Add 40% ethanol in red seven preparations to be measured, make the solution of red seven preparations of 2mg/ml, supersound process 15 minutes obtains need testing solution;
Reference substance and test sample are carried out liquid chromatogram measuring, obtain the content of salvianolic acid B.
Or ginsenoside Rg
1The following mensuration of content:
With the octadecylsilane chemically bonded silica is filler; With acetonitrile-water (18: 82) is mobile phase; The detection wavelength is 203nm; Number of theoretical plate is by the ginsenoside Rg
1The peak calculates should be not less than 4000;
The ginsenoside Rg
1Add methanol in the reference substance and make 400 μ g ginsenoside Rgs
1The solution of/ml obtains reference substance solution;
Add methanol in red seven preparations to be measured, make the solution of red seven preparations of 3mg/ml, supersound process 30 minutes obtains need testing solution;
Reference substance and test sample are carried out liquid chromatogram measuring, obtain the ginsenoside Rg
1Content.
Or the following mensuration of the content of Radix Salviae Miltiorrhizae total phenolic acids:
In the salvianolic acid B reference substance, add 40% ethanol, make the solution of 36 μ g salvianolic acid B/ml, obtain reference substance solution;
Add 40% ethanol in red seven preparations to be measured, make the solution of red seven preparations of 2mg/ml, supersound process 15 minutes obtains need testing solution;
Get reference substance solution and need testing solution, make blank, adopt ultraviolet visible spectrophotometry under 286nm, to measure absorbance, obtain the content of total phenolic acid according to following formula with 40% ethanol:
Total phenolic content (%)=0.626 * (A-B)+B
In the formula:
A adopts ultraviolet spectrophotometry to record the content of total phenolic acid in the test sample for being contrast with the salvianolic acid B
B is the content that high performance liquid chromatography records salvianolic acid B in the test sample.
Or the following mensuration of the content of Radix Notoginseng total arasaponins:
The ginsenoside Rg
1Add methanol in the reference substance, make and contain 800 μ g ginsenoside Rgs
1The solution of/ml obtains reference substance;
In red seven preparations to be measured, add methanol, make the solution that contains red seven preparations of 10mg/ml, supersound process 30 minutes, volatilize solvent, solid content water dissolution, last solid phase extraction column, distinguish water, 20% methanol, methanol-eluted fractions then, collect meoh eluate, obtain need testing solution;
Respectively reference substance solution and need testing solution are volatilized solvent, add 5% vanillin glacial acetic acid solution, perchloric acid respectively, insulation is 15 minutes in 60 ℃ of water-baths, put immediately in the frozen water and cooled off 5 minutes, add glacial acetic acid 5ml, adopt ultraviolet visible spectrophotometry to measure absorbance, obtain the content of Radix Notoginseng total arasaponins at the wavelength place of 545nm.
In another preference of the present invention, determine ginsenoside Rg1, salvianolic acid B or ginsenoside Rb1's content in red seven preparations by the finger printing of measuring red seven preparations.
In another preference, by the high effective liquid chromatography for measuring finger printing.
In another preference of the present invention, the method for measuring finger printing is as follows:
With octadecylsilane chemically bonded silica is filler; Flow velocity 1.0ml/min; 25 ℃ of column temperatures; Detect wavelength 203nm; With acetonitrile-0.1% phosphate aqueous solution is mobile phase, carries out gradient elution by following condition of gradient elution, operation 50min;
In the time of 0-30 minute, the ratio of acetonitrile reduces to 77% by 13% ratio that rises to 23%, 0.026% phosphate aqueous solution by 87%; 30-45 minute, acetonitrile was raised to 45%, 0.026% phosphate aqueous solution by 23% and reduces to 55% by 77%; 45-50 minute, keep acetonitrile-0.026% phosphate aqueous solution to carry out eluting with 45: 55 ratio.The finger printing that obtains is referring to Fig. 1.
On the other hand, the method for described quality control comprises step: control the content of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins in red seven preparations, make both weight ratios be:
Radix Salviae Miltiorrhizae total phenolic acids: Radix Notoginseng total arasaponins=1: 2-8; More preferably be the control Radix Salviae Miltiorrhizae total phenolic acids: Radix Notoginseng total arasaponins=1: 3-7.
In another preference, by the content of colorimetric method for determining Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Description of drawings
Fig. 1 has shown red seven preparations by HPLC finger printing.Wherein 1 is the ginsenoside Rg1, and 2 is salvianolic acid B, and 3 is the ginsenoside Rb1.
Fig. 2 has shown the finger printing that adopts TSQ Quantum LC/MS/MS liquid/pellet seven preparations that the matter combined instrument is set up.
The specific embodiment
The inventor has found the effective ratio range and the best ratio range of effective ingredient in Radix Salviae Miltiorrhizae total phenolic acids and the Radix Notoginseng total arasaponins, thereby a kind of compositions that comprises properly mixed described effective ingredient is provided through extensive and deep research.And,, can carry out quality control to various red seven preparations based on described effective proportioning and best proportioning.Finished the present invention based on this.
As used herein, " red seven preparations " are meant with Radix Salviae Miltiorrhizae and Radix Notoginseng and include but not limited to: the mixture of Radix Salviae Miltiorrhizae extract and Radix Notoginseng extract, the mixture of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins etc. as the general name of the preparation of necessary component.
Particularly, at active component content instability in pellet seven preparations that utilize Radix Salviae Miltiorrhizae extract and Radix Notoginseng extract or Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins to make in the prior art, cause the unsettled defective of therapeutic effect, the inventor has carried out deep research, finds that Radix Salviae Miltiorrhizae total phenolic acids and the optimal components ratio between the Radix Notoginseng total arasaponins as neccessary composition is Radix Salviae Miltiorrhizae total phenolic acids in red seven preparations: Radix Notoginseng total arasaponins=1: 2-8; Further, the inventor detects at the main component that contains in Radix Salviae Miltiorrhizae total phenolic acids in this best ratio range and the Radix Notoginseng total arasaponins, finds that wherein main active component is the ginsenoside Rg
1, salvianolic acid B, ginsenoside Rb
1, their effective proportioning is the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7～4.3: 1.0: 0.7～4.3, and their optimal components ratio is the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=2～2.8: 1.0: 2～2.8, in this ratio range, therapeutic effect the best of red seven preparations.
Therefore, the invention provides a kind of ginsenoside Rg of containing
1, salvianolic acid B, ginsenoside Rb
1Compositions.And new discovery of the present invention also can be used for red seven preparations are carried out quality control.
Compositions
As used herein, term " necessary component " refers to necessary Chinese medicine medical material, i.e. Radix Salviae Miltiorrhizae and Radix Notoginseng.
As used herein, term " neccessary composition " refers to the chemical substance as necessity of active component, i.e. Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins.
As used herein, term " main component " or " main constituent " are meant in Radix Salviae Miltiorrhizae total phenolic acids or Radix Notoginseng total arasaponins, the chemical constituent that the performance treatment is renderd a service, i.e. ginsenoside Rg
1, salvianolic acid B and ginsenoside Rb
1
As used herein, term " contain " or " comprising " comprised " comprising ", " basically by ... constitute " and " by ... constitute ".
As used herein, term " basically by ... constitute " refer in compositions, except containing neccessary composition or necessary component, also can contain a spot of and not influence the submember and/or the impurity of effective ingredient.For example, can contain sweeting agent to improve taste, antioxidant in case oxidation, and other this area additive commonly used.
As used herein, term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent administration, comprises various excipient and diluent.This term refers to some medicament carriers like this: they itself are not necessary active component, and do not have undue toxicity after using.Suitable carriers is well known to those of ordinary skill in the art.In Remington ' s Pharmaceutical Sciences (Mack Pub.Co.N.J.1991), can find discussing fully about pharmaceutically acceptable excipient.Acceptable carrier can contain liquid on combination of Chinese medicine is learned, as water, saline, glycerol and ethanol.In addition, also may there be complementary material in these carriers, as filler, disintegrating agent, lubricant, fluidizer, effervescent, wetting agent or emulsifying agent, correctives, pH buffer substance etc.The inessential composition except that neccessary composition (Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins) that comes from Radix Salviae Miltiorrhizae, Radix Notoginseng, and other inessential composition (for example other complementary medical material) are also included within the definition of pharmaceutically acceptable carrier.
In compositions of the present invention, as main component is (1) ginsenoside Rg
1(2) salvianolic acid B; (3) ginsenoside Rb
1Compositions of the present invention can be directly used in treatment or alleviate cardiovascular disease, or can with the other medicines co-administered.
As used herein, term " compositions of the present invention " comprises pharmaceutical composition, food composition and/or dietary supplement, as long as they contain or basically by the ginsenoside Rg
1, salvianolic acid B and ginsenoside Rb
1Constitute.Usually, ginsenoside Rg
1, salvianolic acid B and ginsenoside Rb
1Weight account for the 1-50% of composition total weight, preferably 3-40%, more preferably 5-25%.
Described compositions can be to contain pure basically above-mentioned three kinds of chemical compounds or their analog, and the mixture of pharmaceutically acceptable carrier; Perhaps, described compositions can be to contain Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, and the mixture of pharmaceutically acceptable carrier; Perhaps described compositions can be the mixture that contains Radix Salviae Miltiorrhizae extract and Radix Notoginseng extract.
In the compositions of the present invention, each main component also can be used with " the acceptable salt of physiology " or " acceptable acid of physiology or the deutero-salt of alkali " form, or uses with the form of " amide ".Described salt includes, but is not limited to: the salt that forms with following mineral acid: example hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and the salt that forms with organic acid, organic acid then refers to acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid and maleic acid.Other salt comprises the salt that forms with alkali metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), with the form (when with this form administration, can change into active part in vivo) of " prodrug " of ester, carbamate or other routine.
Compositions of the present invention can be made the dosage form of any routine by conventional method, includes but not limited to: tablet, Orally-disintegrating tablet, injection, lyophilized injectable powder, granule, capsule, drop pill, pill or oral liquid.From being easy to prepare the position with administration, preferred compositions is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling etc.
Compositions of the present invention is closely related to the content of the therapeutic effect of cardiovascular disease and necessary active component.Studies show that,, should make this active ingredient of drugs content reach certain scope in order to obtain the effect of stable treatment and/or alleviation cardiovascular disease.The scope of the reasonable content of each composition is in the compositions of the present invention:
(a) ginsenoside Rg of 0.7-4.3 weight portion
1
(b) salvianolic acid B of 1.0 weight portions;
(c) the ginsenoside Rb of 0.7-4.3 weight portion
1And
(d) acceptable carrier on the pharmacy of 6-100 weight portion or the bromatology;
Wherein, the total content of component (a)+(b)+(c) is the 1-50% of composition total weight.
The consumption of compositions of the present invention can change with the order of severity of the pattern of administration and disease to be treated.Yet, when compositions of the present invention every day gives with the dosage of about 1-50mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 1-4 time every day, or with the slow release form administration.For most of large mammal, the accumulated dose of every day is about 60-5000mg, preferably is about 80-2000mg.This dosage of scalable is replied so that optimal treatment to be provided.For example, by the needs of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
As a kind of optimal way, compositions of the present invention is when preparation, can directly adopt the main component in Radix Salviae Miltiorrhizae total phenolic acids and the Radix Notoginseng total arasaponins, so activity substance content height, good stability, so can significantly reduce each patient's using dosage, when improving curative effect, also increase patient's compliance.
The extracting method of neccessary composition
Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins or its preparation method of extract are as known in the art.
For example, Radix Notoginseng total arasaponins can extract according to Yunnan Province's provincial standard, and standard No. is WS
3-B-3590-2001 (Z).
Radix Salviae Miltiorrhizae total phenolic acids can be used purification by macroporous resin then with water extract-alcohol precipitation, obtains total phenolic acid effective site.
The method of quality control
Based on ginsenoside Rg provided by the invention
1, salvianolic acid B and ginsenoside Rb
1Effective proportioning and best proportioning, can carry out quality control to the compositions of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins or the compositions of Radix Salviae Miltiorrhizae extract and Radix Notoginseng extract.
As a kind of optimal way, can adopt following method that red seven preparations are carried out quality control: to measure the ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Content is if three's content satisfies the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 does not then adjust the preparation composition; If three's content does not satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 then regulates the wherein consumption of respective components according to measurement result, thereby makes three's content satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3.
As another kind of optimal way, also can adopt following method that red seven preparations are carried out quality control: to measure ginsenoside Rg in Radix Salviae Miltiorrhizae and the Radix Notoginseng raw material
1, salvianolic acid B and ginsenoside Rb
1Content is determined proportion of raw materials according to measurement result, thus the ginsenoside Rg that subsequent preparation is obtained
1, salvianolic acid B and ginsenoside Rb
1Content satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3.
Should understand, those skilled in the art available from described effective proportioning and best proportioning after, can adopt the method for multiple quality analysis to realize that described method includes but not limited to the quality control of the preparation raw material of red seven preparations or red seven preparations: thin layer chromatography, high performance liquid chromatography, gas chromatogram, ultraviolet spectra, nuclear magnetic resonance, NMR, mass spectrum, LC-MS etc.These methods all are included among the present invention.
As a kind of selectable method of quality control, can adopt efficient liquid-phase chromatograph finger print atlas to carry out qualitative and quantitative to red seven preparations.
The method of another kind of selectable quality control is directly to detect main component (ginsenoside Rg in red seven preparations
1, salvianolic acid B or ginsenoside Rb1) or the content of neccessary composition, carry out qualitative and quantitative to red seven composite preparations.
Major advantage of the present invention is:
(1) the present invention has found in the necessary component Radix Salviae Miltiorrhizae of red seven preparations and the Radix Notoginseng for the effective main component of treatment cardiovascular disease, be ginsenoside Rg1, salvianolic acid B and ginsenoside Rb1, and, the present invention has also found these three kinds of components for the effective preferred range of treatment cardiovascular disease first, has the effect of good curing cardiovascular disease according to this preferred range composition prepared.
(2) past people usually causes therapeutic effect not good owing to can't learn the content of wherein bringing into play active main component when red seven preparations of preparation; And various pellet seven preparations that obtain by employing diverse ways or condition are the active component difference often, is difficult to guarantee to obtain good effect.And the invention provides the preferred range of three kinds of components, thereby be convenient to that the may command components contents obtains preferable therapeutic effect when red seven preparations of preparation, overcome in the past when red seven preparations of preparation owing to learning that the content of wherein bringing into play active main component causes the not good technical barrier of therapeutic effect.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to the condition described in medicament book or pharmacopeia, or according to normal condition, unless otherwise indicated, otherwise percentage ratio and umber are calculated by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
The extraction of embodiment 1 drug effective region
Described Radix Notoginseng total arasaponins extracts according to Yunnan Province's provincial standard, and standard No. is WS3-B-3590-2001 (Z).
Described Radix Salviae Miltiorrhizae total phenolic acids is by following method preparation:
Get red rooted salvia, pulverize, 80 ℃ add deionized water extraction twice, filtrate is evaporated to relative density about 1.2 (50 ℃) below 60 ℃, adding ethanol is 70% to containing the alcohol amount, leaves standstill 12 hours, discard precipitation, supernatant is filtered, be evaporated to relative density about 1.3 (room temperature) below 60 ℃, by X-5 type macroporous adsorbent resin, ethanol elution with low concentration, eluent is concentrated into about 1.15 (50 ℃), and spray drying promptly gets Radix Salviae Miltiorrhizae total phenolic acids.
Present embodiment adopts the SD male rat, 200 ± 20g, be divided into blank group, 1: 1 group, 1: 2 group, 1: 3 group, 1: 5 group, 1: 7 group, 1: 8 group, 1: 9 group these eight groups at random, art was pressed 30mg/kg in preceding 30 minutes and is irritated stomach, etherization, open breast, ligation arteria coronaria left anterior descending branch, skin suture, postoperative 4 hours, marrow-breaking is put to death animal, takes out heart rapidly, claims heavy whole-heartedly, Zuo Xinchong, be cut into 1～2mm thin slice, dyeed 15～20 minutes in 37 ℃, 0.1%NBT dye liquor, the dyeing back is cut the infarcted region precision and is weighed from locating to be infarcted region.Be stability and the concordance that reaches experiment, the fixing operation operator eliminate the more and animal that is not in good state of intraoperative hemorrhage.Experimental result such as table 1.
The proportioning screening of table 1 Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins
Compare with the blank group,
*P＜0.05
*P＜0.01
Pharmacological experiment is the result show, the proportioning of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins not simultaneously, its drug effect there are differences.
The result shows that according to listed as parts by weight, Radix Salviae Miltiorrhizae total phenolic acids: the ratio of Radix Notoginseng total arasaponins is 1: 2～8; Preferred, Radix Salviae Miltiorrhizae total phenolic acids: the ratio of Radix Notoginseng total arasaponins is 1: 3～7; Further preferred, Radix Salviae Miltiorrhizae total phenolic acids: the ratio of Radix Notoginseng total arasaponins is 1: 4～6; Most preferred, Radix Salviae Miltiorrhizae total phenolic acids: Radix Notoginseng total arasaponins is 1: 5.
Further, corresponding with pharmacology result, the inventor has also established as the ginsenoside Rg1 of red seven main constituents, salvianolic acid B, ginsenoside Rb
1Ratio range.According to listed as parts by weight, the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb1's ratio is 0.7～4.3: 1.0: 0.7～4.3; Preferred, the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1Ratio be 1～3.8: 1.0: 1～3.8; Preferred, the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1Ratio be 1.5～3.5: 1.0: 1.5～3.5; Further preferred, the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1Ratio be 2～2.8: 1.0: 2～2.8; Most preferred, the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1Ratio be 2.2: 1.0: 2.4.
The results are shown in Table 2 and table 3.
The Radix Salviae Miltiorrhizae total phenolic acids of the different proportionings of table 2-content of the total saponins in radix notoginseng measurement result
The optimal proportion of table 3 main constituent content and effective proportion
In the present embodiment, the prescription such as the table 4 of employing.
The red seven composition tablet prescriptions of table 4
Preparation method is as follows: get the Radix Salviae Miltiorrhizae total phenolic acids of embodiment 1 preparation and Radix Notoginseng total arasaponins mixing in proportion, add microcrystalline Cellulose, lactose, alcoholic solution system soft material with 5% polyvinylpyrrolidone, 16 mesh sieves are granulated, dry back granulate, the disintegrating agent (sodium carboxymethyl cellulose) of adding 5%, 1% magnesium stearate, 0.5% micropowder silica gel, mixing tabletting, or sugar coating or bag film-coat.
After measured, recording every middle content of danshinolic acid B is 5.46%; Ginsenoside Rb
1Content is 19.39%, the ginsenoside Rg
1Content is 18.43%; Radix Salviae Miltiorrhizae total phenolic acids content is 8.74%, and content of the total saponins in radix notoginseng is 43.71%.
Embodiment 4 red seven compositions Orally disintegrating slice prescription and preparations
In the present embodiment, the prescription such as the table 5 of employing.
The red seven compositions Orally disintegrating slice prescriptions of table 5
Preparation method is as follows: the Radix Salviae Miltiorrhizae total phenolic acids of embodiment 1 preparation of wherein adopting and Radix Notoginseng total arasaponins be according to the proper proportion mixing, again with above table in listed other adjuvant mix direct powder compression.
After measured, recording every middle content of danshinolic acid B is 3.16%; Ginsenoside Rb
1Content is 5.64%, the ginsenoside Rg
1Content is 5.29%; Radix Salviae Miltiorrhizae total phenolic acids content is 4.97%, and content of the total saponins in radix notoginseng is 14.12%.
The prescription and the preparation of embodiment 5 red seven composite injections
In the present embodiment, the prescription such as the table 6 of employing.
The red seven composite injection prescriptions of table 6
Get Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins by the method preparation of embodiment 1, add an amount of water for injection and make dissolving, add 0.1% active carbon, 40 ℃ were stirred 15 minutes, after being cooled to room temperature, filter with the filter paper plate earlier, reuse 0.2 μ m microporous filter membrane filters, and adds injection and is diluted with water to 2000ml, embedding, every 2ml, sterilization, promptly.
The prescription and the preparation of embodiment 6 red seven composite freeze-dried powder agent
In the present embodiment, the prescription such as the table 7 of employing.
The prescription and the preparation of the red seven composite freeze-dried powder agent of table 7
Get Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, add a certain amount of water for injection and make dissolving, add 0.1% active carbon, 40 ℃ were stirred 15 minutes, after being cooled to room temperature, filter with the filter paper plate earlier, reuse 0.2 μ m microporous filter membrane filters, and adds injection and is diluted with water to 8000ml, fill, every 4ml, lyophilization promptly gets 2000 powder pins.
After measured, recording every middle content of danshinolic acid B is 10.12%; Ginsenoside Rb
1Content is 25.97%, the ginsenoside Rg
1Content is 25.23%; Radix Salviae Miltiorrhizae total phenolic acids content is 13.68%, and content of the total saponins in radix notoginseng is 66.67%.
The prescription and the preparation of embodiment 7 red seven composition granules
In the present embodiment, the prescription such as the table 8 of employing.
The prescription of red seven composition granules of table 8
Get Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins mixing, add dextrin again, with 90% alcoholic solution system soft material, 14 mesh sieves are granulated, and drying makes 1000 bags of granules, every bag of 1.5g.
After measured, record that content of danshinolic acid B is 4.06% in every bag of granule; Ginsenoside Rb
1Content is 16.73%, the ginsenoside Rg
1Content is 16.05%; Radix Salviae Miltiorrhizae total phenolic acids content is 5.68%, and content of the total saponins in radix notoginseng is 44.17%.
The prescription and the preparation of embodiment 8 red seven composition capsules
In the present embodiment, the prescription such as the table 9 of employing.
The prescription of red seven composition capsules of table 9
Get Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins mixing, add 1% magnesium stearate, fill capsule behind the mixing gets 1000 capsules.
After measured, record that content of danshinolic acid B is 9.9% in every capsules; Ginsenoside Rb
1Content is 26.40%, the ginsenoside Rg
1Content is 25.87%; Radix Salviae Miltiorrhizae total phenolic acids content is 13.50%, and content of the total saponins in radix notoginseng is 66.71%.
The prescription and the preparation of embodiment 9 red seven composition dripping agent
In the present embodiment, the prescription such as the table 10 of employing.
The prescription of the red seven composition dripping agent of table 10
Polyethylene glycol 6000 is put in the water-bath fusion fully, adds Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, stirs and makes dissolving, keeps 80 ℃ to splash in 15 ℃ of liquid paraffin and become ball, is prepared into 1000 bags of drop pill, and every bag 3.0 restrains.
After measured, record every bag in content of danshinolic acid B be 9.30%; Ginsenoside Rb
1Content is 26.75%, the ginsenoside Rg
1Content is 26.32%; Radix Salviae Miltiorrhizae total phenolic acids content is 13.740%, and content of the total saponins in radix notoginseng is 66.34%.
The prescription and the preparation of embodiment 10 red seven compositions pills
In the present embodiment, the prescription such as the table 11 of employing.
The prescription of the red seven compositions pills of table 11
Getting Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins mixing, is wetting agent with water, makes 3000 with conventional agitation procedure.
After measured, record every in content of danshinolic acid B be 7.85%; Ginsenoside Rb
1Content is 26.57%, the ginsenoside Rg
1Content is 25.35%; Radix Salviae Miltiorrhizae total phenolic acids content is 11.64%, and content of the total saponins in radix notoginseng is 70.28%.
The prescription and the preparation of embodiment 11 red seven composition oral liquid
In the present embodiment, the prescription such as the table 12 of employing.
The prescription of the red seven composition oral liquid of table 12
With Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins and Mel, sodium benzoate, add deionized water to 1000ml, stir evenly, filter, fill, sterilization, promptly.Every dress 10ml, totally 1000.
After measured, record that content of danshinolic acid B is 8.65% in every oral liquid; Ginsenoside Rb
1Content is 24.59%, the ginsenoside Rg
1Content is 23.48%; Radix Salviae Miltiorrhizae total phenolic acids content is 12.58%, and content of the total saponins in radix notoginseng is 62.92%.
The foundation of embodiment 12 finger printing
Liquid/(Finnigan MAT, San Jose CA), set up finger printing to the matter combined instrument to adopt U.S. Finnigan company's T SQ Quantum LC/MS/MS.
Liquid phase chromatogram condition:
Zorbax SB-C
18Chromatographic column (100 * 3.0mm); Mobile phase: A is 0.1% formic acid (V/V), and B is a methanol; 20 ℃ of column temperatures, flow velocity are 0.6ml/min; Elution program is:
In the time of 0-6 minute, the ratio of methanol rises to 35%, 0.1% formic acid ratio by 20% and reduces to 65% by 80%; 6-30 minute, methanol was raised to 55%, 0.1% formic acid ratio by 35% and reduces to 45% by 65%; 30-40 minute, the ratio of methanol rose to 70%, 0.1% formic acid ratio by 55% and reduces to 30% by 45%, and 40-50 minute, the ratio of methanol rose to 75%, 0.1% formic acid ratio by 70% and reduces to 25% by 30%.
The mass spectrum condition:
The ESI source; Anion detects; Sweep limits: 120-1400m/z amu; Sheath air-flow: 40arb;
Secondary air: 10arb; Source voltage: 4.00kV; Capillary temperature: 330 ℃.
The preparation of need testing solution:
(1) precision takes by weighing Radix Salviae Miltiorrhizae total phenolic acids 1mg, places the 5ml volumetric flask, with water dissolution and be settled to scale, shake up, and 0.45 μ m filtering with microporous membrane, standby.
(2) precision takes by weighing Radix Notoginseng total arasaponins 5mg, places the 5ml volumetric flask, with water dissolution and be settled to scale, shake up, and 0.45 μ m filtering with microporous membrane, standby.
(3) measure above-mentioned Radix Salviae Miltiorrhizae total phenolic acids solution and each 1ml of Radix Notoginseng total arasaponins solution respectively, mix homogeneously, 0.45 μ m filtering with microporous membrane, promptly.
As a result, the finger printing of acquisition is seen Fig. 2, and the corresponding retention time in each peak, chemical compound and source thereof see Table 13.
Table 13 finger printing peak
| Retention time (min) | Chemical compound | The source | |
| 1 | 2.96 | Protocatechualdehyde | Radix Salviae Miltiorrhizae total |
| 2 | 12.87 | Rosmarinic acid | Radix Salviae Miltiorrhizae total |
| 3 | 14.60 | Salvianolic acid B | Radix Salviae Miltiorrhizae total phenolic acids |
| 4 | 23.08 | Panax Notoginseng saponin R 1 | Radix Notoginseng total arasaponins |
| 5 | 25.86 | The ginsenoside Rg 1 | Radix Notoginseng total arasaponins |
| 6 | 34.88 | Panax Notoginseng saponin R 2 | Radix Notoginseng total arasaponins |
| 7 | 36.46 | The ginsenoside Rh 1 | Radix Notoginseng |
| 8 | 41.61 | Ginsenoside Rb 1 | Radix Notoginseng total arasaponins |
| 9 | 45.40 | The ginsenoside Rd | Radix Notoginseng |
| 10 | 48.91 | Arasaponin K | Radix Notoginseng total arasaponins |
The assay of embodiment 13 main components
1. salvianolic acid B
Measure according to high performance liquid chromatography (" an appendix VI of Chinese pharmacopoeia version in 2005 D).
A. chromatographic condition and system suitability test
With the octadecylsilane chemically bonded silica is filler; With acetonitrile-0.1% phosphoric acid (21: 79) is mobile phase; The detection wavelength is 286nm.Number of theoretical plate calculates by the salvianolic acid B peak should be not less than 4000.
B. the preparation of reference substance solution
It is an amount of to get salvianolic acid B reference substance (111562-200403 of Nat'l Pharmaceutical ﹠ Biological Products Control Institute), and accurate the title decides, and adds 40% ethanol and makes the solution that every 1ml contains 80 μ g, promptly.
C. the preparation of need testing solution
Solid preparation: get the about 50mg of red seven preparations of solid, the accurate title, decide, and puts in the 25ml measuring bottle, and it is an amount of to add 40% ethanol, and supersound process (power 140W, frequency 42kHz) 15 minutes is placed to room temperature, adds 40% ethanol to scale, shakes up, and filters, and gets subsequent filtrate, promptly.
Liquid preparation: it is an amount of to get red seven preparations of liquid, adds deionized water to containing red seven solid content 2mg/ml approximately, promptly.
D. algoscopy
Accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing inject chromatograph of liquid, measure, promptly.
2. ginsenoside Rg
1
Measure according to high performance liquid chromatography (" an appendix VI of Chinese pharmacopoeia version in 2005 D).
A. chromatographic condition and system suitability test
With the octadecylsilane chemically bonded silica is filler; With acetonitrile-water (18: 82) is mobile phase; The detection wavelength is 203nm; Number of theoretical plate is by the ginsenoside Rg
1The peak calculates should be not less than 4000.
B. the preparation of reference substance solution
Get the ginsenoside Rg
1Reference substance (110703-200322 of Nat'l Pharmaceutical ﹠ Biological Products Control Institute) is an amount of, and accurate the title decides, and adds methanol and makes the solution that every 1ml contains 400 μ g, promptly.
C. the preparation of need testing solution
Solid preparation: get the about 30mg of red seven preparations of solid, the accurate title, decide, and puts in the 10ml measuring bottle, and it is an amount of to add methanol, and supersound process (power 140W, frequency 42kHz) 30 minutes is placed to room temperature, adds methanol to scale, shakes up, and filters, and gets subsequent filtrate, promptly.
Liquid preparation: it is an amount of to get red seven preparations of liquid, adds deionized water to containing red seven solid content 3mg/ml approximately, promptly.
D. algoscopy
Accurate respectively reference substance solution and the need testing solution 10 μ l of drawing inject chromatograph of liquid, measure, promptly.
3. Radix Salviae Miltiorrhizae total phenolic acids
Measure according to ultraviolet visible spectrophotometry (" an appendix V of Chinese pharmacopoeia version in 2005 A).
A. the preparation of reference substance solution
It is an amount of to get salvianolic acid B reference substance (111562-200403 of Nat'l Pharmaceutical ﹠ Biological Products Control Institute), and accurate the title decides, and adds 40% ethanol and makes the solution that every 1ml contains 36 μ g, promptly.
B. the preparation of need testing solution
The accurate need testing solution 1ml that draws content of danshinolic acid B mensuration item places the 5ml measuring bottle, adds 40% ethanol to scale, shakes up, promptly.
C. algoscopy
Get the about 5ml of reference substance solution and need testing solution, make blank with 40% ethanol, the photograph ultraviolet visible spectrophotometry (" an appendix V of Chinese pharmacopoeia version in 2005 A), under 286nm, measure absorbance, be converted into the content of total phenolic acid by following formula.
Total phenolic content (%)=0.626 * (A-B)+B
In the formula:
A adopts ultraviolet spectrophotometry to record the content of total phenolic acid in the test sample for being contrast with the salvianolic acid B
B is the content that high performance liquid chromatography records salvianolic acid B in the test sample.
4. Radix Notoginseng total arasaponins
Measure according to ultraviolet visible spectrophotometry (" an appendix V of Chinese pharmacopoeia version in 2005 A).
A. the preparation of reference substance solution
Get the ginsenoside Rg
1Reference substance (110703-200424 of Nat'l Pharmaceutical ﹠ Biological Products Control Institute) is an amount of, and accurate the title decides, and adds methanol and makes the solution that every 1ml contains 800 μ g, promptly.
B. the preparation of need testing solution
Solid preparation: get the red seven preparation 0.1g of solid, the accurate title, decide, and puts in the 25ml tool plug conical flask, the accurate methanol 10ml that adds, close plug claims to decide weight, supersound process (power 140W, frequency 42kHz) 30 minute, be placed to room temperature, claim again to decide weight, supply the weight that subtracts mistake with methanol, shake up, filter, get 2ml filtrate and volatilize, the 2ml water dissolution, standardize solution, get solid phase extraction column on the 0.5ml aqueous solution, distinguish water, 20% methanol, each 2ml eluting of methanol then, collect meoh eluate to the 2ml measuring bottle, shake up, promptly.
Liquid preparation: get the liquid solution 0.5ml that contains the red seven preparation 10mg/ml of liquid, last solid phase extraction column is distinguished water, 20% methanol, each 2ml eluting of methanol then, collects meoh eluate to the 2ml measuring bottle, shakes up, promptly.
C. algoscopy
Accurate respectively absorption reference substance solution and need testing solution be 100 μ l respectively, place the tool plug test tube of 10ml respectively, volatilize solvent, the 5% vanillin glacial acetic acid solution 0.2ml that adds new preparation, perchloric acid 0.8ml, insulation is 15 minutes in 60 ℃ of water-baths, puts immediately in the frozen water and cools off 5 minutes, add glacial acetic acid 5ml, shake up, place 10min, the photograph ultraviolet visible spectrophotometry (" an appendix V of Chinese pharmacopoeia version in 2005 A), wavelength place at 545nm measures absorbance, promptly.
The test of pesticide effectiveness of embodiment 14 red seven preparations
In the present embodiment, the inventor has detected the drug effect of pellet seven preparations of two kinds of prescriptions.Prescription 1 is pellet seven preparations according to embodiment 3 described formulated.Prescription 2 is a kind of pellet seven preparations that utilize Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins preparation, and its prescription is shown in " prescription 2 " row in the table 14 after measured.
This experiment adopts the ligation of anesthetized dog anterior descending coronary to cause myocardial infarction model, observes prescription 1 respectively and with prescription 2 (seeing Table 14) whether the anesthetized dog acute myocardial infarction is had protective effect.Experiment divides 3 groups: 1. solvent control group; 2. write out a prescription 1 group; 3. write out a prescription 2 groups.Cause acute myocardial infarction model by Harris method two step ligation anterior descending coronary.The change of epicardial electrogram variation after the observation medication, myocardial infarction weight and serum cardiac muscle zymetology.
The results are shown in Table 15-1, table 15-2, table 15-3, table 15-4,1 gastric infusion of writing out a prescription can reduce the degree of myocardial infarction behind the dog coronary ligation, dwindles the scope of myocardial infarction, reduces overflowing of lactic acid dehydrogenase, and effect is not remarkable behind 2 gastric infusions of writing out a prescription.Epicardial electrogram, histology's detection by quantitative and serum zymetology testing result show; writing out a prescription writes out a prescription 2 groups behind 1 gastric infusion can significantly reduce myocardial infarction degree behind the anesthetized dog coronary ligation; dwindle myocardial infarct size, acute myocardial infarction is had the better protect effect.
Pellet seven preparation prescriptions of two kinds of different proportions of table 14
| Prescription 1 | |
|
| Radix Salviae Miltiorrhizae total phenolic acids | 40g | 120g |
| Radix Notoginseng total arasaponins | 200g | 120g |
| Microcrystalline Cellulose | 50g | 50g |
| Lactose | 30g | 30g |
| The alcoholic solution of 5% polyvinylpyrrolidone | 25g | 25g |
| Sodium carboxymethyl cellulose | 5％(16g) | 5％(16g) |
| Magnesium stearate | 1％(3.2g) | 1％(3.2g) |
| Micropowder silica gel | 0.5％(1.8g) | 0.5％(1.8g) |
Table 15-1 is to the influence of dog coronary ligation epicardial electrogram ST section summation (∑ ST)
Table 15-2 is to the influence of myocardial infarct size (epicardial electrogram NST)
Compare with the solvent control group,
*P＜0.05
*P＜0.01
Table 15-3 is to the influence of myocardial infarct size (NBT staining mensuration)
Compare with the solvent control group,
*P＜0.05
*P＜0.01
Table 15-4 is to the influence of coronary ligation dog serum biochemical indicator (LDH)
By the result of table 15-1-table 15-4 as seen, apparently higher than prescription 2 and solvent control group, and 2 remission effects for the myocardial infarction of dog of writing out a prescription are equal to the solvent control group to prescription 1 substantially for the remission effect of the myocardial infarction of dog, and 2 drug effects of promptly writing out a prescription are not obvious.
2 further measure and show writing out a prescription according to the inventor, in the prescription 2, content of danshinolic acid B is 19.68%; Ginsenoside Rb
1Content is 9.83%, the ginsenoside Rg
1Content is 9.27%; Radix Salviae Miltiorrhizae total phenolic acids content is 27.21%, and content of the total saponins in radix notoginseng is 28.92%.Also promptly write out a prescription ginsenoside Rg1, salvianolic acid B and the ginsenoside Rb1's contained in 2 content not at 0.7-4.3: 1.0: in effective ratio range of 0.7-4.3.
According to above measurement result, the inventor 2 adjusts writing out a prescription, and wherein Radix Salviae Miltiorrhizae total phenolic acids is adjusted into 80g, and Radix Notoginseng total arasaponins is adjusted into 160g, promptly writes out a prescription 2 ', and other prescription is constant.Measure once more and find that content of danshinolic acid B is 12.02% in the prescription 2 '; Ginsenoside Rb
1Content is 13.11%, the ginsenoside Rg
1Content is 14.86%, belongs to 0.7-4.3: 1.0: the scope of 0.7-4.3.
The inventor will write out a prescription and 2 ' carry out pharmacodynamics test, find that its remission effect for the myocardial infarction of dog is fine, and drug effect clearly.
This shows, be necessary very much various red seven preparations are carried out quality control, in time find out and remove defective medicine, guarantee in red seven preparations content of effective in effective range or preferred range, thereby can improve the medication effect greatly.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (8)
1. compositions, it is characterized in that described compositions contains Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, Radix Salviae Miltiorrhizae total phenolic acids: Radix Notoginseng total arasaponins=1: 2-8, described Radix Salviae Miltiorrhizae total phenolic acids adopts the method preparation of red rooted salvia water extract-alcohol precipitation, and it is WS that described Radix Notoginseng total arasaponins adopts standard No.
3The described product of-B-3590-2001 (Z), wherein contain following composition:
(a) ginsenoside Rg of 0.7-4.3 weight portion
1
(b) salvianolic acid B of 1.0 weight portions;
(c) the ginsenoside Rb of 0.7-4.3 weight portion
1And
(d) acceptable carrier on the pharmacy of 6-100 weight portion or the bromatology;
Wherein, the total content of component (a)+(b)+(c) is the 25-50% of composition total weight.
2. compositions as claimed in claim 1 is characterized in that,
The ginsenoside Rg
1Content be the 1.5-3.5 weight portion;
The content of salvianolic acid B is 1.0 weight portions; Or
Ginsenoside Rb
1Content be the 1.5-3.5 weight portion.
3. compositions as claimed in claim 1 is characterized in that, the dosage form of described compositions is selected from: tablet, injection, lyophilized injectable powder, granule, capsule, drop pill, pill or oral liquid.
4. compositions as claimed in claim 1 is characterized in that, ginsenoside Rg wherein
1, salvianolic acid B and ginsenoside Rb
1Weight ratio satisfy 2-2.8: 1.0: 2-2.8.
5. the purposes of the described compositions of claim 1 is characterized in that, is used to prepare the medicine of prevention or treatment cardiovascular disease.
6. a method for preparing pellet seven preparations of claim 1 is characterized in that, described red seven preparations contain Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, and described method comprises step:
(i) regulate ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Content, make three's weight ratio be: the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3;
And, set up the composition that finger printing is measured red seven preparations, wherein: Zorbax SB-C
18Chromatographic column; Mobile phase: A is a 0.1V/V% formic acid, and B is a methanol; 20 ℃ of column temperatures, flow velocity are 0.6ml/min; Elution program is: in the time of 0-6 minute, the ratio of methanol rises to 35%, 0.1% formic acid ratio by 20% and reduces to 65% by 80%; 6-30 minute, methanol was raised to 55%, 0.1% formic acid ratio by 35% and reduces to 45% by 65%; 30-40 minute, the ratio of methanol rose to 70%, 0.1% formic acid ratio by 55% and reduces to 30% by 45%, and 40-50 minute, the ratio of methanol rose to 75%, 0.1% formic acid ratio by 70% and reduces to 25% by 30%;
Mass spectrum condition: ESI source; Anion detects; Sweep limits: 120-1400m/z amu; Sheath air-flow: 40arb; Secondary air: 10arb; Source voltage: 4.00kV; Capillary temperature: 330 ℃;
The preparation of need testing solution:
(1) precision takes by weighing Radix Salviae Miltiorrhizae total phenolic acids 1mg, places the 5ml volumetric flask, with water dissolution and be settled to scale, shake up, and 0.45 μ m filtering with microporous membrane, standby;
(2) precision takes by weighing Radix Notoginseng total arasaponins 5mg, places the 5ml volumetric flask, with water dissolution and be settled to scale, shake up, and 0.45 μ m filtering with microporous membrane, standby;
(3) measure above-mentioned Radix Salviae Miltiorrhizae total phenolic acids solution and each 1ml of Radix Notoginseng total arasaponins solution respectively, mix homogeneously, 0.45 μ m filtering with microporous membrane, promptly.
7. method as claimed in claim 6 is characterized in that, regulates ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Weight ratio be:
The ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=1.5-3.5: 1.0: 1.5-3.5.
8. method as claimed in claim 6 is characterized in that, described step (i) comprising:
Measure the ginsenoside Rg in red seven preparations
1, salvianolic acid B and ginsenoside Rb
1Content is if three's content satisfies the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 does not then adjust the preparation composition; If three's content does not satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3 then regulates the wherein consumption of respective components according to measurement result, thereby makes three's content satisfy the ginsenoside Rg
1: salvianolic acid B: ginsenoside Rb
1=0.7-4.3: 1.0: 0.7-4.3;
Perhaps described step (i) comprising:
Measure ginsenoside Rg in Radix Salviae Miltiorrhizae and the Radix Notoginseng raw material
1, salvianolic acid B and ginsenoside Rb
1Content, and determine proportion of raw materials according to measurement result.
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| CNB2006101188032A CN100563662C (en) | 2006-11-28 | 2006-11-28 | Chinese medicine active ingredient composition of treatment cardiovascular disease and preparation method thereof |
| PCT/CN2007/070811 WO2008064592A1 (en) | 2006-11-28 | 2007-09-28 | A composition comprising chinese traditional medicine as active ingredient for treating cardiovascular diseases and quality control method thereof |
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| CN101428050B (en) * | 2008-12-15 | 2011-10-12 | 云南白药集团股份有限公司 | Active composition for treating thrombus, cardio-cerebrovascular system diseases |
| CN102908355B (en) * | 2011-08-04 | 2014-06-04 | 中国科学院上海药物研究所 | Medicinal composition and application thereof |
| CN109900826A (en) * | 2019-03-26 | 2019-06-18 | 广州莱泰制药有限公司 | A kind of Fufang Danshen Pian Radix Notoginseng Content Test method |
| JP2022545968A (en) * | 2019-08-29 | 2022-11-01 | 中国科学院上海薬物研究所 | Pharmaceutical compositions and uses thereof |
| CN111855833B (en) * | 2020-06-09 | 2022-10-21 | 纳谱分析技术（苏州）有限公司 | Analysis method for determining tetracyclic triterpenoid saponin in compound salvia miltiorrhiza preparation based on polymer-coated silica gel bonded filler |
| CN117883432A (en) * | 2023-10-25 | 2024-04-16 | 广州白云山和记黄埔中药有限公司 | New application of salvianolic acid B |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1470255A (en) * | 2002-07-22 | 2004-01-28 | 王智民 | Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use |
| CN1600319A (en) * | 2003-09-23 | 2005-03-30 | 天津天士力制药股份有限公司 | Combination of Chinese traditional medicine for curing cardiovascular and cerebrovascular diseases |
| CN1600318A (en) * | 2003-09-23 | 2005-03-30 | 天津天士力制药股份有限公司 | Combination of Chinese traditional medicine for curing cardiovascular diseases and cerebrovascular disease |
| CN1772041A (en) * | 2005-11-02 | 2006-05-17 | 中国药科大学 | Quality detection method for compound prepn of red sage and notoginseng |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1470255A (en) * | 2002-07-22 | 2004-01-28 | 王智民 | Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use |
| CN1600319A (en) * | 2003-09-23 | 2005-03-30 | 天津天士力制药股份有限公司 | Combination of Chinese traditional medicine for curing cardiovascular and cerebrovascular diseases |
| CN1600318A (en) * | 2003-09-23 | 2005-03-30 | 天津天士力制药股份有限公司 | Combination of Chinese traditional medicine for curing cardiovascular diseases and cerebrovascular disease |
| CN1772041A (en) * | 2005-11-02 | 2006-05-17 | 中国药科大学 | Quality detection method for compound prepn of red sage and notoginseng |
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