WO2008064592A1 - Composition comprenant un médicament chinois traditionnel en tant qu'ingrédient actif pour le traitement de maladies cardiovasculaires, et procédé de contrôle qualité de celle-ci - Google Patents

Composition comprenant un médicament chinois traditionnel en tant qu'ingrédient actif pour le traitement de maladies cardiovasculaires, et procédé de contrôle qualité de celle-ci Download PDF

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Publication number
WO2008064592A1
WO2008064592A1 PCT/CN2007/070811 CN2007070811W WO2008064592A1 WO 2008064592 A1 WO2008064592 A1 WO 2008064592A1 CN 2007070811 W CN2007070811 W CN 2007070811W WO 2008064592 A1 WO2008064592 A1 WO 2008064592A1
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ginsenoside
content
danqi
salvianolic acid
preparation
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PCT/CN2007/070811
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English (en)
Chinese (zh)
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De'an Guo
Wanying Wu
Zhigang Gao
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2008064592A1 publication Critical patent/WO2008064592A1/fr

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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
    • 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
    • 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)
    • 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)
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • 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

Definitions

  • the invention belongs to the technical field of medicines, and particularly relates to a traditional Chinese medicine active ingredient composition for treating cardiovascular diseases and a quality control method for the Danqi preparation. Background technique
  • cardiovascular and cerebrovascular diseases have become the most important diseases affecting the health of residents.
  • the incidence of coronary heart disease is 3-5%, and in some areas it is 8-10%, which has been on the rise in recent years. China has entered an aging society.
  • the proportion of the population over 65 years old has exceeded 10%, and the population of coronary heart disease will also expand.
  • cardiovascular and cerebrovascular diseases there are about 2.6 million people every year, and about 7,000 people die every day from cardiovascular and cerebrovascular diseases.
  • cardiovascular and cerebrovascular drugs have become the world's largest drug market.
  • cardiovascular drugs ranked first in the global pharmaceutical market, with a market share of 16.09. %, the market size is 75 billion US dollars.
  • cardiovascular and cerebrovascular drugs ranked second in the Chinese pharmaceutical market, second only to anti-infective drugs, with a market share of 14.36%.
  • the pathogenesis of cardiovascular and cerebrovascular diseases is complex, and modern drug therapy based on molecular biology is still difficult to effectively exert therapeutic effects in some fields.
  • Cardio-cerebral vascular medicine is a proprietary Chinese medicine for treating cardiovascular and cerebrovascular diseases such as coronary heart disease, stroke, myocardial infarction and combined with shock, arrhythmia, angina pectoris and hypertension, including oral Chinese patent medicines, traditional Chinese medicine injections and other dosage forms.
  • cardiovascular and cerebrovascular diseases such as coronary heart disease, stroke, myocardial infarction and combined with shock, arrhythmia, angina pectoris and hypertension
  • traditional Chinese medicine injections and other dosage forms including oral Chinese patent medicines, traditional Chinese medicine injections and other dosage forms.
  • proprietary Chinese medicines occupy a very important position in the market of cardiovascular and cerebrovascular drugs in China. Market size is the most important indicator to measure the characteristics of the market economy.
  • Salvia miltiorrhiza is the dry root and stem of Salvia miltiorrhiza, a plant of the Labiatae family. It has the effect of promoting blood circulation and removing phlegm.
  • Sanqi is the dry root of Panax notoginseng, Panax notoginseng, which has the effect of dilating and stopping bleeding, reducing swelling and relieving pain, and tonifying Qi and nourishing blood.
  • Danshen compound preparation consisting of Danshen and Sanqi compatibility is used for clinical treatment of cardiovascular diseases such as coronary heart disease and angina pectoris. The function and indication of Danqi Tablet is for promoting blood circulation and removing blood stasis.
  • composition comprising the following ingredients:
  • the total content of the components (a) X (b) X (c) is from 1 to 50% by weight based on the total weight of the composition.
  • composition comprises:
  • the content of ginsenoside R gl is 1.5-3.5 parts by weight
  • the content of salvianolic acid B is 1.0 part by weight; or
  • the content of ginsenoside is 1.5 to 3.5 parts by weight.
  • the dosage form of the composition is selected from the group consisting of (including but not limited to): a tablet, an orally disintegrating tablet, an injection, a lyophilized powder, a granule, a capsule, a pill, Pill or oral solution.
  • the pharmaceutically or foodly acceptable carrier is selected from the group consisting of a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, and a coating material. , or other excipients or excipients.
  • the composition comprises: salvianolic acid and panax notoginseng saponins.
  • the composition comprises salvia total phenolic acid and panax notoginseng saponin, and wherein the weight ratio of ginsenoside Rgi, salvianolic acid B and ginsenoside Rbi satisfies 0.7-4.3: 1.0 : 0.7-4.3 o
  • the composition for the preparation of a medicament for the prevention or treatment of cardiovascular diseases.
  • a method for quality control of a Danqi preparation comprising the steps of: controlling a content of ginsenoside R gl , salvianolic acid B, and ginsenoside Rb in a Danqi preparation, so that the three The weight ratio is:
  • the weight ratio of ginsenoside R gl , salvianolic acid B, and ginsenoside Rbi in the Danqi preparation is controlled as follows:
  • the quality control includes the following steps:
  • control includes the following steps:
  • ginsenoside Rgi, salvianolic acid B and ginsenoside Rbi in Danshen and Sanqi raw materials were determined, and the ratio of the raw materials of the medicinal materials was determined according to the measurement results.
  • the content of ginsenoside Rgl, salvianolic acid B, or ginsenoside Rbl in the Danqi preparation is determined by chromatography (e.g., liquid chromatography;
  • the content of salvianolic acid B is determined as follows:
  • the octadecylsilane-bonded silica gel is used as a filler; the acetonitrile-0.1% phosphoric acid (21:79) is used as the mobile phase; the detection wavelength is 286 nm, and the theoretical plate number is not less than 4000 according to the peak of salvianolic acid B;
  • a solution of 80 ⁇ ⁇ salvianolic acid B/ml was prepared by adding 40% ethanol to the salvianolic acid B reference product to obtain a reference solution;
  • the reference substance and the test sample were subjected to liquid chromatography to obtain the content of salvianolic acid B.
  • the octadecylsilane bonded silica gel is used as a filler; the acetonitrile-water (18:82) is used as the mobile phase; the detection wavelength is 203 nm ; the theoretical plate number is not less than 4000 according to the ginsenoside R gl peak;
  • the reference substance and the test sample were subjected to liquid chromatography to obtain a content of ginsenoside R gl .
  • the content of total phenolic acid in the test sample was determined by ultraviolet spectrophotometry with barium sulphate as the control.
  • B is the content of salvianolic acid B in the test sample measured by high performance liquid chromatography.
  • the reference solution and the test solution were separately evaporated to a solvent, and respectively added with 5% vanillin glacial acetic acid solution and perchloric acid, and incubated in a water bath at 60 ° C for 15 minutes, immediately cooled in ice water for 5 minutes, and added with glacial acetic acid 5 ml.
  • the absorbance value is measured by ultraviolet-visible spectrophotometry at a wavelength of 545 nm, and the content of the total saponins of Panax notoginseng is obtained in another preferred embodiment of the present invention, and the ginseng in the Danqi preparation is determined by measuring the fingerprint of the Danqi preparation. Saponin Rgl, salvianolic acid B, or ginsenoside Rbl content.
  • the fingerprint is determined by high performance liquid chromatography.
  • the method of determining the fingerprint is as follows:
  • the octadecylsilane bonded silica gel was used as a filler; the flow rate was 1.0 ml/min ; the column temperature was 25 ° C ; the detection wavelength was 203 nm ; and the acetonitrile-0.1% phosphoric acid aqueous solution was used as the mobile phase, and the gradient washing was carried out according to the following gradient elution conditions. Take off, run for 50min;
  • the method of quality control comprises the steps of: controlling the content of total phenolic acid and total saponins of salvia miltiorrhiza in the Danqi preparation, so that the weight ratio of the two is:
  • the content of total phenolic acid and total saponins of Salvia miltiorrhiza is determined by colorimetry.
  • Figure 1 shows the HPLC fingerprint of Danqi preparation. 1 is ginsenoside Rgl, 2 is salvianolic acid
  • B, 3 is ginsenoside Rbl.
  • Figure 2 shows the fingerprint of the Danqi preparation established by the TSQ Quantum LC/MS/MS liquid/mass spectrometer.
  • “Danqi preparation” refers to a general term for preparations containing Salvia miltiorrhiza and Panax notoginseng as essential components, including but not limited to: a mixture of Salvia miltiorrhiza extract and Panax notoginseng extract, Salvia total phenolic acid and Panax notoginseng saponins. Mixtures, etc.
  • the present invention is directed to the disadvantage that the content of the active ingredient in the Danqi preparation prepared by using the Salvia miltiorrhiza extract and the Panax notoginseng extract or the Salvia total phenolic acid and the Panax notoginseng saponin is unstable, resulting in unstable therapeutic effect.
  • the present invention provides a composition comprising ginsenoside R gl , salvianolic acid B, and ginsenoside. Moreover, the novel findings of the present invention can also be used for quality control of Danqi preparations. combination
  • essential component refers to the necessary Chinese herbal medicines, namely Salvia miltiorrhiza, and Panax notoginseng.
  • essential ingredient refers to the essential chemical substance as an active ingredient, ie, salvia miltiorrhiza. Acid, and Panax notoginseng saponins.
  • main component or “principal component” refers to a chemical component that exerts therapeutic efficacy in total phenolic acid or total saponins of Panax notoginseng, namely ginsenoside R gl , salvianolic acid B and ginsenoside Rb.
  • the term "consisting essentially of” means that in the composition, in addition to containing the essential ingredients or essential components, it may contain minor minor components which do not affect the active ingredient and/or Or impurities.
  • sweeteners may be included to improve taste, antioxidants to prevent oxidation, and other additives commonly used in the art.
  • the term "pharmaceutically acceptable carrier” refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
  • the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co. N. J. 1991).
  • the pharmaceutically acceptable carrier in the composition may contain a liquid such as water, saline, glycerol and ethanol.
  • auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting or emulsifying agents, flavoring agents, pH buffering substances and the like may also be present in these carriers.
  • Non-essential ingredients other than essential components (danshen total phenolic acid, panax notoginseng saponins) from Danshen and Panax notoginseng, and other non-essential ingredients (such as other auxiliary medicines), also included in pharmaceutically acceptable carriers In the definition.
  • composition of the present invention as a main component, (1) ginsenoside Rg 1 ; (2) salvianolic acid B; and (3) ginsenoside Rb
  • the composition of the present invention can be directly used for treating or relieving cardiovascular disease
  • the disease may be co-administered with other drugs.
  • composition of the invention includes pharmaceutical compositions, food compositions and/or dietary supplements as long as they comprise or consist essentially of ginsenoside R gl , salvianolic acid B and ginsenoside Rbi.
  • the weight of ginsenoside R gl , salvianolic acid B and ginsenoside Rbi is from 1 to 50%, preferably from 3 to 40%, more preferably from 5 to 25% by weight based on the total weight of the composition.
  • the composition may be a mixture containing substantially pure of the above three compounds or their analogs, and a pharmaceutically acceptable carrier; or, the composition may be a total of ginseng total phenolic acid and notoginseng a saponin, and a mixture of pharmaceutically acceptable carriers; or the composition may be a mixture comprising Salvia miltiorrhiza extract and Panax notoginseng extract.
  • each main component may also be used in the form of "physiologically acceptable salt” or “physiologically acceptable acid or base derived salt” or in the form of "amide".
  • the salts include, but are not limited to, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids. Salt, while organic acids refer to acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid and maleic acid.
  • salts include those formed with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates or other conventional "prodrugs" (when administered in this form) , can be converted into active part in the body).
  • composition of the present invention can be prepared into any conventional preparation form by a conventional method, including but not limited to: a tablet, an orally disintegrating agent, an injection, a lyophilized powder injection, a granule, a capsule, a pill, a pill, or an oral preparation. liquid. From the standpoint of ease of preparation and administration, preferred compositions are solid compositions, especially tablets and solid filled or liquid filled capsules and the like.
  • compositions of the invention on cardiovascular disease is closely related to the level of essential active ingredients. Studies have shown that in order to achieve stable treatment and / or alleviate the effects of cardiovascular disease, the active ingredient content of the drug should be within a certain range.
  • the range of reasonable amounts of each component in the compositions of the present invention is:
  • the total content of the components (a) X (b) X (c) is from 1 to 50% by weight based on the total weight of the composition.
  • the amount of the composition of the present invention may vary depending on the mode of administration and the severity of the condition to be treated. However, usually, when the composition of the present invention is administered at a dose of about 1 to 50 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably administered in a divided dose of 1 to 4 times per day, or as a sustained release.
  • Formal administration For most large mammals, the total daily dose is about 60-5000 mg, preferably about 80-2000 mg.
  • This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as needed for the therapeutic condition.
  • the composition of the present invention can directly adopt the main components of the total phenolic acid and the total saponins of Panax notoginseng, and thus the active substance content is high and the stability is good, so that the patient can be greatly reduced.
  • the use of a dose increases patient compliance while increasing efficacy.
  • the total saponins of Panax notoginseng can be extracted according to the local standards of Yunnan province.
  • the standard number is
  • the total phenolic acid of Salvia miltiorrhiza can be extracted with water and then purified with macroporous resin to obtain the effective part of total phenolic acid.
  • Quality control method Based on the effective ratio and optimal ratio of ginsenoside R gl , salvianolic acid B and ginsenoside provided by the present invention, the composition of salvia miltiorrhiza total phenolic acid and panax notoginseng saponins or the extract of Salvia miltiorrhiza and Panax notoginseng extract The composition is quality controlled.
  • the quality control of the Danqi preparation can also be carried out by the following methods: determining the contents of ginsenoside R gl , salvianolic acid B and ginsenoside Rbi in Danshen and Sanqi raw materials, and determining the ratio of raw materials according to the measurement results.
  • the content of ginsenoside R gl , salvianolic acid B and ginsenoside Rbi obtained in the subsequent preparation satisfies the ginsenoside Rgi: salvianolic acid B: ginsenoside Rb ⁇ O.7-4.3: 1.0: 0.7-4.3.
  • high performance liquid chromatographic fingerprints can be used to characterize and quantify Danqi preparations.
  • Another alternative quality control method is to directly detect the main component of Danqi preparation (ginsenoside)
  • the content of Rgi, salvianolic acid B or ginsenoside Rbl) or essential ingredients is used to characterize and quantify the formulation of the Danqi composition.
  • the main advantages of the invention are:
  • the present invention finds the essential component of the Danqi preparation, which participates in the main components effective in the treatment of cardiovascular diseases, namely ginsenoside Rgl, salvianolic acid B and ginsenoside Rbl, and the invention is also found for the first time.
  • the three components are effective for treating cardiovascular diseases, and the compositions formulated according to the preferred range have a good effect of treating cardiovascular diseases.
  • the total saponins of Panax notoginseng are extracted according to local standards of Yunnan province, and the standard number is
  • the total phenolic acid of Salvia miltiorrhiza is prepared by the following method:
  • the ratio of total phenolic acid: the total saponin of Panax notoginseng is 1: 2 ⁇ 8; more preferably, the ratio of total phenolic acid of Salvia miltiorrhiza: total saponins of Panax notoginseng is 1: 3 ⁇ 7; further preferred The ratio of total phenolic acid of Salvia miltiorrhiza: total saponins of Panax notoginseng is 1: 4 ⁇ 6; most preferably, total phenolic acid of Salvia miltiorrhiza: total saponins of Panax notoginseng is 1:5.
  • ginsenoside Rgl a ratio range of ginsenoside Rgl, salvianolic acid B, and ginsenoside which are main components of Danqi.
  • the ratio of ginsenoside R gl : salvianolic acid B : ginsenoside Rbl is 0.7 to 4.3: 1.0: 0.7-4.3; more preferably, ginsenoside Rgi: salvianolic acid B: ginsenoside Rbi is calculated by weight 1 to 3.8: 1.0: 1 to 3.8; more preferably, ginsenoside Rg 1 : salvianolic acid B: ginsenoside RbJ ratio is 1.5 to 3.5: 1.0 : 1.5 to 3.5; further preferably, ginsenoside Rg 1 : dansolic Acid B: ginsenoside RbJ ratio is 2 to 2.8: 1.0: 2 to 2.8; most preferably, ginsenoside Rgi: salvianolic acid B: ginsen
  • the preparation method is as follows: taking the total phenolic acid and the total saponins of Salvia miltiorrhiza prepared in Example 1 and mixing them in proportion, Microcrystalline cellulose, lactose, soft material made of 5% polyvinylpyrrolidone alcohol solution, 16 mesh sieved granules, dried and granulated, adding 5% disintegrant (carboxymethylcellulose sodium;), 1 % magnesium stearate, 0.5% micronized silica gel, mixed into tablets, or coated or coated.
  • the content of salvianolic acid B in each tablet was 5.46%; the content of ginsenoside Rbi was 19.39%, the content of ginsenoside R gl was 18.43%; the total phenolic acid content of Salvia miltiorrhiza was 8.74%, and the total saponin content of Panax notoginseng was 43.71. %.
  • the preparation method is as follows: the salvianolic acid total phenolic acid prepared in Example 1 and the total saponin of Panax notoginseng are mixed in an appropriate ratio, and then mixed with other auxiliary materials listed in the above table, and the powder is directly compressed.
  • the content of salvianolic acid B in each tablet was determined to be 3.16%; the content of ginsenoside Rbi was 5.64%, the content of ginsenoside R gl was 5.29%; the total phenolic acid content of salvia miltiorrhiza was 4.97%, total saponin content of Panax notoginseng It is 14.12%.
  • Example 6 Made of 1000 Take the total phenolic acid and the Panax notoginseng saponins prepared according to the method of Example 1, add appropriate amount of water for injection to dissolve, add 0.1% activated carbon, stir at 40 ° C for 15 minutes, cool to room temperature, then filter with filter paper. Then use 0.2 ⁇ microporous membrane to filter, add water for injection to 2000ml, potting, 2ml each, sterilized, that is.
  • Example 6 Formulation and preparation of Danqi composition freeze-dried powder injection
  • the content of each of the dendritic acid B was determined to be 10.12%; the content of ginsenoside Rbi was 25.97%, the content of ginsenoside R gl was 25.23%; the total phenolic acid content of Salvia miltiorrhiza was 13.68%, and the total saponin content of Panax notoginseng was 66.67. %.
  • the phenolic acid of Salvia miltiorrhiza and the total saponin of Panax notoginseng were mixed, then dextrin was added, soft material was prepared with 90% alcohol solution, and sieved by 14 mesh sieve, and dried to obtain 1000 bags of granules, 1.5 g per bag.
  • the content of salvianolic acid B in each bag of granules was determined to be 4.06%; the content of ginseng saponin was 16.73%, the content of ginsenoside R gl was 16.05%; the total phenolic acid content of salvia miltiorrhiza was 5.68%, and the total saponin content of panax notoginseng was 5.68%. 44.17%.
  • Example 8 Formulation and preparation of Danqi composition capsule
  • the content of salvianolic acid B in each capsule was determined to be 9.9%; the content of ginsenoside Rbi was 26.40%, the content of ginsenoside R gl was 25.87%; the total phenolic acid content of salvia miltiorrhiza was 13.50%, and the total saponin content of Panax notoginseng was 13.50%. 66.71%.
  • the polyethylene glycol 6000 was completely melted on the water bath, and the total phenolic acid and the total saponins of Panax notoginseng were added, dissolved and dissolved, and kept at a temperature of 80 ° C and dropped into a liquid paraffin at 15 ° C to prepare pellets of 1000 bags, each bag. 3.0 grams.
  • the content of salvianolic acid B in each bag was determined to be 9.30%; the content of ginsenoside Rbi was 26.75%, the content of ginsenoside R gl was 26.32%; the total phenolic acid content of salvia miltiorrhiza was 13.740%, and the total saponin content of panax notoginseng was 66.34. %.
  • the content of salvianolic acid B in each capsule was determined to be 7.85%; the content of ginsenoside Rbi was 26.57%, the content of ginsenoside R gl was 25.35%; the total phenolic acid content of Salvia miltiorrhiza was 11.64%, and the total saponin content of Panax notoginseng was 70.28. %.
  • Example 11 Formulation and preparation of Danqi composition oral solution
  • Fingerprints were created using a Finnigan TSQ Quantum LC/MS/MS liquid/mass spectrometer (Finnigan MAT, San Jose, CA).
  • Zorbax SB-C 18 column (100x3. O mm); mobile phase: A is 0.1% formic acid (V/V), B is methanol; column temperature is 20 ° C, flow rate is 0.6 ml / min; elution procedure is:
  • Auxiliary gas flow 10 arb; Source voltage: 4.00 kV; Capillary temperature: 330 °C.
  • the octadecylsilane-bonded silica gel was used as a filler; the mobile phase was acetonitrile-0.1% phosphoric acid (21:79); the detection wavelength was 286 nm.
  • the number of theoretical plates should be no less than 4000 according to the peak of salvianolic acid B.
  • Solid preparation Take about 50mg of solid Danqi preparation, accurately weigh it, put it into 25ml volumetric flask, add 40% ethanol, sonicate (power 140W, frequency 42kHz) for 15 minutes, put it to room temperature, add 40% ethanol to the scale, Shake well, filter, and take the filtrate to obtain.
  • Liquid preparation Take appropriate amount of liquid Danqi preparation, add deionized water to about 2mg/ml containing Dandan solids, that is.
  • Each of the reference solution and the test solution are accurately taken up by 10 ⁇ l, injected into a liquid chromatograph, and measured.
  • the octadecylsilane-bonded silica gel was used as a filler; the acetonitrile-water (18:82) was used as the mobile phase; the detection wavelength was 203 nm ; the theoretical plate number was not less than 4,000 according to the ginsenoside Rgi peak.
  • Solid preparation Take about 30mg of solid Danqi preparation, accurately weighed, put it in a 10ml volumetric flask, add appropriate amount of methanol, sonicate (power 140W, frequency 42kHz) for 30 minutes, place it at room temperature, add methanol to the mark, shake well, filter After that, take the filtrate and get it.
  • Liquid preparation Take the appropriate amount of liquid Danqi preparation, add deionized water to about 3mg/ml containing Dandan solid, which is obtained.
  • the content of total phenolic acid in the test sample was determined by ultraviolet spectrophotometry with barium sulphate as the control.
  • B is the content of salvianolic acid B in the test sample measured by high performance liquid chromatography.
  • Solid preparation Take 0.1g of solid Danqi preparation, accurately weighed, placed in 25ml stoppered conical flask, precision added methanol 10ml, densely packed, weighed, sonicated (power 140W, frequency 42kHz) for 30 minutes, placed to At room temperature, weigh the weight again, make up the lost weight with methanol, shake well, filter, take 2ml filtrate and dry, dissolve in 2ml water, make up to volume, take 0.5ml aqueous solution on the solid phase extraction cartridge, then use water, 20 % methanol and methanol were eluted in 2 ml each. The methanol eluate was collected into a 2 ml volumetric flask and shaken to obtain.
  • Liquid preparation Take 0.5 ml of a liquid solution containing 10 mg/ml of liquid Danqi preparation, and apply a solid phase extraction cartridge, then elute with 2 ml each of water, 20% methanol and methanol, and collect the methanol eluate into a 2 ml volumetric flask. Shake well, that is.
  • Formulation 1 is a Danqi formulation prepared in accordance with the formulation described in Example 3.
  • Prescription 2 is a Danqi preparation prepared by using total phenolic acid of Salvia miltiorrhiza and total saponins of Panax notoginseng. The formulation is determined as shown in the "Prescription 2" column in Table 14.
  • a myocardial infarction model was induced by anterior descending coronary artery ligation in anesthetized dogs.
  • the prescription 1 and prescription 2 (see Table 14) were observed to have protective effects on acute myocardial infarction in anesthetized dogs.
  • the experiment was divided into 3 groups: 1 solvent control group; 2 prescription 1 group; 3 prescription 2 groups.
  • An acute myocardial infarction model was induced by two-step ligation of the anterior descending coronary artery by the Harris method. Changes in epicardial electrograms, myocardial infarction weight, and changes in serum myocardial enzymology were observed after administration.
  • Group Weight (kg) Left ventricular weight (g) Infarct area weight (g) Infarct area weight /
  • Solvent control group 10.7 ⁇ 0.79 54.2 ⁇ 3.3 1 7.20 ⁇ 1.53 0.133 ⁇ 0.03
  • Prescription 1 1 1.3 ⁇ 0.74 58.2 ⁇ 7.47 5.05 ⁇ 2.42 0.0842 ⁇ 0.03 *Prescription 2 10.6 ⁇ 0.82 48.4 ⁇ 8.02 5.66 ⁇ 0.66 0.120 ⁇ 0.02
  • Group weight kg
  • Left ventricular weight g
  • Infarct area weight g
  • Infarct area weight/left Heart heavy solvent control group 10.7 ⁇ 0.79 54.2 ⁇ 3.3 1 7.20 ⁇ 1.53 0.133 ⁇ 0.03
  • the ginsenoside Rbi content is 9.83%, the ginsenoside R gl content is 9.27%; the salvia miltiorrhiza totals.
  • the phenolic acid content was 27.21%, and the total saponin content of Panax notoginseng was 28.92%.
  • the content of the ginsenoside Rg l, the salvianolic acid B, and the ginsenoside Rb l contained in the prescription 2 is not in the range of the effective ratio of 0. 7-4. 3 : 1. 0 : 0. 7-4. According to the above measurement results, the inventors adjusted the prescription 2, and adjusted the total phenolic acid of the salvia miltiorrhiza.
  • the inventors conducted a pharmacodynamic test on the prescription 2' and found that it has a good effect on the myocardial infarction of the dog, and the effect is very obvious.

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Abstract

La présente invention concerne une composition de Danqi comprenant les ingrédients suivants : (a) 0,7 à 4,3 parties en poids de ginsénoside Rg1 ; (b) 1,0 parties en poids d'acide salvianolique B ; et (c) 0,7 à 4,3 parties en poids de ginsénoside Rb1. Le procédé de contrôle qualité de la composition de Danqi comprend la surveillance du respect des proportions suivantes dans ladite composition : ginsénoside Rg1 : acide salvianolic B : ginsénoside Rb1 = 0,7 à 4,3 : 1 : 0,7 à 4,3. La présente invention révèle, pour la première fois, les principaux ingrédients destinés au traitement efficace de maladies cardiovasculaires, ainsi que les proportions préférées de ceux-ci dans la racine de sauge rouge et de notoginseng en tant qu'ingrédients essentiels de la formulation de Danqi. La plage de proportions indiquée permet de contrôler de manière pratique la teneur des différents ingrédients lors de la préparation de la formulation de Danqi, afin d'obtenir des effets thérapeutiques préférés. Ceci permet de résoudre le problème d'obtention d'effets thérapeutiques non satisfaisants, qui survenait par le passé lors de la préparation de la formulation de Danqi, car les principaux ingrédients actifs et leur teneur étaient inconnus.
PCT/CN2007/070811 2006-11-28 2007-09-28 Composition comprenant un médicament chinois traditionnel en tant qu'ingrédient actif pour le traitement de maladies cardiovasculaires, et procédé de contrôle qualité de celle-ci WO2008064592A1 (fr)

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CN117100733A (zh) * 2023-10-25 2023-11-24 广州白云山和记黄埔中药有限公司 丹酚酸b和/或三七总皂苷组合物及其应用

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CN101428050B (zh) * 2008-12-15 2011-10-12 云南白药集团股份有限公司 一种用于治疗心脑血管系统疾病的活性组合物
CN102908355B (zh) * 2011-08-04 2014-06-04 中国科学院上海药物研究所 一种药物组合物及其用途
CN109900826A (zh) * 2019-03-26 2019-06-18 广州莱泰制药有限公司 一种复方丹参片三七含量检验方法
US20220331281A1 (en) * 2019-08-29 2022-10-20 Shanghai Institute Of Matteria Medica, Chinese Academy Of Sciences Pharmaceutical composition and application thereof
CN111855833B (zh) * 2020-06-09 2022-10-21 纳谱分析技术（苏州）有限公司 一种基于聚合物包覆硅胶键合填料测定复方丹参制剂中四环三萜类皂苷的分析方法

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CN1470255A (zh) * 2002-07-22 2004-01-28 王智民 自丹参三七中提取的制备物及其复方制备方法和医疗用途
CN100339085C (zh) * 2003-09-23 2007-09-26 天津天士力制药股份有限公司 治疗心脑血管疾病的中药组合物
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CN117100733A (zh) * 2023-10-25 2023-11-24 广州白云山和记黄埔中药有限公司 丹酚酸b和/或三七总皂苷组合物及其应用
CN117100733B (zh) * 2023-10-25 2024-04-05 广州白云山和记黄埔中药有限公司 丹酚酸b和/或三七总皂苷组合物及其应用

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