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WO2019192599A1 - 一种药物组合物及其应用 - Google Patents

一种药物组合物及其应用 Download PDF

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Publication number
WO2019192599A1
WO2019192599A1 PCT/CN2019/081505 CN2019081505W WO2019192599A1 WO 2019192599 A1 WO2019192599 A1 WO 2019192599A1 CN 2019081505 W CN2019081505 W CN 2019081505W WO 2019192599 A1 WO2019192599 A1 WO 2019192599A1
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Prior art keywords
pharmaceutical composition
acid
heart failure
composition according
group
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Ceased
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PCT/CN2019/081505
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English (en)
French (fr)
Inventor
周水平
孙鹤
张依倩
马晓慧
史嘉文
何毅
李欣欣
王静
李孝庆
范立君
张晶晶
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Tasly Pharmaceutical Group Co Ltd
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Tasly Pharmaceutical Group Co Ltd
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Priority to CA3090831A priority Critical patent/CA3090831A1/en
Priority to AU2019248307A priority patent/AU2019248307C1/en
Priority to EP19781789.3A priority patent/EP3777866B1/en
Priority to RU2020128443A priority patent/RU2786387C2/ru
Priority to JP2020552723A priority patent/JP7345493B2/ja
Priority to US16/976,832 priority patent/US11491173B2/en
Publication of WO2019192599A1 publication Critical patent/WO2019192599A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • A61K31/185—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 
    • 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
    • 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
    • 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
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • 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 
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of medicine, in particular to a pharmaceutical composition and application thereof.
  • Heart failure refers to the failure of the heart to fully discharge the blood from the heart due to the systolic function and/or diastolic function of the heart, resulting in blood stasis in the venous system and insufficient blood perfusion in the arterial system.
  • Cardiac circulatory disorder syndrome which is characterized by pulmonary congestion and vena cava congestion.
  • Heart failure is not an independent disease, but the end of the development of heart disease. The vast majority of heart failure begins with left heart failure, which is first manifested as pulmonary circulation congestion.
  • Heart failure can be divided into systolic heart failure and diastolic heart failure according to the difference in left ventricular ejection fraction (LVEF).
  • LVEF left ventricular ejection fraction
  • DHF left ventricular ejection fraction retention heart failure
  • Left ventricular ejection fraction Retention heart failure is caused by impaired ventricular diastolic active relaxation and increased myocardial stiffness, resulting in impaired left ventricular diastolic filling. In recent years, the incidence of this type of heart failure is increasing. Because left ventricular ejection fraction retention heart failure occurs clinically in the early stage of heart failure and occurs earlier than systolic dysfunction, slowing down the course and progress of HF-PEF and even curing can alleviate the suffering of patients and reduce the economic burden of patients. .
  • the treatment of HF-PEF includes active control of blood pressure, correction of atrial fibrillation, control of ventricular rate of atrial fibrillation, application of diuretics, ACEI, ⁇ -blockers to reverse left ventricular hypertrophy and improve diastolic function, but in clinical practice, often Some patients are still unsatisfied after the above drug treatment, resulting in a significant decline in quality of life.
  • 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.
  • the phenolic acid component is divided into: phenolic acid component with benzoic acid as the mother nucleus, such as yellow dandelion; dandelion; cinnamic acid is the phenolic acid component of the mother nucleus, such as water-soluble extract of Chinese herbal medicine such as Chinese angelica, Chuanxiong and dandelion.
  • the main monomer active ingredient ferulic acid; shikonic acid isolated from Salvia miltiorrhiza; phenylacetic acid is the phenolic acid component of the mother nucleus: for example, p-hydroxyphenylacetic acid in dandelion, the amount obtained in forsythia fruit Hydroxyphenylacetic acid.
  • Tanshinone is also known as total tanshinone. It is a fat-soluble phenanthrenequinone compound extracted from the traditional Chinese medicine Salvia miltiorrhiza (Salvia miltiorrhiza Bunge root), which is divided into more than 10 kinds of tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone and cryptotanshinone.
  • the tanshinone monomer, wherein the cryptotanshinone, dihydrotanshinone II, hydroxy tanshinone, methyl salicylate, and tanshinone IIB have antibacterial effects, and have anti-inflammatory and cooling effects.
  • tanshinone IIA tanshinone IIA sulfonate
  • tanshinone IIA tanshinone IIA sulfonate
  • Saponins are a class of glycosides in which aglycones are triterpenes or helical decane compounds. They are 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.
  • Flavonoids originally refer to a class of compounds whose basic core is 2-phenylchromanone. Generally speaking, it generally refers to a class of chemical components having two benzene rings connected to each other through an intermediate three carbon chain. The main natural flavonoids can be classified according to the degree of oxidation of the three carbon chains in the middle of the A ring and the B ring, the position of the B ring and the formation of the three carbon chains. Flavonoids are secondary metabolites of plants. They have anti-oxidation, anti-angiogenesis, anti-inflammatory, anti-viral, hypoglycemic, hypolipidemic, anti-osteoporosis and other biological activities. They are widely distributed in vegetables, fruits and other plants. in. Studies have shown that dietary intake of flavonoids will reduce the risk of cancer such as colon cancer, prostate cancer, and breast cancer.
  • the volatile oil of traditional Chinese medicine is mainly derived from aromatic Chinese medicine, and is a general term for a kind of volatile oily component which is miscible with water obtained by steam distillation. It is widely found in plants, and it can be said that all odorous plants contain varying amounts of volatile oil.
  • the plants with higher volatile oil content are mainly concentrated in: Compositae, Rutaceae, Polygonaceae, Labiatae, Umbelliferae, Myrtaceae, Rhododendron, Gramineae, Gingeraceae, Leguminosae, Rosaceae, Magnolia Branch, Liliaceae, Cypress, etc.
  • Volatile oils are mainly composed of terpenoids and aromatic compounds and their oxygen-containing derivatives such as alcohols, aldehydes, ketones, phenols, ethers, lactones, etc., and also include nitrogen-containing and sulfur-containing compounds. It is a five-color or light yellow large amount of a transparent oily liquid that volatilizes at room temperature. It has anti-inflammatory, anti-allergic, anti-microbial, anti-mutation and anti-cancer, insect repellent effects, enzyme inhibition, effects on the central nervous system, and effects on the respiratory system.
  • the present invention provides a pharmaceutical composition.
  • the invention also provides the effect of a pharmaceutical composition in the treatment of heart failure.
  • the application provides a pharmaceutical composition comprising the following ingredients:
  • composition comprising the following ingredients:
  • composition comprising the following ingredients:
  • the oxidized product of nerolidol includes (3R,6S,7R)-3,7,11-trimethyltryptophan-3,7-epoxy-1,10-dodecadien-6-ol ,(3R,6R,7S)-3,7,11-trimethyltryptophan-3,7-epoxy-1,10-dodecadien-6-ol, (3S,6R,7S -3,7,11-trimethyltryptophan-3,6-epoxy-1,10-dodecadien-7-ol and (3S,6S,7R)-3,7,11- Trimethyltryptophan-3,6-epoxy-1,10-dodecadien-7-ol in a weight ratio of (3-6):(4-7):(25-33
  • the phenolic acid component of the pharmaceutical composition of the present invention (danshensu, protocatechuic aldehyde, salvianolic acid T, salvianolic acid U, salvianolic acid D, salvianolic acid G, rosmarinic acid, lithosperic acid, salvianolic acid B, salvianolic acid A, isomalenol C), tanshinones (dihydrotanshinone I, cryptotanshinone, tanshinone I, tanshinone IIA), saponin components (tricaside saponin R1, ginsenoside Rg1, ginsenoside Rb1 Astragaloside IV, ginsenoside Rd), flavonoids (musk isoflavone glucoside, formononetin, veratium isoflavone, formononetin) can be prepared by the prior art, obtained by extraction and purification, or obtained by commercially available products.
  • Volatile oil component trans-neryl tertiary alcohol belongs to the prior art, (3R, 6S, 7R)-3,7,11-trimethyltryptophan-3,7-epoxy-1,10-dode carbon Diene-6-ol, (3R,6R,7S)-3,7,11-trimethyltryptophan-3,7-epoxy-1,10-dodecadien-6-ol, (3S,6R,7S)-3,7,11-trimethyltryptophan-3,6-epoxy-1,10-dodecadien-7-ol, (3S,6S,7R) -3,7,11-trimethyltryptophan-3,6-epoxy-1,10-dodecadien-7-ol is also known in the art as "Tao Y, Wang Y.” Bioactive sesquiter penes isolated from the essential oil of Dalbergia odorifera T. Chen [J]. Fitorick, 2010, 81(5): 393-399.”
  • the present invention further provides a pharmaceutical preparation comprising the pharmaceutical 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 in the form of a unit dose of a pharmaceutical preparation, which means 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 liquid; buccal; granule; granule; pill; powder; ointment; dan; 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 liquid buccal; granule; granule; pill; powder; ointment; dan; suspension; powder; solution; injection; suppository; ointment, such as ointment, plaster; cream; Drops and patches.
  • 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 dan, an ointment, etc.; and an injection such as a powder injection, an injection, an infusion or the like.
  • the formulation of the 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 lauryl sulfate, and the like.
  • Preferred exemplary binders include: alpha-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, trehalose , dextrin, amylopectin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pyrrolidone, and the like.
  • Preferred exemplary disintegrants include: lactose, sugar, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium aminoalkyl, sodium carboxymethyl starch, light anhydrous silicic acid, low substituted hydroxypropyl Cellulose, starch, polyvinylpyrrolidone and sodium starch glycolate.
  • Preferred exemplary coating agents include: hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, 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-mentioned 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-mentioned 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, and 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 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, fractionated coconut oil, oily ester, propylene glycol or ethanol; Agents such as methyl or propyl paraben, sorbic acid. Conventional fragrances or colorants may be included if desired.
  • suspending agents such as sorbitol syrup, methylcellulose, glucose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate or Hydrogenated edible fat
  • emulsifier such as lecithin, sorbitan monooleate or gum arabic
  • non-aqueous carrier which may include edible oils
  • Agents
  • 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 metered containers, such as sealed ampoules and vials, and may be stored under lyophilized (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, prior to temporary use.
  • Formulations for rectal administration may be presented as a suppository containing conventional suppository bases such as cocoa butter, hard fatty acids or other glycerides, 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 matrix may 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 (for example 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 (for example, 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 invention also describes the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of coronary heart disease.
  • the invention also describes the use of the pharmaceutical composition of the invention in the manufacture of a medicament for the improvement of myocardial injury, in particular myocardial damage caused by heart failure.
  • the present invention also describes the use of the pharmaceutical composition of the present invention for the preparation of a medicament for treating or preventing heart failure, wherein the heart failure is preferably ejection fraction reduced heart failure and ejection fraction retention heart failure.
  • the pharmaceutical composition of the present invention is capable of inhibiting an inflammatory response and/or myocardial fibrosis and/or apoptosis of cardiomyocytes after heart failure.
  • the present invention describes a method of improving myocardial damage, the method comprising administering an effective amount of a pharmaceutical composition of the present invention to a subject having or at risk of developing myocardial damage, wherein the myocardial injury is preferably heart failure Caused by myocardial damage.
  • the present invention describes the above pharmaceutical composition of the present invention for improving myocardial damage, wherein the myocardial damage is preferably myocardial damage caused by heart failure.
  • the present invention describes a method of treating or preventing heart failure, the method comprising administering an effective amount of a pharmaceutical composition of the present invention to a subject suffering from heart failure or at risk of developing heart failure, wherein said heart failure
  • the ejection fraction is reduced in heart failure and the ejection fraction is retained in heart failure.
  • the present invention also describes the above pharmaceutical composition of the present invention for treating or preventing heart failure, wherein said heart failure is preferably ejection fraction-reducing heart failure and ejection fraction-preserving heart failure.
  • Fig. 1 is a representative image of M-mode ultrasound measured on day 28 of each experimental group on the effect of LAD-induced heart failure rats on cardiac dysfunction in measuring left ventricular function.
  • Figure 2 is a representative picture of HE staining (400 x magnification) and the DAPI core is marked blue.
  • Figure 3 is a representative micrograph of TUNEL staining (400 x magnification) with apoptotic nuclei labeled green.
  • Figure 4 is a graph showing the protective effects of hypoxia-induced H9c2 cardiomyocyte injury on nuclear number and mitochondrial biological function in each experimental group.
  • the nucleus of the nucleus was blue after transfection of Hoechst fluorescent dye; the mitochondria were red after infection with Mitotracker fluorescent dye; Merge was the combined imaging of the two.
  • Figure 5 is a graph showing the change in peak velocity of mitral annulus ( ⁇ Ea) in early diastolic phase of each group during drug administration of the present invention.
  • Figure 6 is a graph showing the degree of change in the diastolic function E/Ea value ( ⁇ E/Ea) of each group during administration of the drug of the present invention.
  • 16 g of the phenolic acid component, 3.5 g of the flavonoid component, 0.2 g of the tanshinone component, and 16 g of the saponin component were uniformly mixed, and then mixed with the volatile oily component 16 g to obtain a pharmaceutical composition.
  • the pharmaceutical composition comprises 11.55 g of Danshensu, 0.15 g of protocatechuic aldehyde, 0.6 g of salvianolic acid T, 0.6 g of salvianolic acid U, 1.3 g of salvianolic acid D, 0.05 g of salvianolic acid G, and 0.8 of rosmarinic acid.
  • the pharmaceutical composition was obtained by mixing 15.36 g of a phenolic acid component, 3.33 g of a flavonoid component, 0.13 g of a tanshinone component, and 18.6 g of a saponin component, and then uniformly mixing with a volatile oily component of 16 g.
  • the pharmaceutical composition includes Danshensu 11g, protocatechuic aldehyde 0.15g, salvianolic acid T 0.55g, salvianolic acid U 0.55g, salvianolic acid D 1.3g, salvianolic acid G 0.05g, rosmarinic acid 0.8g , oxalic acid 0.4g, salvianolic acid B 0.4g, salvianolic acid A 0.12g, isomalenic acid C 0.04g, verbascoside glucoside 1.8g, formononetin 0.7g, veratium isoflavone 0.18g, foreskin 0.65g, dihydrotanshinone I 0.03g, cryptotanshinone 0.04g, tanshinone I 0.025g, tanshinone IIA 0.03g, notoginsenoside R1 3.5g, ginsenoside Rg1 5.4g, ginsenoside Rb1 5g, astragaloside 0.6g, Ginsenoside Rd 0.6g, trans
  • the pharmaceutical composition includes Danshensu 3g, protocatechuic aldehyde 0.06g, salvianolic acid T 0.2g, salvianolic acid U 0.2g, salvianolic acid D 0.4g, salvianolic acid G 0.02g, rosmarinic acid 0.3g , licorice acid 0.05g, salvianolic acid B 0.1g, salvianolic acid A 0.07g, isomalenic acid C 0.015g, vermiculin glucoside 0.6g, formononetin 0.3g, vermiculene 0.03g, foreskin 0.03g, dihydrotanshinone I 0.001g, cryptotanshinone 0.005g, tanshinone I 0.002g, tanshinone IIA 0.004g, notoginsenoside R1 1.8g, ginsenoside Rg1 2.5g, ginsenoside Rb1 1.3g, astragaloside 0.3g Ginsenoside Rd 0.4g, trans-
  • the flavonoid component includes the following parts by weight: musk
  • Flavonoid glucoside: formononetin: flavonoids: formononetin 0.6:0.3:0.03:0.03;
  • Example 1 0.5g of the traditional Chinese medicine composition of Example 1 and 10.5g of PEG-6000 were uniformly mixed, heated and melted, and then transferred to a drip irrigation drip irrigation, and the medicine was dropped into liquid paraffin at 6-8 ° C to remove oil and make a drop. 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 calcium edetate and 2 ml of distilled water were mixed, and the above components were mixed, lyophilized, and 300 parts were dispensed to obtain a powder injection.
  • 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 by capsule filling.
  • the present invention illustrates the beneficial effects of the present invention by the following test examples.
  • Drug group of the present application the drug of Example 2, 169 g
  • Example 2 does not contain volatile oil component, 169g
  • Rats were fasted for 12 hours before surgery, free to drink water, and the body weight of the rats was recorded.
  • the rats were anesthetized by intraperitoneal injection with 5% chloral hydrate (6 mL/kg). After the rats were anesthetized (about 2-5 min, the rat's toes were not painfully reacted by hand), the following operations were performed.
  • iodophor alcohol disinfection opening in the third and fourth intercostals of the left chest of the rat, about 5mm long.
  • the muscle layer was bluntly separated, and the thoracic cavity was opened with a hemostat between the 3 and 4 intercostals, and pulled with a pulling hook to expose the chest cavity.
  • Under the stereo microscope field determine the position of the heart, carefully tear the happy capsule, and determine the position of the left anterior descending coronary artery (the junction of the pulmonary artery cone and the left atrial appendage).
  • the needle was ligated with a 5-0 needle.
  • the corresponding area of the heart surface was changed from bright red to pale, and myocardial purpura appeared in the blood supply range; the heart rate of the rats was significantly accelerated, the breathing was rapid, and the degree of heart beat was weakened.
  • Loosen the pulling hook use a cotton swab to remove the liquid remaining in the chest cavity, squeeze out the gas in the chest cavity, and quickly suture the muscles and skin with a 3-0 thread.
  • the postoperative rats were placed on an electric blanket. After the rats resumed spontaneous breathing, the tracheal intubation was withdrawn and penicillin was given after surgery.
  • the sham operation group only threaded under the anterior descending coronary artery without ligation, and the rest were treated as above.
  • Rats with successful modeling were randomly divided into four groups, namely model group and sham operation group (blank in cell experiment).
  • Control group the pharmaceutical composition of the present application
  • the comparative drug group The pharmaceutical composition group of the present application is administered on a daily dose of a clinical person, starting from 14 days after surgery, and the composition of the present application is administered to the rats per day by a clinically equivalent dose of 100 mg/kg for 14 days.
  • the comparative drug group was administered on a daily basis according to the clinical person, and the rats were intragastrically administered for 14 days at a clinical equivalent dose of 100 mg/kg for 14 days after surgery.
  • Blood sample After hemodynamic testing, the rats were subjected to blood sampling from the abdominal aorta. The blood was taken and labeled in the tube, placed in a 37 ° C water bath for 30 min, 3000 rpm, centrifuged for 15 min, and serum was dispensed into a 1.5 mL artillery tube. Store at -80 ° C for later use.
  • Cardiac sample After blood was taken from the abdominal aorta, after the blood was taken, the heart was cut out and washed twice with 4% paraformaldehyde solution. The heart was placed in formalin solution and stored for later use.
  • the heart samples were dehydrated, embedded, and sectioned, and sections were stained by HE staining and TUNEL fluorescent staining.
  • the experimental data were statistically processed with SPSS 22.0 software.
  • the experimental results were in the mean ⁇ standard deviation.
  • One-way ANOVA was used for the comparison. The difference was statistically significant at P ⁇ 0.05.
  • the data in the figure are in mean ⁇ standard deviation (x ⁇ SD).
  • the change of the short-axis shortening rate of the left ventricle was consistent with the left ventricular ejection fraction, and the difference between the FS value and the model group was statistically significant.
  • the experimental group (the drug group of the present invention, the comparative drug group) had a large heart failure induced by the LAD method.
  • the cardiac function of the mouse was protective.
  • the data of ejection fraction (EF) and short axis shortening rate (FS) were measured from the 28th day. See Tables 1 and 2.
  • the EF and FS of the drug group of the present invention were higher than those of the comparative drug group.
  • the volatile oil in the composition of the present invention has an effect of promoting absorption of salvianolic acid, saponin, flavonoid and tanshinone composition, and synergistically exerts a cardioprotective effect on heart failure patients.
  • each experimental group (the drug group of the present invention and the comparative drug group) on myocardial enzyme release and myocardial histology in LAD-induced heart failure rats.
  • the serum levels of CK, LDH, and CK-MB in the administration group were lower than those in the model group, and the administration group had the effect of reducing myocardial enzymes.
  • the drug group of the present invention was the same as the control drug group, and the levels of creatine kinase isoenzyme CK-MB and lactate dehydrogenase LDH were lower than those of the comparative drug group, and the volatile oil of the drug group of the present invention was observed. There is synergy. See Tables 3, 4, and 5.
  • HE staining The results of HE staining are shown in Figure 2.
  • the model group had significantly increased leukocyte infiltration and obvious myocardial fiber rupture.
  • the myocardial damage was significantly reduced after treatment and pre-intervention in each group.
  • the study of 5.1-5.3 showed that the anterior wall motion of the left ventricle of the left anterior descending coronary artery was significantly attenuated, and the myocardial contractility was significantly reduced.
  • the cardiac function of the model group was significantly lower than that of the sham operation group.
  • the drug group of the invention can significantly reduce the left ventricular changes, and can significantly slow down the continuous reduction of EF and FS values caused by coronary artery ligation induced by coronary artery ligation in the left anterior descending artery, maintain myocardial contractility, and ensure cardiac blood supply.
  • the results of myocardial enzymology experiments showed that the content of CK, CK-MB and LDH in the model rats decreased after administration.
  • the drug group of the present invention also showed a role in reducing myocardial enzymes, indicating that a certain cardioprotective effect can be exerted after administration.
  • HE staining and Tunel results showed that after administration, the inflammatory reaction, myocardial fibrosis and cardiomyocyte apoptosis in the model rats after heart failure can be inhibited, thereby achieving the effect of protecting cardiomyocytes.
  • the drug group and the comparative drug group of the present invention are the same as test case 1.
  • Each active ingredient group has 160g each: Danshensu, protocatechuic aldehyde, salvianolic acid T, salvianolic acid U, salvianolic acid D, dansolic Acid G, rosmarinic acid, lithosperic acid, salvianolic acid B, salvianolic acid A, isomalenol C, flavonoid glucoside, formononetin, verruflone, formononetin, dihydrotanshinone I, Cryptotanshinone, tanshinone I, tanshinone IIA, notoginsenoside R1, ginsenoside Rg1, ginsenoside Rb1, astragaloside IV, ginsenoside Rd.
  • the logarithmic growth phase cells were collected and added to a 96-well black clear bottom culture plate at a concentration of 5000 cells per well, 100 ⁇ L per well, and cultured in a 37 ° C, 5% CO 2 incubator for 24 hours. Subsequently, the experimental group was added to each test group, incubated for 24 hours, then placed in a hypoxic chamber, and passed through a mixed gas consisting of 95% nitrogen and 5% CO 2 at a flow rate of 15 L/min for 10 min, and induced at 37 ° C. After oxygen injury, the rats were incubated for another 8 hours. The model group was incubated only for 8 hours under hypoxia, and the blank control group was incubated normally.
  • the fluorescent probe labeling procedure was as follows: the fluorescent probe Hoechst 33342 mother liquor was diluted 1000-fold into DMEM basal medium; the MitoTracker Deep Red FM mother liquor was diluted 10,000-fold into a Peggy containing Hoechst 33342 as a "cocktail” stain. Discard the medium in the culture plate and replace it with “cocktail” stain, 50 ⁇ L per well, and incubate in the incubator for 30 min in the dark. The plate was taken out from the light, and the plate was washed 3 times with DMEM high glucose base, and live cell imaging was performed 5 minutes later.
  • Live cell imaging with HCS was performed as follows: Hoechst 33342 labeled nuclei were imaged with excitation light 360-400/emitting light 410-480; mitochondria labeled with MitoTracker Deep Red FM were selected with excitation light 620-640/luminescence 650-760 Perform imaging. Imaging of HCS was performed using Harmony 3.0 software to read nuclear fluorescence intensity/cytoplasmic fluorescence intensity. The HCS screening system combines automated fluorescence microscopy imaging for high-throughput, multi-indicator analysis. The Columbus efficient image and data management and analysis system was used to perform secondary analysis and management of images and data, and the dose-dependent curve relationship was drawn.
  • the components all have a certain protective effect on the number of cardiomyocytes, but the effects of the components are inferior to the protective effect of the pharmaceutical composition of the present invention on cardiomyocyte injury, indicating that the components of the drug group of the present invention can synergistically combine.
  • the model group in Fig. 3 and Table 6 showed insufficient oxygen supply after myocardial hypoxia injury, and the compensatory regulation of intracellular oxygen receptors increased the utilization of oxygen, so the mitochondrial mass of the model group was obvious. It was elevated, and the experimental group showed a very obvious protective effect after pre-administration of the drug group of the present invention, which was superior to the comparative drug group which did not contain volatile oil.
  • Table 7 The protective effect of the drug group of the present invention and the single component thereof on mitochondrial function of hypoxia-induced H9c2 cardiomyocyte injury, and the results show that the phenolic acid component, flavonoid component, saponin component, and tanshinone component in the drug group of the present invention Both have certain protective effects on mitochondrial function of cardiomyocytes, but the effects of each component are inferior to the protective effect of the pharmaceutical composition of the present invention on mitochondrial function after myocardial injury, indicating that the components of the drug group of the present invention can be synergistically combined. effect.
  • Tables 4 to 7 show that the pharmaceutical composition of the present invention is evaluated in comparison with a pharmaceutical composition (control pharmaceutical composition) composed of 24 components and a single component, and the present invention has significant activity, There is a synergistic effect between the pharmaceutical ingredients of the invention.
  • Level Normal level. Qualification before the test, including physical examination, 2 tuberculosis test, parasite, Salmonella, Herba and B virus.
  • Animal logo stainless steel number plate with Arabic numerals on the collar, chest tattoo
  • HFpEF moderately above impaired: e' ⁇ 8 or E/e'>10 (according to clinical diagnostic criteria);
  • the medicament of the present invention (Example 1) is provided by Tasly Pharmaceutical Group Co., Ltd., and is convenient for administration, and is prepared by mixing with PEG in a certain ratio to prepare a dropping pill preparation for use in animal experiments, batch number: 20180215.
  • the test was divided into three groups, a placebo group, a low dose group of the present invention, a high dose group of the present invention, and 4 animals in each group.
  • Route of administration nasal feeding, once a day.
  • Dosage amount calculation The amount of administration for the next week was calculated for each weighing body weight.
  • Dosing time daily administration from 08:00 to 10:00.
  • Main efficacy index The heart function of heart failure monkeys was measured before, 30d, 60d, 90d, respectively.
  • the left ventricular group of the left ventricular long-axis view of the sternum was used to measure the left ventricular diameter of the left ventricular and the end-systolic, and the left ventricular diastolic was calculated.
  • Daily observation Daily performance of the animals, such as the amount of activity, feed intake, and body weight, were observed daily during the administration period.
  • the results of the study showed that the drug of the present invention had a statistically significant difference in the left ventricular ejection fraction of the heart failure monkey and the vehicle group, suggesting that the drug of the present invention has a certain influence on the left ventricular contractility of the heart failure monkey, and can improve the heart to some extent.
  • the left heart function of the monkey The results are shown in Table 10.
  • Ea and E/Ea are commonly used parameters and sensitive indicators for evaluating left ventricular diastolic function in the heart, and the E/Ea value of the monkey is ideal at about 9.
  • the experimental animals were observed. It was observed that the animals in the placebo group had less activity, and after the activity, there were many dyspnea, physical decline, fatigue, and less feed intake, while the drug administration group of the present invention was administered. The average activity was higher than that of placebo animals, and it was active, good physical strength, shortness of breath and other symptoms, and the animal intake was normal.
  • the continuous administration of the drug of the invention for 90 days can improve the ejection fraction of the ejection fraction retention type heart failure monkey model, improve its contraction function, and also improve the diastolic function.

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Abstract

本发明公开了一种药物组合物及其应用，本发明药物组合物包括如下重量份成分酚酸类成分2-20份、黄酮类成分0.5-5份、丹参酮类成分0.005-0.5份、皂苷类成分5-20份和挥发油类成分10-18份，该药物组合物具有保护心肌损伤及治疗心衰的作用。

Description

一种药物组合物及其应用 技术领域
本发明涉及药物领域，特别涉及一种药物组合物及其应用。
背景技术
心力衰竭(heart failure)简称心衰，是指由于心脏的收缩功能和(或)舒张功能发生障碍，不能将静脉回心血量充分排出心脏，导致静脉系统血液淤积，动脉系统血液灌注不足，从而引起心脏循环障碍症候群，此种障碍症候群集中表现为肺淤血、腔静脉淤血。心力衰竭并不是一个独立的疾病，而是心脏疾病发展的终末阶段。其中绝大多数的心力衰竭都是以左心衰竭开始的，即首先表现为肺循环淤血。
心力衰竭根据左心室射血分数(LVEF)的差别可分为收缩性心力衰竭和舒张性心力衰竭。流行病学研究显示，40％～71％的慢性心力衰竭患者属于舒张性心力衰竭(diastolic heart failure，DHF)，且多发生在老年人、女性、有高血压、糖尿病的人群。
欧洲心脏病年会(ESC)2008年的心力衰竭指南中把DHF命名为左室射血分数保留的心力衰竭(HF-PEF)。长期以来临床工作中更多关注的是左室收缩性心衰，左室射血分数正常性心衰占总心衰患者的50％左右，其预后并不优于收缩性心力衰竭，且猝死率高。
Figure PCTCN2019081505-appb-000001
左室射血分数保留性心衰是由于心室舒张期主动松弛能力受损和心肌僵硬度增加致左室在舒张期的充盈受损所致，近年来此型心衰发病率在上升。由于左室射血分数保留性心衰在临床上常发生于心衰早期且早于收缩功能障碍出现，因此减缓HF-PEF的病程和进展甚至治愈，能够减轻患者的痛苦，减少患者的经济负担。
目前HF-PEF的治疗包括积极控制血压、纠正房颤、控制房颤心室率，应用利尿剂、ACEI、β-受体阻滞剂逆转左室肥厚，改善舒张功能，但临床实际工作中，常常有些患者经过以上药物治疗后效果仍不满意，导致生活质量明显下降。
中药酚酸类成分广泛分布在药用植物中，如忍冬科忍冬属的金银花，蔷薇科的托盘根，菊科的蒲公英、灯盏花，唇形科的鼠尾草，橄榄科的方榄，伞形科的当归、川芎等。这些植物中的各种酚酸类成分具有的药理学活性，如清除自由基、抗炎、抗病毒、免疫调节、抗凝血及抗肿瘤作用已经被越来越多的人所重视。
酚酸类成分分为：苯甲酸为母核的酚酸类成分，例如黄独；蒲公英；桂皮酸为母核的酚酸类成分，例如当归、川芎、蒲公英等中药材水溶性提取物中的主要单体活性成分阿魏酸；唇形科鼠尾草丹参中分离的紫草酸；苯乙酸为母核的酚酸类成分：例如蒲公英中的对羟基苯乙酸，连翘果实中得到的额对羟基苯乙酸。
丹参酮亦称总丹参酮。是从中药丹参(唇形科植物丹参Salvia miltiorrhiza Bunge根)中提取的具有抑菌作用的脂溶性菲醌化合物，从中分得丹参酮I、丹参酮IIA、丹参酮IIB、隐丹参酮、异隐丹参酮等10余个丹参酮单体，其中隐丹参酮、二氢丹参酮II，羟基丹参酮、丹参酸甲酯、丹参酮IIB5个单体具有抗菌作用，尚有抗炎、降温作用。丹参酮IIA的磺化产物丹参酮IIA磺酸钠能溶于水，经临床试用证明治疗心绞痛效果显著，副作用小，为一治疗冠心病的新药。总丹参酮有抗菌、消炎、活血化瘀、促进伤口愈合等多方面作用，长期服用未见有明显副作用。
皂苷是苷元为三萜或螺旋甾烷类化合物的一类糖苷，主要分布于陆地高等植物中，许多中草药如人参、桔梗、柴胡等的主要有效成分都含有皂苷。皂苷具有抗癌活性，抑制肿瘤细胞增殖、诱导细胞凋亡、影响肿瘤细胞信号转导，抑制肿瘤血管生成及肿瘤细胞转移。具有降糖降血脂、抗病毒和免疫调节等作用，已成为国内外研究的热门话题。
黄酮类化合物原指基本母核为2-苯基色原酮的一类化合物。现一般泛指具有2个苯环通过中间三碳链相互联结而成的一类化学成分。根据A环与B环中间三碳链的氧化程度，B环连接位置以及三碳链是否成环等特点，可将主要的天然黄酮类化合物进行分类。黄酮是一类植物次生代谢产物，具有抗氧化、防止血管增生、抗炎、抗病毒、降血糖、降血脂、抗骨质疏松等多种生物活性，广泛分布于蔬菜、水果等多种植物中。已有研究表明，饮食中摄入丰富的黄酮，将降低罹患结肠癌、前列腺癌、乳腺癌等癌症的风险。
中药挥发油主要来源于芳香类中药，是一类可随水蒸气蒸馏得到的与水不相混溶的挥发性油状成分的总称。它广泛地存在于植物体中，几乎可以说：凡是有气味的植物均含有多少不等的挥发油。其中挥发油含量较高的植物主要集中在：菊科、芸香科、樟科、唇形科、伞形科、桃金娘科、杜鹃花科、禾本科、姜科、豆科、蔷薇科、木兰科、百合科、柏科等。
挥发油主要是由萜类和芳香族化合物以及它们的含氧衍生物如醇、醛、酮、酚、醚、内脂等组成，此外还包括含氮及含硫化合物。它是一种五色或淡黄色大量的透明油状液体，在常温下就能挥发。具有抗炎、抗过敏、抗微生物、抗突变和抗癌、驱虫作用、酶抑制作用、对中枢神经系统的作用、对呼吸系统的作用等。
现有技术中没有报道关于丹酚酸类成分、丹参酮类成分、皂苷类成分、黄酮类成分及挥发油类成分进行组合的药物。更未报道过这些成分按照一定的比例进行组合可用于治疗心衰。
发明内容
为了解决上述技术问题，本发明提供了一种药物组合物。
本发明还提供药物组合物在治疗心衰中的作用。
本发明是通过下述技术方案实现的：
本申请提供了一种药物组合物，该组合物包括如下成分：
Figure PCTCN2019081505-appb-000002
进一步地，本申请提供了一种药物组合物，该组合物包括如下成分：
Figure PCTCN2019081505-appb-000003
更进一步，本申请提供了一种药物合物，该组合物包括如下成分：
Figure PCTCN2019081505-appb-000004
上述药物组合物中，所述酚酸类成分包括下述重量份比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝(3.0-11.0)：(0.06-0.15)：(0.2-0.55)：(0.2-0.55)：(0.4-1.3)：(0.02-0.05)：(0.3-0.8)：(0.05-0.40)：(0.10-0.40)：(0.07-0.12)：(0.015-0.04)。
上述药物组合物中，所述黄酮类成分包括下述重量份比的物质：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝(0.6-1.8)：(0.3-0.7)：(0.03-0.18)：(0.03-0.65)。
上述药物组合物中，所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝(0.001-0.03)：(0.005-0.04)：(0.002-0.025)：(0.004-0.03)。
上述中药组合物中，所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝(1.8-3.5)：(2.5-5.4)：(1.3-5.0)：(0.30-0.60)：(0.4-0.6)。
上述药物组合物中，所述挥发油类成分包括下述重量份比的物质：反式-橙花叔醇：橙花叔醇氧化产物＝(25-38)：(55-76)。其中橙花叔醇氧化产物包括(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇和(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇，其重量份比为(3-6)：(4-7)：(25-33)：(23-30)。
本发明药物组合物中酚酸类成分(丹参素、原儿茶醛、丹酚酸T、丹酚酸U、丹酚酸D、丹酚酸G、迷迭香酸、紫草酸、丹酚酸B、丹酚酸A、异丹酚酸C)，丹参酮类成分(二氢丹参酮I、隐丹参酮、丹参酮I、丹参酮IIA)，皂苷类成分(三七皂苷R1、人参皂苷Rg1、人参皂苷Rb1、黄芪甲苷、人参皂苷Rd)，黄酮类成分(毛蕊异黄酮葡萄糖苷、芒柄花苷、毛蕊异黄酮、芒柄花素)可以由现有技术制备，通过提取精制方式获得，或者通过市购获得。挥发油成分反式-橙花叔醇属于现有技术，(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇、(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇也属于现有技术，如文献“Tao Y,Wang Y.Bioactive sesquiterpenes isolated from the essential oil of Dalbergia odorifera T.Chen[J].Fitoterapia,2010,81(5):393-399.”。
Figure PCTCN2019081505-appb-000005
F1：rel-(3R,6S,7R)-3,7,11-trimethyl-3,7-epoxy-1,10-dodecadien-6-ol
F2：rel-(3R,6R,7S)-3,7,11-trimethyl-3,7-epoxy-1,10-dodecadien-6-ol
F3：rel-(3S,6R,7S)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol
F4：rel-(3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol
F5：反式橙花叔醇
本发明进一步提供包含本发明所述药物组合物的药物制剂，在优选的实施方式中，所述中药组合物作为有效成分在药物制剂中所占的重量百分比为0.1％～99.9％，其余为药学上可接受的载体。在另一个实施方式中，将本发明的中药组合物制成单位剂量的药物制剂形式，所述单位剂量形式是指制剂的单位，如片剂的每片，胶囊的每粒胶囊，口服液的每瓶，颗粒剂每袋等。
本发明所述的制剂适用于口服、胃肠外(包括皮下例如注射或药库片；真皮内；鞘内；肌内例如药库；静脉内等)、直肠和局部(如舌下)给药，但最适合的给药途径应取决于患者的病症。
本文中，所用的药用载体是可与中药组合物联用给药的各种有机或无机载体，例如：用于固体制剂的赋形剂、润滑剂、粘合剂、崩解剂和包衣剂；也可使用药用添加剂，例如着色剂和甜味剂。所述药用载体选自：糖醇，例如甘露醇、山梨醇、木糖醇；氨基酸，例如盐酸半胱氨酸、蛋氨酸、甘氨酸；维生素C；EDTA二钠、EDTA钙钠；无机盐，例如一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液；氯化钠、氯化钾；焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠；碳酸钙、碳酸氢钙；硬脂酸盐，例如硬脂酸钙、硬脂酸镁；无机酸，例如盐酸、醋酸、硫酸、磷酸；有机酸盐，例如乳酸钠；寡糖、多糖、纤维素及其衍生物，例如麦芽糖、葡萄糖、果糖、右旋糖苷、蔗糖、乳糖、环糊精(例如β-环糊精)、淀粉；硅衍生物；藻酸盐；明胶；聚乙烯吡咯烷酮；甘油；琼脂；表面活性剂，例如吐温80；聚乙二醇；磷脂类材料；高岭土；滑石粉等。
本发明所述的药物制剂可以是任何可药用的剂型，这些剂型包括：片剂，例如糖衣片剂、薄膜衣片剂、肠溶衣片剂；胶囊剂，例如硬胶囊剂、软胶囊剂；口服液；口含剂；颗粒剂；冲剂；丸剂；散剂；膏剂；丹剂；混悬剂；粉剂；溶液剂；注射剂；栓剂；膏剂，例如软膏剂、硬膏剂；霜剂；喷雾剂；滴剂以及贴剂。本发明的制剂优选：口服剂型，如胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等；以及注射剂，如粉针剂、注射液、输液等。本发明的制剂最优选为片剂。
其口服给药的制剂可含有常用的赋形剂、粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色 剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适宜的示例性填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。
优选的示例赋形剂包括：乳糖、D-甘露醇、D-山梨醇、淀粉如α-淀粉、糊精、结晶纤维素、低取代的羟丙基纤维素、羧甲基纤维素钠、阿拉伯胶、支链淀粉、轻质无水硅酸、合成硅酸铝、硅酸铝镁等。
优选的示例润滑剂包括：硬脂酸镁、硬脂酸钙、滑石粉、硅胶、十二烷基硫酸钠等。
优选的示例粘合剂包括：α-淀粉、蔗糖、明胶、阿拉伯胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、结晶纤维素、糖、D-甘露醇、海藻糖、糊精、支链淀粉、羟丙基纤维素、羟丙基甲基纤维素、吡咯烷酮等。
优选的示例崩解剂包括：乳糖、糖、淀粉、羧甲基纤维素、羧甲基纤维素钙、氨烷基钠、羧甲基淀粉钠、轻质无水硅酸、低取代的羟丙基纤维素、淀粉、聚乙烯吡咯烷酮和羟基乙酸淀粉钠等。
优选的示例包衣剂包括：羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羧甲基纤维素、聚乙烯醇等。
优选的示例着色剂包括：水溶性食用枸橼黄染料(食用染料例如食用红No.2和No.3，食用黄No.4和No.5，食用蓝No.1和No.2)；水不溶性色沉染料(例如上述水溶性食用枸橼黄染料的铝盐)；天然染料(例如β-胡萝卜素、叶绿素、铁丹)等。
优选的示例甜味剂包括：糖精钠、甘草次酸、阿斯帕坦、甜菊等。
片剂的制备方法一般为，将本发明的中药组合物与一种或多种药学上可接受的辅料一起压制或模制。
本发明的中药组合物还可以制成口服液体制剂，例如水性或油性悬液、溶液、乳剂、糖浆剂等。本发明的中药组合物还可以是干燥产品，使用前用水或其它适合的载体混合。这类液体制剂可以含有常规的添加剂，可以包括悬浮剂，例如山梨醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪；乳化剂，例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶；非水性载体(可以包括食用油)，如杏仁油、分馏椰子油、油性酯、丙二醇或乙醇；以及防腐剂，如对羟基苯甲酸甲酯或丙酯、山梨酸。如果需要，可含有常规的香味剂或着色剂。
用于胃肠道外给药的制剂包括水性与非水性无菌注射液，其中可以含有抗氧化剂、缓冲剂、制菌剂、等渗剂等；以及水性与非水性无菌混悬液，其中可以包括悬浮剂和增稠剂。制剂可以存放在单剂量或多计量容器内，例如密封的安瓿和小瓶，并且可以贮存在冷冻干燥(冻干)条件下，仅需要在临时用前加入无菌的液体载体，例如注射用水。
用于直肠给药的制剂可以是栓剂，含有常规的栓剂基质，例如可可脂、硬脂肪酸或其它甘油酯，或乙二醇。
用于口腔局部、例如颊部或舌下给药的制剂包括锭剂，其中在加味的基质中包含活性成分，该基质例如蔗糖和阿拉伯胶；还包括软锭剂，其中在基质中含有活性成分，该基质可以是明胶和甘油、或蔗糖和阿拉伯胶。
本发明的中药组合物还可以配制成药库制剂。这类长效制剂可以通过植入(如皮下或肌内)或肌内注射给药。所以，本发明中药组合物可以与适合的聚合物或疏水性材料(例如在可接受的油中的乳剂)或离子交换树脂进行配制，或者配制成微溶性衍生物，例如微溶性盐。
本发明还描述了本发明的药物组合物在制备治疗冠心病药物中的应用。
本发明还描述了本发明的药物组合物在制备改善心肌损伤药物中的应用，尤其是心衰造成的心肌损伤。
本发明还描述了本发明的药物组合物在制备治疗或预防心衰的药物中的应用，其中，所述心衰优选为射血分数降低性心衰及射血分数保留性心衰。
本发明的药物组合物能够抑制心衰后的炎症反应和/或心肌纤维化和/或心肌细胞的凋亡。
本发明描述了改善心肌损伤的方法，所述方法包括将有效量的本发明的药物组合物给予患有心肌损伤或存在患心肌损伤风险的受试者，其中，所述心肌损伤优选为心衰造成的心肌损伤。
本发明描述了用于改善心肌损伤的本发明的上述药物组合物，其中，所述心肌损伤优选为心衰造成的心肌损伤。
本发明描述了治疗或预防心衰的方法，所述方法包括将有效量的本发明的药物组合物给予患有心衰或存在患心衰风险的受试者，其中，所述所述心衰优选为射血分数降低性心衰及射血分数保留性心衰。
本发明还描述了用于治疗或预防心衰的本发明的上述药物组合物，其中，所述所述心衰优选为射血分 数降低性心衰及射血分数保留性心衰。
附图说明
图1是表示各实验组对LAD法诱导的心衰大鼠在心动超声测定左心室功能方面的影响作用的在第28天测定的M型超声代表性图像。
图2是HE染色代表性图片(400×放大)，DAPI核标记为蓝色。
图3是TUNEL染色代表性显微图片(400×放大)，凋亡细胞核标记为绿色。
图4是各实验组对缺氧诱导的H9c2心肌细胞损伤在核数量和线粒体生物功能方面的保护作用。采用荧光染料对H9c2细胞核数量和线粒体质量的高内涵成像代表性图片。Hoechst荧光染料转染后细胞核显蓝色；Mitotracker荧光染料传染后线粒体显红色；Merge为两者合并后的成像。
图5是本发明药物给药期间各组心脏舒张早期二尖瓣环运动峰速变化值(ΔEa)。
图6是本发明药物给药期间各组心脏舒张功能E/Ea值变化度(ΔE/Ea)。
具体实施方式
下面结合附图，对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
实施例
实施例1
将酚酸类成分16g、黄酮类成分3.5g、丹参酮类成分0.2g、皂苷类成分16g混合均匀后，再与挥发油性类成分16g混合均匀即得药物组合物。
该药物组合物包括丹参素11.55g、原儿茶醛0.15g、丹酚酸T 0.6g、丹酚酸U 0.6g、丹酚酸D 1.3g、丹酚酸G 0.05g、迷迭香酸0.8g、紫草酸0.4g、丹酚酸B 0.4g、丹酚酸A 0.12g、异丹酚酸C 0.04g、毛蕊异黄酮葡萄糖苷2.1g、芒柄花苷0.8g、毛蕊异黄酮0.2g、芒柄花素0.78g、二氢丹参酮I 0.048g、隐丹参酮0.064、丹参酮I 0.04g、丹参酮IIA 0.048g、三七皂苷R1 3g、人参皂Rg1 4.6g、人参皂苷Rb1 4.3g、黄芪甲苷0.52g、人参皂苷Rd 0.52g、反式-橙花叔5.3g、(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇0.84g、(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇0.98g、(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇4.63g、(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇4.21g。
实施例2
将酚酸类成分15.36g、黄酮类成分3.33g、丹参酮类成分0.13g、皂苷类成分18.6g混合均匀后，再与挥发油性类成分16g混合均匀即得药物组合物。
该药物组合物包括丹参素11g、原儿茶醛0.15g、丹酚酸T 0.55g、丹酚酸U 0.55g、丹酚酸D 1.3g、丹酚酸G 0.05g、迷迭香酸0.8g、紫草酸0.4g、丹酚酸B 0.4g、丹酚酸A 0.12g、异丹酚酸C 0.04g、毛蕊异黄酮葡萄糖苷1.8g、芒柄花苷0.7g、毛蕊异黄酮0.18g、芒柄花素0.65g、二氢丹参酮I 0.03g、隐丹参酮0.04g、丹参酮I 0.025g、丹参酮IIA 0.03g、三七皂苷R1 3.5g、人参皂苷Rg1 5.4g、人参皂苷Rb1 5g、黄芪甲苷0.6g、人参皂苷Rd 0.6g、反式-橙花叔5.3g、(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇0.84g、(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇0.98g、(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇4.63g、(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇4.21g。
实施例3
将酚酸类成分4.42g、黄酮类成分0.96g、丹参酮类成分0.012g、皂苷类成分6.3g混合均匀后，再与挥发油性类成分15g混合均匀即得药物组合物。
该药物组合物包括丹参素3g、原儿茶醛0.06g、丹酚酸T 0.2g、丹酚酸U 0.2g、丹酚酸D 0.4g、丹酚酸G 0.02g、迷迭香酸0.3g、紫草酸0.05g、丹酚酸B 0.1g、丹酚酸A 0.07g、异丹酚酸C 0.015g、毛蕊异黄酮葡萄糖苷0.6g、芒柄花苷0.3g、毛蕊异黄酮0.03g、芒柄花素0.03g、二氢丹参酮I 0.001g、隐丹参酮0.005g、丹参酮I 0.002g、丹参酮IIA 0.004g、三七皂苷R1 1.8g、人参皂苷Rg1 2.5g、人参皂苷Rb1 1.3g、黄芪甲苷0.3g、人参皂苷Rd 0.4g、反式-橙花叔醇6.8g、(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇0.82g，(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇1.09g，(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇6.82g，(3S,6S,7R)-3,7,11-三甲基色氨酸 -3,6-环氧基-1,10-十二碳二烯-7-醇6.27g。
实施例4
将酚酸类成分18g、黄酮类成分4g、丹参酮类成分0.3g、皂苷类成分18g混合均匀后，再与挥发油性类成分16g混合均匀即得药物组合物。
其中酚酸类成分包括下述重量比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝11：0.15：0.55：0.55：1.3：0.05：0.8：0.40：0.40：0.12：0.04；所述黄酮类成分包括下述重量份比的物质：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝1.8：0.7：0.18：0.65；所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝0.03：0.04：0.025：0.03。所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝3.5：5.4：5.0：0.60：0.6。所述挥发油类成分包括下述重量份比的物质反式-橙花叔醇：(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇：(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇＝38:6:7:33:30。
实施例5
将酚酸类成分18g、黄酮类成分4g、丹参酮类成分0.3g、皂苷类成分18g混合均匀后，再与挥发油性类成分17g混合均匀即得药物组合物。
其中酚酸类成分包括重量比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝3:0.06:0.2:002:0.4:0.02:0.3:0.05:0.1:0.07:0.015；所述黄酮类成分包括下述重量份比的物质：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝0.6:0.3:0.03:0.03；所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝0.001:0.005:0.002:0.004。所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝1.8:25:1.3:0.3:0.4。所述挥发油类成分包括下述重量份比的物质：反式-橙花叔醇：(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇：(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇＝25:3:4:25:23.
实施例6
将酚酸类成分20g、黄酮类成分5g、丹参酮类成分0.5g、皂苷类成分20g混合均匀后，再与挥发油性类成分18g混合均匀即得药物组合物。
其中酚酸类成分包括如下重量份比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝11：0.15：0.55：0.55：1.3：0.05：0.8：0.40：0.40：0.12：0.04；所述黄酮类成分包括下述重量份比：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝1.8：0.7：0.18：0.65；所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝0.03：0.04：0.025：0.03。所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝3.5：5.4：5.0：0.60：0.6。所述挥发油类成分包括下述重量份比的物质：反式-橙花叔醇：(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇：(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇＝38:6:7:33:30.
实施例7
将酚酸类成分2g、黄酮类成分0.5g、丹参酮类成分0.005g、皂苷类成分5g混合均匀后，再与挥发油性类成分10g混合均匀即得药物组合物。
其中酚酸类成分包括如下重量份比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝3:0.06:0.2:002:0.4:0.02:0.3:0.05:0.1:0.07:0.015；所述黄酮类成分包括下述重量份比的物质：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝0.6:0.3:0.03:0.03；所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝0.001:0.005:0.002:0.004。所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝1.8:25:1.3:0.3:0.4。所述挥发油类成分包括下述重量份比的物质：反式-橙花叔醇：(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇：(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇：(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇＝25:3:4:25:23。
实施例8
取实施例1的中药组合物0.5g与PEG-6000 10.5g混合均匀，加热熔融，化料后移至滴丸滴灌中，药液滴至6～8℃液体石蜡中，除油，制得滴丸400粒。
实施例9
取实施例2的中药组合物0.5g、葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1ml，上述组分混合均匀后，冷冻干燥，分装500支，即得粉针剂。
实施例10
取实施例2的中药组合物0.5g、甘露醇5.5g、依地酸钙钠0.9g和蒸馏水2ml，上述组分混匀后，冷冻干燥，分装300支，即得粉针剂。
实施例11
取实施例2的中药组合物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，压片即得片剂。
实施例12
取实施例2的中药组合物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，装胶囊即得胶囊剂。
试验例
本发明通过下述试验例来阐述本发明的有益效果
试验例一、射血分数降低性心衰
1.动物模型和给药方式
1.1实验动物
所有动物均经天津中医药大学实验动物管理中心批准(TCM-LAEC2017003)。选用体重200±20g清洁级的SD雄性大鼠，饲养温度22-25℃，湿度40-70％，饲养过程中昼夜提供光照，定时投喂标准颗粒饲料，提供消毒饮用水，实验环境中适应性饲养一周后进行试验。
1.2实验药品
本申请药物组：实施例2的药物，169g
对比药物组：实施例2中不含有挥发油成分，169g
1.3实验方法
大鼠于术前禁食12小时，自由饮水，记录大鼠体重，用5％水合氯醛(6mL/kg)腹腔注射麻醉。等待大鼠处于麻醉状态后(约2-5min，用手捏大鼠脚趾无疼痛反应)，进行以下操作。
胸前手术区，碘伏酒精消毒，于大鼠左胸第三、四肋间开口，长约5mm。钝性分离肌肉层，于3、4肋间用止血钳撑开胸腔，并用牵拉钩牵拉，以便暴露胸腔。于体视显微镜视野下，确定心脏位置，小心撕开心包膜，确定左冠状动脉前降支位置(肺动脉圆锥与左心耳交界处)。于距离左心耳根部，冠状动脉起始点下方2-3mm处，用5-0号带针丝线结扎。结扎后，肉眼可见心脏表面相应区域由鲜红色变为苍白色，血管供应范围出现心肌紫绀；大鼠心率明显加快，呼吸急促，心脏搏动程度减弱。松开牵拉钩，用棉签吸除残留在胸腔内的液体，挤出胸腔内气体，迅速用3-0线缝合肌肉及皮肤。将术后大鼠放置在电热毯上，待大鼠恢复自主呼吸后，拔出气管插管，术后给予青霉素。其中，假手术组在冠状动脉前降支下只穿线不进行结扎，其余处理同上。
至造模后第12-13天，分别进行大鼠心动超声评价造模成功与否，将造模成功的大鼠随机分为四组，分别为模型组、假手术组(细胞实验中为空白对照组)、本申请药物组合物和对比药物组。本申请药物组合物组基于临床人的日服用剂量，术后14天开始，按照100mg/kg的临床等效剂量每日灌胃大鼠给予本申请组合物，共14天。对比药物组基于临床人的日服用剂量，术后14天开始，按照100mg/kg的临床等效剂量每日灌胃大鼠给予共14天。
2.样本采集
血液样本：进行血流动力学检测后，对大鼠进行腹主动脉取血，取血后于管口标记，置于37℃水浴30min，3000rpm，离心15min，取血清分装于1.5mL炮弹管放入-80℃保存备用。
心脏样本：在腹主动脉取血后进行，取血完毕后，剪下心脏，用4％多聚甲醛溶液冲洗2次，取心脏置于福尔马林溶液中固定，保存备用。
3.动物模型评价
超声评价：术后14天进行大鼠心动超声评价，EF值在38-50％范围内判断心衰造模成功。采用双抗体夹心酶联免疫吸附测定法(enzyme-linked immunosorbent assay，ELISA)对血清样本中TNF-α、IL-6和IL1-β含量进行检测。采用全自动生化仪检测CK、CK-MB、LDH。
对心脏样本进行脱水、包埋、切片，采用HE染色法和TUNEL荧光染色法对切片染色。
4.统计
实验数据用SPSS22.0软件进行统计学处理，实验结果以均数±标准差
Figure PCTCN2019081505-appb-000006
进行表示，组建比较采用单因素方差分析(one-way ANOVA)，P<0.05为差异有统计学意义。图中数据以均数±标准差(x±SD)。
5.结果
5.1各治疗组对大鼠心功能的影响
超声评价M-Mode结果显示发现模型组心室腔相较于正常对照组呈进行性扩张，且左室室壁运动减弱，收缩力下降，而给予本申请药物组、对比药物组后，心室腔扩张程度及收缩力均有改善，见图1，M型超声代表性图像。结扎左前降支冠脉造模后，大鼠的射血分数、短轴缩短率及左室面积变化分数与正常对照组(假手术组)相比明显降低，在给予各组药物治疗后与模型组比较，给药组大鼠左室射血分数的持续降低速度受限，并且差异具有统计学意义。左室短轴缩短率的变化与左室射血分数一致，并且FS值与模型组比较差异有统计学意义，各实验组(本发明药物组，对比药物组)对LAD法诱导的心衰大鼠心功能有保护作用，从第28天测定射血分数(EF)、短轴缩短率(FS)的数据，见表1、2，本发明药物组的EF、FS都高于对比药物组，说明本发明组合物中的挥发油对丹酚酸类、皂苷类、黄酮类，丹参酮类组合物有促进吸收的作用，协同发挥心衰患者的心功能保护作用。
表1 各给药组大鼠心功能射血分数EF
Figure PCTCN2019081505-appb-000007
表2 各给药组大鼠心功能短轴缩短率FS
Figure PCTCN2019081505-appb-000008
5.2心肌酶学指标结果
各实验组(本发明药物组、对比药物组)对LAD法诱导的心衰大鼠在心肌酶释放和心肌组织学方面的影响作用。给药组大鼠血清中CK、LDH、和CK-MB含量与模型组CK、LDH、CK-MB比较均有所降低，给药组具有降低心肌酶的作用。在肌酸激酶CK水平，本发明药物组与对比药物组持平，肌酸激酶同工酶CK-MB水平和乳酸脱氢酶LDH水平降低效果均优于对比药物组，可见本发明药物组的挥发油有协同发挥作用。见表3、4、5。
表3 各给药组大鼠血清中的肌酸激酶CK水平
Figure PCTCN2019081505-appb-000009
表4 各给药组大鼠血清中的肌酸激酶同工酶CK-MB水平
Figure PCTCN2019081505-appb-000010
表5 各给药组大鼠血清中的乳酸脱氢酶LDH水平
Figure PCTCN2019081505-appb-000011
5.3病理结果
HE染色结果如图2所示，HE染色代表性图片(400×放大)，DAPI核标记为蓝色。模型组与正常假手术组相比，白细胞浸润明显增加，心肌纤维破裂明显，各组治疗给药和预干预给药后可明显减轻心肌受损程度。
Tunel染色结果图3，TUNEL染色代表性显微图片(400×放大)，凋亡细胞核标记为绿色显示左前降支冠脉结扎可造成大鼠心肌细胞的损伤，染色后从图2中可以看到明显的荧光素标记的凋亡小体，心肌细胞凋亡率与正常假手组相比明显升高。
综上5.1-5.3研究表明，结扎大鼠左冠状动脉前降支心衰模型左室前壁运动大幅减弱，心肌收缩力明显降低，模型组较之假手术组心功能有很明显的下降。本发明药物组可以明显减轻左心室的改变，并且可明显减缓左前降支冠脉结扎诱导的大鼠心脏损伤导致的EF、FS值的持续降低，维持心肌收缩力，保证心脏供血量。心肌酶学实验结果显示给药后会降低模型大鼠CK、CK-MB及LDH的含量，可能由于造模时间过长，这些酶在心肌受损后含量急性升高的现象会随着时间逐渐恢复，本发明药物组也显示出了降低心肌 酶的作用，说明给药后可以起到一定的心脏保护作用。此外，HE染色及Tunel结果显示，给药后可以抑制心衰后模型大鼠炎症反应、心肌纤维化及心肌细胞的凋亡等，从而达到保护心肌细胞的效果。
试验例二、细胞培养和活性评价
1.实验药品：本发明药物组、对比药物组同试验例一，各活性成分组各160g：丹参素、原儿茶醛、丹酚酸T、丹酚酸U、丹酚酸D、丹酚酸G、迷迭香酸、紫草酸、丹酚酸B、丹酚酸A、异丹酚酸C、毛蕊异黄酮葡萄糖苷、芒柄花苷、毛蕊异黄酮、芒柄花素、二氢丹参酮I、隐丹参酮、丹参酮I、丹参酮IIA、三七皂苷R1、人参皂苷Rg1、人参皂苷Rb1、黄芪甲苷、人参皂苷Rd。
2.实验方法：本发明药物组、对比药物组、各活性成分组，以DMSO超声溶解配置为0.4mg/mL的储备液，在进行体外活性评价时，分别以实验培养基同等倍量稀释。
收集对数生长期细胞，以每孔5000个细胞浓度加入96孔黑色透明底的培养板中，每孔100μL，37℃，5％CO 2培养箱中培养24h。随后实验组分别加入各待测组，孵育24h，随后再放入低氧室中，以15L/min的流速通过由95％氮气和5％CO 2组成的混合气体10min，于37℃下诱导缺氧损伤后再孵育8h，模型组仅缺氧孵育8h，空白对照组正常孵育。
细胞荧光探针标记操作如下：将荧光探针Hoechst 33342母液稀释1000倍到DMEM基础培养基中；再将MitoTracker Deep Red FM母液稀释10000倍到含有Hoechst 33342的培基中作为“鸡尾酒”染色剂。弃去培养板中的培养基，换成“鸡尾酒”染色剂，每孔50μL，在孵箱中避光培养30min。将培养板避光取出，用DMEM高糖基培洗板3次，每次5min后进行活细胞成像。
用HCS进行活细胞成像操作如下：选取激发光360-400/发射光410-480对Hoechst 33342标记的细胞核进行成像；选取激发光620-640/发射光650-760对MitoTracker Deep Red FM标记的线粒体进行成像。用Harmony 3.0软件对HCS的成像进行分析，读取细胞核荧光强度/细胞浆荧光强度。HCS筛选系统结合了自动荧光显微镜成像功能，可进行高通量多指标分析。应用Columbus高效图像及数据管理和分析系统对图像和数据进行二次分析及管理，并绘制剂量-依赖曲线关系。
统计方法：同试验例一
3.实验结果：图3表4缺氧诱导的心肌细胞损伤模型中，活细胞核数量与空白对照组相比明显减少，而在实验组预给药本发明药物组体现出非常明显的保护作用，优于不含有挥发油的对照药物组。表5中表示本发明药物其中单一成分对缺氧诱导的H9c2心肌细胞损伤在核数量方面的保护作用的结果表明，本发明药物组中酚酸类成分、黄酮类成分、皂苷类成分、丹参酮类成分都具有一定的心肌细胞数量保护的作用，但是各成分的作用均劣于本发明药物组合物对心肌细胞损伤保护作用，说明本发明药物组中各成分组合后可起到协同作用。
表4 各实验组对缺氧诱导的H9c2心肌细胞损伤在核数量方面的保护作用
Figure PCTCN2019081505-appb-000012
表5 本发明药物其中单一成分对缺氧诱导的H9c2心肌细胞损伤在核数量方面的保护作用
Figure PCTCN2019081505-appb-000013
Figure PCTCN2019081505-appb-000014
注：**为本发明药物组相比，P﹤0.01；*为和本发明药物组相比，P﹤0.05
在线粒体质量方面，图3、表6模型组与空白对照组相比，由于心肌缺氧损伤后，供氧不足，细胞内氧感受器代偿性调节提高氧的利用能力，因此模型组线粒体质量明显升高，而在实验组预给本发明药物组后体现出非常明显的保护作用，优于不含有挥发油的对比药物组。表7本发明药物组和其中单一成分对缺氧诱导的H9c2心肌细胞损伤在线粒体功能方面的保护作用，结果显示本发明药物组中酚酸类成分、黄酮类成分、皂苷类成分、丹参酮类成分都具有一定的对心肌细胞线粒体功能的保护作用，但是各成分的作用均劣于本发明药物组合物对心肌损伤后线粒体功能的保护作用，说明本发明药物组中各成分组合后可起到协同作用。
表6 各实验组对缺氧诱导的H9c2心肌细胞损伤在线粒体生物功能方面的保护作用
Figure PCTCN2019081505-appb-000015
表7 本发明药物组和其中单一成分对缺氧诱导的H9c2心肌细胞损伤在线粒体功能方面的保护作用
Figure PCTCN2019081505-appb-000016
Figure PCTCN2019081505-appb-000017
注：**为本发明药物组相比，P﹤0.01；*为和本发明药物组相比，P﹤0.05
4.结论：表4-表7活性评价方面显示出了本发明药物组合物比24个成分组成的药物组合物(对照药物组合物)和单一成分性进行评价，本发明具有明显的活性，本发明药物成分之间有协同效应。
试验例三、射血分数保留性心衰
本发明药物连续给药90天对自发性慢性心力衰竭恒河猴有效性研究
1.研究目的
评价本发明药物临床等效剂量下连续给药90天，观察自发性慢性心力衰竭(NYHAII-IV级，HfpEF)恒河猴(中年/老年)有效性研究，主要药效学指标为超声心动图指标分析心脏结构和给药前后收缩、舒张功能变化。
2.实验材料及方法
2.1实验材料
2.1.1实验动物
动物种属：恒河猴
等级：普通级。试验前检疫合格，内容包括体检、2次结核杆菌试验、寄生虫、沙门氏菌、致贺氏菌和B病毒检查。
动物标识：脖环上戴刻有阿拉伯数字的不锈钢号牌，胸口纹身
(1)入选标准
雄性，年龄12-23岁(等同于40-70岁成年人)；
体重：9-13kg；
NYHAII级-IV级；其中每组一半动物为HFpEF
HFpEF(中度以上受损)：e’<8或E/e’>10(依据临床诊断标准)；
(2)排除标准
二级和三级高血压(SBP＞140mmHg，DBP＞90mmHg)
严重肝肾功能异常，贫血、白细胞增多、血小板减少，电解质紊乱，体重异常波动的动物。
有明显内分泌，免疫，凝血，泌尿生殖道临床异常症状或疾病的动物。
任何可能会影响药效评价的其他疾病史。
2.1.2受试物
本发明药物(实施例1)，由天士力医药集团股份有限公司提供，为方便给药，按一定比例与PEG混合制备成滴丸制剂用于动物实验中，批号：20180215。
2.2实验分组及给药
本试验共分3组，安慰剂组，本发明药物低剂量组，本发明药物高剂量组，每组4只动物。
给药途径：鼻饲给药，每天1次。
给药量计算：以每次称量的体重计算下一周的给药量。
给药时间：每天08:00-10:00给药。
详见下表8。
表8 实验分组及给药
Figure PCTCN2019081505-appb-000018
2.3检测指标
主要药效指标：分别于用药前、用药30d、60d、90d对心衰猴心功能进行测量,取胸骨旁左室长轴切面左室波群测量舒张及收缩末期左室内径,计算左室舒张末期容积(Left ventricular end-diastolic volume,LVEDV)、左室收缩末期容积(Left ventricular end-systolic volume,LVESV)、每搏量(stroke volume,SV)、Ea值、E/Ea值等参数，评估本发明药物对心衰猴收缩功能及舒张功能的影响。
次要药效学指标：分别于用药前、用药30d、60d、90d对猴血压的变化。
日常观察：给药期间每日对动物日常表现，如活动量及采食量、体重进行观察。
3.统计方法
所有数据为计量资料，用均数±标准差(x±s)表示，采用SPSS11.5软件，组间比较重复测量的方差分析(若数据不服从球形分布则应用二次方曲线拟和分析)。检验水平α＝0.05。
4.实验结果
1)对自发性慢性心力衰竭恒河猴血压作用
研究结果显示，本发明药物对心衰猴收缩压具有一定的改善作用，降压效果呈剂量依赖性，结果见表9。
表9 本发明药物对心衰猴血压的影响
Figure PCTCN2019081505-appb-000019
2)对自发性慢性心力衰竭恒河猴心功能作用
研究结果显示，本发明药物对心衰猴的左室射血分数与溶媒组具有统计学显著性差异学，提示本发明药物对心衰猴左心室收缩力具有一定影响，可一定程度上改善心衰猴的左心功能。结果见表10。
另外，针对舒张功能的检测中，Ea和E/Ea均是评价心脏左室舒张功能的常用参数和敏感指标，其中猴的E/Ea值在9左右较为理想。研究发现给药组舒张早期二尖瓣环运动峰速变化值(ΔEa)和E/Ea值变化度(ΔE/Ea)与模型组比较，均有较好改善(参见图5、6)。
表10 本发明药物给药90天心衰猴M型超声心动图的影响
Figure PCTCN2019081505-appb-000020
注：*，与基础数值比较有显著性差异； #，与同期溶媒组比较有显著性差异。
3)日常观察
给药期间每日对实验动物进行观察，观察发现安慰剂组动物活动较少，活动后多有呼吸困难、体力下降、乏力，采食量较少等表现，而本发明药物给药组动物日平均活动量较安慰剂动物多，活泼好动，体力较好，呼吸急促等症状较少见，动物采食量正常。
5.结论
本发明药物连续给药90天可提高射血分数保留型心衰猴模型射血分数，改善其收缩功能，对其舒张功能也有一定的改善作用。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。

Claims (10)

  1. 一种药物组合物，其包括如下成分：
    Figure PCTCN2019081505-appb-100001
  2. 如权利要求1所述的一种药物组合物，其包括如下成分：
    Figure PCTCN2019081505-appb-100002
  3. 如权利要求2所述的一种药物组合物，其包括如下成分：
    Figure PCTCN2019081505-appb-100003
  4. 如权利要求1-3任意一项所述的药物组合物，其特征在于，所述酚酸类成分包括下述重量份比的物质：丹参素：原儿茶醛：丹酚酸T：丹酚酸U：丹酚酸D：丹酚酸G：迷迭香酸：紫草酸：丹酚酸B：丹酚酸A：异丹酚酸C＝(3.0-11.0)：(0.06-0.15)：(0.2-0.55)：(0.2-0.55)：(0.4-1.3)：(0.02-0.05)：(0.3-0.8)：(0.05-0.40)：(0.10-0.40)：(0.07-0.12)：(0.015-0.04)。
  5. 如权利要求1-3任意一项所述的药物组合物，其特征在于，所述黄酮类成分包括下述重量份比的物质：毛蕊异黄酮葡萄糖苷：芒柄花苷：毛蕊异黄酮：芒柄花素＝(0.6-1.8)：(0.3-0.7)：(0.03-0.18)：(0.03-0.65)。
  6. 如权利要求1-3任意一项所述的药物组合物，其特征在于，所述丹参酮类成分包括下述重量份比的物质：二氢丹参酮I：隐丹参酮：丹参酮I：丹参酮IIA＝(0.001-0.03)：(0.005-0.04)：(0.002-0.025)：(0.004-0.03)。
  7. 如权利要求1-3任意一项所述的药物组合物，其特征在于，所述皂苷类成分包括下述重量份比的物质：三七皂苷R1：人参皂苷Rg1：人参皂苷Rb1：黄芪甲苷：人参皂苷Rd＝(1.8-3.5)：(2.5-5.4)：(1.3-5.0)：(0.30-0.60)：(0.4-0.6)。
  8. 如权利要求1-3任意一项所述的药物组合物，其特征在于，所述挥发油类成分包括下述重量份比的物质：反式-橙花叔醇：橙花叔醇氧化产物＝(25-38)：(55-76)。
  9. 如权利要求8所述的药物组合物，其特征在于，所述橙花叔醇氧化产物包括(3R,6S,7R)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3R,6R,7S)-3,7,11-三甲基色氨酸-3,7-环氧基-1,10-十二碳二烯-6-醇、(3S,6R,7S)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇和(3S,6S,7R)-3,7,11-三甲基色氨酸-3,6-环氧基-1,10-十二碳二烯-7-醇，其重量份比为(3-6)：(4-7)：(25-33)：(23-30)。
  10. 如权利要求1-9任一项所述的药物组合物在制备改善心肌损伤药物中的应用或治疗或预防心衰的药物中的应用，其中，所述心衰优选为射血分数降低性心衰或射血分数保留性心衰。
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