WO2015027929A1 - 一种中药组合物 - Google Patents
一种中药组合物 Download PDFInfo
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- WO2015027929A1 WO2015027929A1 PCT/CN2014/085362 CN2014085362W WO2015027929A1 WO 2015027929 A1 WO2015027929 A1 WO 2015027929A1 CN 2014085362 W CN2014085362 W CN 2014085362W WO 2015027929 A1 WO2015027929 A1 WO 2015027929A1
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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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
- A61K31/11—Aldehydes
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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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
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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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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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
- A61P9/10—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
Definitions
- the present invention relates to the field of medicine, and in particular to a traditional Chinese medicine composition having a cardiovascular therapeutic effect and a preparation thereof.
- Angina is a clinical syndrome characterized by episodes of chest pain or chest discomfort caused by transient myocardial ischemia and hypoxia.
- Coronary heart disease angina pectoris refers to angina caused by myocardial ischemia and hypoxia due to coronary arteriosclerosis or spasm, accounting for about 90% of patients with angina pectoris.
- the method for treating angina pectoris is to dilate blood vessels, reduce blood viscosity, resist platelet aggregation, and resist blood coagulation.
- the traditional western medicines used are nitrates, nitrites, ⁇ -blockers, calcium antagonists, etc., but all have large toxic side effects, which are not suitable for long-term use, mostly symptomatic treatment and no progress on the course of the disease. Great effect. For example, after taking nitroglycerin, there may be head swelling, jumping in the head, rapid heartbeat, and even fainting [see New Pharmacology (14th Edition), page 264].
- the phenolic acids of traditional Chinese medicine are widely distributed in medicinal plants, such as honeysuckle of Lonicera edulis, tray root of Rosaceae, dandelion of asteraceae, breviscapus, sage of Labiatae, sage of olive family, umbrella Angelica, Chuanxiong, etc.
- the pharmacological activities of various phenolic acids in these plants such as scavenging free radicals, anti-inflammatory, antiviral, immunomodulatory, anticoagulant and antitumor effects, have been recognized by more and more people.
- Phenolic acids are classified into: phenolic acids with benzoic acid as the mother nucleus, for example, huangdan; cinnamic acid is the phenolic acid component of the mother nucleus, such as water-soluble extracts of Chinese herbal medicines such as Chinese angelica, Chuanxiong, and dandelion.
- Tanshinone also known as total tanshinone, is a bacteriostatic fat-soluble phenanthrene compound extracted from the traditional Chinese medicine Salvia miltiorrhiza (Salvia miltiorrhiza Bunge root), from which tanshinone I, tanshinone oxime, tanshinone oxime, cryptotanshinone, More than 10 tanshinones such as cryptotanshinone, including 5 components of cryptotanshinone, dihydrotanshinone II, hydroxydanshenone, methyl salicylate and tanshinone oxime, have antibacterial and cooling effects.
- Saponins are a class of glycosides in which aglycones are triterpenes or helical terpenoids, mainly distributed in higher terrestrial plants. Many of the main active ingredients of Chinese herbal medicines such as ginseng, platycodon, and Bupleurum contain saponins. Saponins have anticancer activity, inhibit tumor cell proliferation, induce apoptosis, affect tumor cell signal transduction, inhibit tumor angiogenesis and tumor cell metastasis. It has the functions of reducing blood sugar, lowering blood fat, anti-virus and immune regulation, and has become a hot topic at home and abroad.
- Salvia miltiorrhiza is the root of the genus Salvia, which is bitter, slightly cold, heart-to-heart, liver, with phlegm and pain, and blood circulation. The effect of clearing the heart and clearing the trouble. Modern pharmacological studies have shown that Salvia miltiorrhiza has the functions of dilating coronary artery, improving microcirculation, and protecting the heart, inhibiting and relieving platelet aggregation, improving the body's ability to resist hypoxia, and anti-hepatitis, anti-tumor and anti-viral activities.
- the object of the present invention is to provide a traditional Chinese medicine composition for treating acute myocardial infarction and acute myocardial ischemia, wherein the traditional Chinese medicine composition is 30% to 80% by weight of phenolic acid component, and tanshinone component 2 % ⁇ 10% and saponin components 15% ⁇ 60%,
- the phenolic acid component is composed of the following components, and the weight ratio of each component is:
- A: Salvianolic acid G isomer: salvianolic acid G: salvianolic acid D (2-6) : (0.01-0.05) : ( 1-3) : (0.01-0.06) : (0.5-2) : (0.2-1) : (0.05-0.3) : (0.5-2) : (0.2-1) : (0.1-0.5) : (0.1-0.5) : (0.2-1);
- the tanshinone component consists of the following components Composition, the weight ratio of each component is:
- the saponin component is composed of the following components, and the weight ratio of each component is:
- the traditional Chinese medicine composition of the present invention can be formulated into various preparations such as injections, tablets, capsules, dropping pills and micropellets.
- the present invention includes the following technical solutions:
- a traditional Chinese medicine composition wherein the traditional Chinese medicine composition comprises 30% to 80% of a phenolic acid component, 2% to 10% of a tanshinone component, and 15% to 60% of a saponin component.
- a pharmaceutical preparation comprising the traditional Chinese medicine composition according to any one of paragraphs 1 to 14 and a pharmaceutically acceptable carrier, preferably, the weight percentage of the traditional Chinese medicine composition in the pharmaceutical preparation may be It is from 0.1% to 99.9%, and the rest is a pharmaceutically acceptable carrier.
- Figure 1 shows a high-resolution mass spectrum of barium strontium strontium silicate, A: (R)-sodium salvianolate; hydrazine: (5)-salvian acid hydrazine.
- Figure 2 is a 1 H-NMR chart of barium salvianolate (500 MHz, DMSO), A: (R)-salvian acid T; ⁇ : (5)-sodium salvianolate.
- Figure 3 is a 13 C-NMR chart of barium salvianolate (125 MHz, DMSO), A: (R)-salvianolic acid T; B: (5)-salvianolic acid T.
- Figure 4 is a DEPT spectrum of barium salvianolate, A: (R)-salvianolic acid T; B: (S)-sodium salvianolate.
- Figure 5 shows the COSY spectrum of barium salvianolate, A: (R)-salvianolic acid T; B: (5)-salvianolic acid T.
- Figure 6 shows the ROESY spectrum of bismuth phenolate, A: (R)-sodium salvianolate; ⁇ : (5)-sodium salvianolic acid.
- Figure 7 shows the HSQC spectrum of bismuth phenolate, A: (R)-sodium salvianolate; ⁇ : (5)-sodium salvianolic acid.
- Figure 8 shows the HMBC spectrum of bismuth phenolate, A: (R)-salvian ruthenium hydride; ⁇ : (5)- salvianolic acid hydrazine.
- Figure 9 shows the CD spectrum of barium salvianolate, A: (R)-salvianolic acid T; B: (5)-salvianolic acid T.
- Figure 10 is a comparison of the CD spectrum of salvianolate with the ECD mimetic spectrum, A: (R)-salvianolic acid T; B: (5)-salvianolic acid T.
- Figure 11A is a heart colored with triphenyltetrazolium chloride.
- Figures 11B to 11G show myocardial infarct size, creatine kinase-MB in the sham operation group, myocardial infarction group, and treatment group.
- CK-MB Schematic diagram of serum levels, lactate dehydrogenase (LDH) serum levels, tumor necrosis factor alpha (TNF- ⁇ ) levels, cardiac diastolic and systolic functions.
- the invention provides a traditional Chinese medicine composition.
- the traditional Chinese medicine composition is composed of 30% to 80% by weight of the phenolic acid component, 2% to 10% of the tanshinone component, and 15% to 60% of the saponin component.
- the preferred Chinese medicinal composition of the present invention is composed of 50% to 70% by weight of the phenolic acid component, 2% to 6% of the tanshinone component, and 25% to 45% of the saponin component.
- a further preferred Chinese medicinal composition of the present invention is composed of 66% by weight of a phenolic acid component, 3% of a tanshinone component, and 31% of a saponin component.
- the phenolic acid component of the present invention is composed of the following components, and the weight ratio of each component is:
- Salvianolic acid G isomer: salvianolic acid G: salvianolic acid D (2-6) : (0.01-0.05) : ( 1-3 ) : (0.01-0.06) : (0.5-2) : (0.2-1) : (0.05-0.3) : (0.5-2) : (0.2-1) : (0.1-0.5) : (0.1-0.5) : (0.2 ⁇ 1).
- the phenolic acid component is composed of the following components, and the weight ratio of each component is:
- the phenolic acid component of the present invention may also be composed of the following components, and the weight ratio of each component is:
- the phenolic acid component is composed of the following components, and the weight ratio of each component is:
- the salvianolic acid U+dansolic acid T is derived from the root of the Salvia miltiorrhiza Bge of the Labiatae plant, which is a pale yellow powder; preferably, the salvianolic acid U+salvianolic acid T is used in combination, and the combination is Prepared by the method: Extraction process and conditions: Take the cut salvia miltiorrhiza, decoction twice with water, first decocted under alkaline conditions for 2 hours, filtered; second decocted for 1 hour, filtered; filtrate Concentrate, let cool, add ethanol to stand, filter the supernatant, and recover ethanol.
- the salvianolic acid U+ salvianolic acid T is separated by the following method:
- the salvianolic acid U and salvianolic acid T were resolved by the following methods:
- the salvianolic acid U/T mixture was dissolved, applied to a Sephadex LH-20 Sephadex column, eluted with 20% ethanol, and the eluate was monitored by HPLC to collect salvianolic acid U and salvianolic acid T, respectively. Concentrated to a non-alcoholic flavor, lyophilized to give salvianolic acid U and salvianolic acid T (purity 90%).
- the above compound can be used after purification and purification by a compound monomer, a reference substance or by extraction of a traditional Chinese medicine, and the compound has a purity of 90% or more.
- the compound salvia miltiorrhiza extract was dissolved in water with C18 as a filler, and water (0.02% formic acid) and acetonitrile (0.02% formic acid) were used as eluents A and B, respectively, and eluted according to the following gradient conditions: 15 80 20
- the eluate is collected, concentrated under reduced pressure, and dried to obtain a single compound of a certain purity, which is a salvianolic acid G isomer.
- the tanshinone component of the present invention is composed of the following components, and the weight ratio of each component is:
- the tanshinone component is composed of the following components, and the weight ratio of each component is:
- the tanshinone component of the present invention may also be composed of the following components, and the weight ratio of each component is:
- Tanshinone IIA (0.01-0.05) : (0.05-0.1) : (0.02-0.1) :
- the tanshinone component is composed of the following components, and the weight ratio of each component is:
- the dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone oxime, and salvia miltiorrhiza D according to the present invention are prepared by the prior art.
- the above compound may be used as a compound monomer, a control substance or purified by purification of a traditional Chinese medicine, and the compound has a purity of 90% or more.
- the saponin component of the present invention is composed of the following components, and the weight ratio of each component is:
- the saponin component is composed of the following components, and the weight ratio of each component is:
- the ginsenoside Rgl, ginsenoside Re, and ginsenoside R 2 may be present simultaneously or in two or more forms.
- the same ginsenoside Rd or Rhl-R can also exist at the same time.
- ginsenoside Rgl and ginsenoside Re are simultaneously present, and the weight ratio thereof is (16-17):1.
- the ginsenoside Rgl (or Re or R 2), ginsenoside Rbl, ginsenoside Rhl-S, and ginsenoside Rd (or Rhl-R) according to the present invention are prepared by the prior art.
- the above compound may be used as a compound monomer, a control substance or purified by a Chinese medicine extraction preparation, and the compound has a purity of 90% or more.
- the salvianolic acid T of the present invention is a novel phenolic acid compound, and the physical and chemical properties of the compound, high resolution mass spectrometry (QFT- ESI), electrospray ionization mass spectrometry (ESI-MS), The identification of 13 C-NMR, DEPT, COSY, HMBC, HMQC, and other maps (Fig. 1 - Fig. 10) confirmed the structure.
- the optical isomers of the two isomers of the present invention are: -157.5°, 196.6°.
- the molecular structure was optimized for the C-8' absolute configuration with the 5/R configuration, and then the BPV86 method with TD-SCF was used, under the 6-31++G (2d, ⁇ ) basis group. The calculation was performed, and the calculated results were compared with the CD spectrum of the compound of the present invention. The final result was found to be substantially coincident with the experimental CD spectrum of the compound of the present invention, and the two isomers of the present invention were inferred.
- the absolute configuration of -8' is the 5 configuration and the R configuration, respectively (see Figure 10).
- the compounds of the invention are primarily related to HMBC
- Salvianolic acid T can be prepared by the following method:
- Extraction Water is extracted from the mixture of Salvia miltiorrhiza medicinal herbs or Salvia miltiorrhiza medicinal herbs and other medicinal materials, and the filtrate is concentrated to a water extracting extract, followed by alcohol precipitation to concentrate the supernatant into an alcoholic immersion cream; 2. Separation: After the alcohol precipitation extract obtained in the step 1 is diluted with water, the resin is adsorbed through the macropores, and the impurities are washed away with an acidic aqueous solution, and then eluted with ethanol to concentrate the ethanol eluate into an extract;
- the extract obtained in step 2 is purified by high-pressure preparative liquid chromatography.
- the chromatographic packing is a C 18 reversed-phase silica gel column.
- the eluent is acetonitrile-water-formic acid, isocratic or gradient elution.
- the wavelength was 280 nm ; the elution process was monitored by high performance liquid chromatography, and the eluate containing salvianolic acid T was collected and concentrated to obtain the salvianolic acid T.
- the present invention further provides a pharmaceutical preparation comprising the traditional Chinese medicine composition of the present invention.
- the traditional Chinese medicine composition as an active ingredient accounts for 0.1% to 99.9% by weight of the pharmaceutical preparation, and the rest is pharmacy.
- An acceptable carrier In another embodiment, the traditional Chinese medicine composition of the present invention is formulated into a unit dosage form of a pharmaceutical preparation, and the unit dosage form refers to a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, and the oral solution. Each bottle, granules, etc. per bag.
- the preparation of the present invention is suitable for oral, parenteral (including subcutaneous injection or drug tablet; intradermal; intrathecal; intramuscular, for example, drug store; intravenous, etc.), rectal and topical (e.g., sublingual) administration.
- parenteral including subcutaneous injection or drug tablet; intradermal; intrathecal; intramuscular, for example, drug store; intravenous, etc.
- topical e.g., sublingual
- the pharmaceutically acceptable carrier used is various organic or inorganic carriers which can be administered in combination with a traditional Chinese medicine composition, for example: excipients, lubricants, binders, disintegrators and coatings for solid preparations.
- Medicament additives such as coloring agents and sweeteners can also be used.
- the pharmaceutically acceptable carrier is selected from the group consisting of: sugar alcohols such as mannitol, sorbitol, xylitol; amino acids such as cysteine hydrochloride, methionine, glycine; vitamin C ; disodium EDTA, calcium EDTA; inorganic salts, for example Monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution; sodium chloride, potassium chloride; sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate; calcium carbonate, calcium hydrogencarbonate; stearic acid Salts, such as calcium stearate, magnesium stearate; inorganic acids such as hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid; organic acid salts such as sodium lactate; oligosaccharides, polysaccharides, cellulose and derivatives thereof, such as maltose, glucose, fructose , dextran, sucrose, lactose
- the pharmaceutical preparations of the present invention may be in any pharmaceutically acceptable dosage form, including: tablets, such as sugar-coated tablets, film-coated tablets, enteric coated tablets; capsules, such as hard capsules, soft capsules. Oral solution; buccal; granule; granule; granule; powder; powder; ointment; embolizer; suspension; powder; solution; injection; suppository; ointment, such as ointment, plaster; cream; Drops and patches.
- tablets such as sugar-coated tablets, film-coated tablets, enteric coated tablets
- capsules such as hard capsules, soft capsules.
- Oral solution buccal
- the preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, a remedy, a plaster, etc.; and an injection such as a powder injection, an injection, an infusion or the like.
- the formulation of the present invention is most preferably a tablet.
- the preparation for oral administration may contain commonly used excipients, binders, fillers, diluents, compressed tablets, lubricants, disintegrating agents, coloring agents, flavoring agents and humectants, and if necessary, tablets Carry out the coating.
- Suitable exemplary fillers include cellulose, mannitol, lactose, and other similar fillers.
- Preferred exemplary excipients include: lactose, D-mannitol, D-sorbitol, starches such as alpha-starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, arab Glue, amylopectin, light anhydrous silicic acid, synthetic aluminum silicate, aluminum magnesium silicate, and the like.
- Preferred exemplary lubricants include: magnesium stearate, calcium stearate, talc, silica gel, sodium dodecyl sulfate, and the like.
- Preferred exemplary binders include: (X-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, seaweed Sugar, dextrin, amylopectin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pyrrolidone, and the like.
- Preferred exemplary disintegrants include: lactose, sugar, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium sulfonate, sodium carboxymethyl starch, light anhydrous silicic acid, low substituted hydroxypropyl Cellulose, starch, polyvinylpyrrolidone and sodium starch glycolate.
- Preferred exemplary coating agents include: hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, polyvinyl alcohol, and the like.
- Preferred exemplary colorants include: water soluble edible yellow dyes (food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2); An insoluble coloring dye (for example, an aluminum salt of the above water-soluble edible yellow dye); a natural dye (for example, ⁇ -carotene, chlorophyll, and iron oxide).
- water soluble edible yellow dyes food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2
- An insoluble coloring dye for example, an aluminum salt of the above water-soluble edible yellow dye
- a natural dye for example, ⁇ -carotene, chlorophyll, and iron oxide
- Preferred exemplary sweeteners include: sodium saccharin, glycyrrhetinic acid, aspartame, stevia, and the like.
- Tablets are generally prepared by compressing or molding the traditional Chinese medicine composition of the present invention together with one or more pharmaceutically acceptable excipients.
- the traditional Chinese medicine composition of the present invention can also be formulated into an oral liquid preparation such as an aqueous or oily suspension, a solution, an emulsion, a syrup or the like.
- the traditional Chinese medicine composition of the present invention may also be a dry product, which is mixed with water or other suitable carrier before use.
- Such liquid preparations may contain conventional additives, and may include suspending agents such as sorbitol syrup, methylcellulose, glucose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fat; emulsifier, such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carrier (which may include edible oils), such as almond oil, tiller coconut oil, oily ester, propylene glycol or ethanol; Preservatives, such as methyl or propyl paraben, sorbic acid. If desired, it may contain conventional flavoring or coloring agents.
- suspending agents such as sorbitol syrup, methylcellulose, glucose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fat
- emulsifier such as lecithin, sorbitan monooleate or gum arabic
- non-aqueous carrier which may include edible
- Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, isotonic agents, and the like; and aqueous and nonaqueous sterile suspensions, which may Includes suspending agents and thickeners.
- the formulations may be stored in single or multiple metering containers, such as sealed ampoules and vials, and may be stored under lyophilization (freeze-drying) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, prior to temporary use.
- the preparation for rectal administration may be a suppository containing a conventional suppository base such as cocoa butter, a hard fatty acid or other glyceryl ester, or ethylene glycol.
- a conventional suppository base such as cocoa butter, a hard fatty acid or other glyceryl ester, or ethylene glycol.
- Formulations for topical administration include lozenges wherein the active ingredient is included in the flavored base, such as sucrose and acacia, and soft lozenges containing the active ingredient in the base
- the substrate can be gelatin and glycerin, or sucrose and gum arabic.
- the traditional Chinese medicine composition of the present invention can also be formulated into a pharmaceutical preparation. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Therefore, the traditional Chinese medicine composition of the present invention can be formulated with a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or an ion exchange resin, or can be formulated as a sparingly soluble derivative such as a sparingly soluble salt.
- the traditional Chinese medicine composition of the invention has the therapeutic cardiovascular effect, in particular, can expand the coronary artery to inhibit platelet aggregation and inhibit Thrombotic antiplatelet aggregation and anti-acute myocardial infarction.
- 66 g of a phenolic acid component, 3 g of a tanshinone component, and 31 g of a saponin component were uniformly mixed to prepare a traditional Chinese medicine composition of the present invention, wherein the specific active ingredient was danshensu 27 g, protocatechuic acid 0.16 g, and protocatechuic aldehyde 9.30.
- salvianolic acid G isomer 2.14g, salvianolic acid G2.31g, salvianolic acid D4.29g ; dihydrotanshinone I0.1g, tanshinone I0.33g, cryptotanshinone 0.22g, tanshinone IIA 1.14g: salvia miltiorrhiza D 1.14g; ginsenoside Rgl Or Re or R 2 12.38g, ginsenoside Rbll 2.38g, ginsenoside R lS 3.12g, ginsenoside Rd or Rhl-R 3.06g, notoginsenoside Rl 2.29g.
- 62 g of a phenolic acid component, 4 g of a tanshinone component, and 34 g of a saponin component were uniformly mixed to prepare a traditional Chinese medicine composition of the present invention, wherein the specific active ingredient was 26.5 g of Danshensu, 0.17 g of protocatechuic acid, and protocatechuic aldehyde.
- salvianolic acid G isomer 1.25g, salvianolic acid G 0.125g, salvianolic acid D2.5g ; dihydrotanshinone I 0.14g, tanshinone I 0.7g, cryptotanshinone 0.28g, tanshinone IIA 1.4g: salvia miltiorrhiza D 1.4g; ginsenoside Rgl+ Re 14.17g, ginsenoside Rbl l4.17g, ginsenoside Rhl-S 2.83g, ginsenoside Rd or Rhl-R 2.83g, notoginsenoside Rl 2.62g.
- Example 1 0.5g of the traditional Chinese medicine composition of Example 1 was uniformly mixed with 10.5g of PEG-6000, heated and melted, and then transferred to drip irrigation, and the liquid was dropped into liquid paraffin at 6-8 ° C to remove oil. 400 pills.
- Example 2 0.5 g of the traditional Chinese medicine composition of Example 2, 5.5 g of mannitol, 0.9 g of sodium edetate and 2 ml of distilled water were mixed, and the above components were mixed, lyophilized, and 300 parts were obtained.
- Example 2 0.5 g of the traditional Chinese medicine composition of Example 2, 50 g of starch, and 50 g of sucrose were added, and the above components were mixed, granulated, and tablets were obtained by tableting.
- Example 2 0.5 g of the traditional Chinese medicine composition of Example 2, 50 g of starch, and 50 g of sucrose were added, and the above components were mixed, granulated, and capsules were obtained into capsules.
- Example 16 Preparation of salvianolic acid T, (S)-salvian ruthenium and (R)-salvian ruthenium
- a French NOVASEP LC80-600 dynamic axial high pressure preparative liquid chromatograph for C18 reverse phase silica gel column
- the elution process was monitored by high performance liquid chromatography, and the (5)-salvianolic acid T component and the 23.9-25.3 mm (R)-salvianolic acid T component were collected for a retention time of 19.5-21.
- the eluate was concentrated at 30 ° C on a rotary evaporator and then lyophilized to obtain (5)-salvianolic acid T and (R)-salvian acid T pure product.
- Rats were randomly divided into three groups: treatment group (CP), myocardial infarction group (Ml), and pseudo surgery group (Sham).
- a rat model of myocardial infarction was established by the following procedure: Rats were anesthetized with trichloroacetaldehyde GOOmg.kg ip ), and a ventilator (HX-100E, Taimeng Co., Ltd., China) was used with a tidal volume of 10 ml/kg and 80 rpm. Ventilation rate of /min.
- a left thoracotomy was performed in the fourth intercostal portion, and myocardial infarction was induced by ligation of the left anterior descending artery 2 mm from the tip of the left auricle.
- the sham-operated group (Sham) rats were not subjected to left anterior descending branch ligation, and only the same thoracotomy was performed.
- the electrocardiogram was recorded before and after the surgical procedure. The appearance of the electrocardiogram in the ST segment and the appearance of the epicardial cyanosis can determine myocardial infarction.
- the rats of the treatment group were orally administered with a Chinese medicine composition prepared in Example 1 of the present invention at a concentration of 20 mg/kg for three days.
- the sham operation group (Sham) and the myocardial infarction group (Ml) only took saline.
- LV left ventricular
- LVEDP left ventricular isovolumetric diastolic
- LVSP left ventricular isovolumic systolic
- the rate of pressure rise and fall can be recorded by the Biomechanical Experimental System (BL420, Taimeng Co., Ltd., China).
- CK-MB creatine kinase-MB
- LDH lactate dehydrogenase
- TNF-alpha tumor necrosis factor alpha
- Myocardial infarction group caused a significant increase in serum levels of creatine kinase and lactate dehydrogenase (Fig. 11C, Fig. 11C, Fig. 11C, Fig. 11C, Fig. 11C, Fig.
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CA2922231A CA2922231C (en) | 2013-08-29 | 2014-08-28 | Traditional chinese medicine composition |
EP14840475.9A EP3040077A4 (en) | 2013-08-29 | 2014-08-28 | Traditional chinese medicine composition |
JP2016537117A JP6372897B2 (ja) | 2013-08-29 | 2014-08-28 | 漢方薬組成物 |
AU2014314774A AU2014314774B2 (en) | 2013-08-29 | 2014-08-28 | Traditional Chinese medicine composition |
US14/910,088 US10300030B2 (en) | 2013-08-29 | 2014-08-28 | Traditional Chinese medicine composition |
HK16109713.9A HK1221423A1 (zh) | 2013-08-29 | 2016-08-15 | 種中藥組合物 |
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HUE054609T2 (hu) | 2013-07-11 | 2021-09-28 | Tasly Pharmaceutical Group Co | Elkészítési eljárás hagyományos kínai gyógyszer mikrocsepp pilulához, és a hagyományos kínai gyógyszer mikrocsepp pilula, amely ennek az eljárásnak az alkalmazásával van elkészítve |
CN104418744B (zh) * | 2013-08-29 | 2017-03-01 | 天士力制药集团股份有限公司 | 一种新的丹酚酸化合物t、其制备方法和用途 |
CN107957452A (zh) * | 2016-10-17 | 2018-04-24 | 天士力医药集团股份有限公司 | 一种检测血浆中酚酸类物质的方法 |
CN108310055A (zh) * | 2018-03-23 | 2018-07-24 | 兰纬 | 一种冠心宁注射液的制备方法 |
CN110339202B (zh) * | 2018-04-04 | 2022-10-25 | 天士力医药集团股份有限公司 | 一种药物组合物及其应用 |
CN111876447B (zh) * | 2019-06-25 | 2022-04-01 | 陕西鸿道生物分析科学技术研究院有限公司 | 一种生产迷迭香酸的菌株及方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN102526186A (zh) * | 2012-01-17 | 2012-07-04 | 中国中医科学院广安门医院 | 一种用于预防和治疗心血管疾病的药物组合物及其用途 |
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CN100512830C (zh) * | 2006-05-17 | 2009-07-15 | 广州白云山和记黄埔中药有限公司 | 治疗老年痴呆症的药物组合物 |
CN101508965B (zh) | 2008-10-27 | 2011-08-03 | 昆明诺唯金参生物工程有限责任公司 | 一种链霉菌发酵三七皂苷制备20(S)-人参皂苷Rh1的方法 |
SG174548A1 (en) * | 2009-03-30 | 2011-10-28 | Tianjin Tasly Pharmaceutical | New salvianolic acid compound l, preparation method and use thereof |
CN102675407B (zh) | 2011-03-11 | 2015-11-25 | 上海医药工业研究院 | 一种隐丹参酮的制备方法 |
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 |
CN102757336B (zh) | 2012-07-17 | 2014-11-05 | 湖北远成赛创科技有限公司 | 咖啡酸的制备方法 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1759855A (zh) * | 2004-10-15 | 2006-04-19 | 合肥恒星药物研究所 | 一种治疗慢性肝炎的药物 |
CN102526186A (zh) * | 2012-01-17 | 2012-07-04 | 中国中医科学院广安门医院 | 一种用于预防和治疗心血管疾病的药物组合物及其用途 |
Non-Patent Citations (7)
Title |
---|
"New Pharmaceutics", pages: 264 |
BULLETIN OF MEDICAL RESEARCH, vol. 30, no. 7, 2001 |
CHINA JOURNAL OF MORDEN MEDICINE, vol. 7, no. 4, 1997, pages 42 |
JOURNAL OF XINJIANG MEDICAL UNIVERSITY, vol. 25, no. 3, 2002 |
NANFANG JOURNAL OF NURSING, vol. 3, no. 5, 1996, pages 7 - 9 |
See also references of EP3040077A4 |
SHANXI MEDICINE JOURNAL, vol. 25, no. 2, 1996, pages 315 |
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