WO2010009619A1 - 用于治疗高血压和代谢综合症的药物组合物及其应用 - Google Patents

用于治疗高血压和代谢综合症的药物组合物及其应用 Download PDF

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WO2010009619A1
WO2010009619A1 PCT/CN2009/000824 CN2009000824W WO2010009619A1 WO 2010009619 A1 WO2010009619 A1 WO 2010009619A1 CN 2009000824 W CN2009000824 W CN 2009000824W WO 2010009619 A1 WO2010009619 A1 WO 2010009619A1
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pharmaceutically acceptable
acceptable salt
pharmaceutical composition
amlodipine
pioglitazone
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PCT/CN2009/000824
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English (en)
French (fr)
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赵志全
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鲁南制药集团股份有限公司
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Priority to JP2011519008A priority Critical patent/JP5504263B2/ja
Priority to EP09799935.3A priority patent/EP2329820B1/en
Priority to KR1020117004035A priority patent/KR101303841B1/ko
Priority to US13/055,175 priority patent/US8722697B2/en
Publication of WO2010009619A1 publication Critical patent/WO2010009619A1/zh
Priority to HK11112324.9A priority patent/HK1158057A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • composition for treating hypertension and metabolic syndrome and application thereof
  • the invention relates to the field of medicine, in particular to a pharmaceutical composition and a preparation thereof for treating hypertension or metabolic syndrome
  • Hypertension is one of the most common cardiovascular diseases, and it is closely related to the main diseases causing human death such as coronary heart disease and cerebrovascular diseases.
  • cardiovascular diseases with high blood pressure, high blood fat and high cholesterol are also increasing.
  • Chinese patients with hypertension have It has reached 1.5 million people and is increasing at a rate of 5 million a year. All countries in the world attach great importance to the study of the prevention and treatment of hypertension from the pathogenesis.
  • High blood pressure disease mainly damages human blood vessels. It can promote the hardening of the arterial wall, and the narrowing of the lumen is called "arteriosclerosis". If hypertension is combined with diabetes, it will accelerate and aggravate vascular damage, and the disease will deteriorate rapidly. It should be treated actively.
  • Amlodipine is a calcium blocker that blocks calcium ions from entering the myocardium and vascular smooth muscle cells and thus has antihypertensive effects.
  • Amlodipine has two isoforms, left-handed and right-handed. The activity of left-handed calcium is 1000 times that of the right-handed body and twice that of the racemate.
  • the selective effect of amlodipine on vascular smooth muscle is greater than that of nifedipine. It can increase cardiac output and coronary flow in patients with myocardial ischemia, increase myocardial oxygen supply, reduce oxygen consumption, and improve exercise capacity.
  • amlodipine may also activate LDL receptors, reduce fat accumulation in the arterial wall and inhibit collagen synthesis, and thus have anti-atherosclerotic effects.
  • the mechanism of anti-hypertensive effect of amlodipine is to directly relax vascular smooth muscle.
  • the exact mechanism of relieving angina is not completely certain, but it can dilate peripheral arterioles and coronary arteries, reduce total peripheral vascular resistance, relieve coronary spasm, and lower the heart. Afterload, reducing heart energy consumption and oxygen demand, thereby relieving angina.
  • Rosuvastatin Calcium was developed by Japan's Yanoyi Company (Osaka Shionogi Co., Ltd.) and is a synthetic statin. It was transferred to AstraZeneca in April 1998. Rosuvastatin is a selective 3-hydroxy 3-methylisoglutaryl coenzyme A (HMG-CoA) reductase inhibitor that can be used to treat atherosclerosis, hyperlipidemia, familial cholesterol Many and similar diseases.
  • HMG-CoA 3-hydroxy 3-methylisoglutaryl coenzyme A reductase inhibitor that can be used to treat atherosclerosis, hyperlipidemia, familial cholesterol Many and similar diseases.
  • the molecular formula of rosuvastatin calcium is as follows:
  • rosuvastatin calcium is not called “super statin”, its lipid-lowering effect is very good, is the most powerful to date Lipid-lowering drugs.
  • the Chinese invention patent application CN200510094723.3 discloses a pharmaceutical composition comprising 5% to 40% by weight of amlodipine besylate and 5% to 40% by weight of rosuvastatin calcium, and a preparation method thereof.
  • Chinese invention patent application CN200610028434.8 discloses a pharmaceutical composition comprising a therapeutically effective amount of amlodipine and a therapeutically effective amount of rosuvastatin calcium and a process for the preparation thereof.
  • amlodipine and rosuvastatin in the above two patent applications can be used for lipid-lowering therapy while antihypertensive, but cardiovascular disease is a high-risk disease in patients with hypertension, only in the treatment of hypertension Lipid is not enough. Long-term high blood pressure may cause damage to vital organs such as the cardiovascular system and kidneys. Therefore, antihypertensive therapy not only reduces blood pressure to the target level, but also corrects risk factors such as cardiovascular disease. And choose appropriate drugs to improve metabolic disorders and patients' prognosis. Therefore, look for a multi-drug combination to effectively control the occurrence of cardiovascular diseases and better improve the survival prognosis of patients with hypertension while treating hypertension.
  • the treatment method has become an urgent problem to be solved in clinical treatment. Summary of the invention
  • An object of the present invention is to provide a novel pharmaceutical composition which can effectively control the occurrence of cardiovascular diseases and improve the survival prognosis of hypertensive patients while treating hypertension or metabolic syndrome.
  • antihypertensive therapy lowers blood pressure to the target level, it corrects risk factors such as cardiovascular disease, improves metabolic disorder and patient prognosis, and improves survival rate of hypertensive patients.
  • the present invention provides a pharmaceutical composition comprising the following active ingredients:
  • the pharmaceutically acceptable salt of amlodipine is selected from the group consisting of betaines, maleates, hydrochlorides, formates, acetates, hydrobromides, days of amlodipine. Butyrate, mesylate, sulfate or tartrate.
  • amlodipine is a left-handed body of amlodipine or a mixture of a left-handed body and a right-handed body.
  • the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is 1 : 0.1 ⁇ 18: 0.1 ⁇ 16, wherein the weight of the pharmaceutically acceptable salt of amlodipine is based on amlodipine, the weight of the pharmaceutically acceptable salt of pioglitazone is based on pioglitazone, and the weight of the pharmaceutically acceptable salt of rosuvastatin is rosuvastole He is statistic.
  • the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof is 1: 0.1 to 9: 0.1 to 8, wherein amlodipine is acceptable.
  • the weight of the pharmaceutically acceptable salt is based on amlodipine
  • the weight of the pharmaceutically acceptable salt of pioglitazone is based on pioglitazone
  • the weight of the pharmaceutically acceptable salt of rosuvastatin is calculated as rosuvastatin.
  • the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof is 1: 0.1 to 4.5: 0.1 to 4, wherein amlodipine
  • the weight of the pharmaceutically acceptable salt is in terms of amlodipine
  • the weight of the pharmaceutically acceptable salt of pioglitazone is based on pioglitazone
  • the weight of the pharmaceutically acceptable salt of rosuvastatin is calculated as rosuvastatin.
  • the pharmaceutically acceptable salt of pioglitazone in the pharmaceutical composition of the invention is preferably pioglitazone hydrochloride.
  • the pharmaceutically acceptable salt of rosuvastatin in the pharmaceutical composition of the invention is preferably rosuvastatin calcium.
  • the invention is based on the latest research progress of clinical treatment for hypertension and the disease development trend of hypertensive patients, and creatively introduces the insulin sensitizer pioglitazone for treating diabetes in the existing antihypertensive program, and achieves a very good therapeutic effect. .
  • the experiment proves that the pharmaceutical composition of the invention not only has obvious advantages in blood pressure reduction, but also effectively reduces the damage of cardiovascular organs, kidneys and other vital organs caused by long-term hypertension, and effectively corrects the risk factors such as cardiovascular diseases at the same time. Improve the metabolic disorder and the prognosis of patients, and achieve good synergy and unexpected effects in the treatment and control of various cardiovascular and cerebrovascular complications caused by hypertension.
  • the invention demonstrates that the pharmaceutical composition provided by the invention can reverse cardiac hypertrophy and effectively control the occurrence of cardiovascular diseases by measuring the cardiac hypertrophy and carotid intima-media thickness of the rat, and proves its advantages in preventing and treating cardiovascular diseases. .
  • the present invention also demonstrates that the pharmaceutical composition of the present invention has a certain protective effect on the kidney by measuring the urine microalbumin of the rat, and can effectively alleviate the kidney damage of the hypertensive patient.
  • the present invention provides the use of the pharmaceutical composition of the present invention for the preparation of a medicament for the treatment of hypertension or metabolic syndrome.
  • the invention also provides a pharmaceutical composition of the invention for treating hypertension or metabolic syndrome comprising administering to a patient in need of treatment an effective amount of a composition of the invention.
  • the present invention also provides the above pharmaceutical compositions useful for the treatment of hypertension or metabolic syndrome.
  • ⁇ Metabolic syndrome refers to a pathological phenomenon in which a variety of metabolic abnormalities are present in a person, including obesity (especially abdominal obesity), insulin resistance, impaired glucose regulation, diabetes, hypertension, dyslipidemia, microalbuminuria or Hyperuricemia and so on.
  • the pharmaceutical composition of the invention can effectively reduce total cholesterol TC, high density lipoprotein cholesterol HDLC, glycosylated hemoglobin (HbAlC), fasting blood glucose (FBG), fasting insulin (FINS) and fibrinogen (Fg) content in patients with metabolic syndrome, Effectively control related cardiovascular diseases and reduce morbidity and mortality.
  • An effective amount means that the pharmaceutical composition of the present invention is administered in an amount such that the composition produces a desired therapeutic effect in a patient.
  • the pharmaceutical composition of the present invention is prepared into a solid pharmaceutical preparation according to the nature of the drug and the convenience of the patient's administration. Such as tablets, capsules, granules, pills, dropping pills, and the like.
  • the tablet includes a common tablet, a coated tablet, a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, an effervescent tablet, a chewable tablet, a multilayer tablet, a disintegrating tablet, a dispersible tablet, a sublingual tablet, a buccal tablet, a plant Tablets, solution tablets, sustained release tablets, etc.
  • the solid pharmaceutical preparation of the invention has the advantages of convenient carrying and convenient use, simple and convenient administration route, and is easy for the patient to accept.
  • the pharmaceutical compositions of the invention are in the form of tablets, capsules or granules, but are not limited to these dosage forms.
  • compositions of the present invention are formulated according to conventional formulation techniques and can be prepared according to conventional techniques using the following additives: excipients (for example, lactose, sucrose, glucose, mannitol, sorbitol, starch, dextrin, crystalline cellulose, Acacia gum, dextran, etc.), lubricants (magnesium stearate, calcium stearate, talc, silica gel, boric acid, sodium decyl sulfate, etc.), binder (hydroxypropylcellulose, hydroxyl Propyl propylcellulose, polyvinylpyrrolidone, polyethylene glycol, etc., disintegrant (low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethyl starch, cross-linked polyvinylpyrrolidone, etc.), emulsified Agent (bentonite, magnesium hydroxide, aluminum hydroxide, sodium lauryl sulfate, etc.), stabilizer (methylparab
  • the pharmaceutical composition of the present invention can be prepared into a sustained-release tablet in combination with the needs of the patient, so that the blood pressure can be adjusted efficiently and safely, and the slow release maintains a relatively stable blood concentration and a longer action time, and has toxic side effects.
  • the sustained release tablet prepared by the pharmaceutical composition of the present invention comprises a cellulose derivative or a vinyl polymer as a sustained release substrate, and these sustained release substrates may be methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, Mixture of one or more of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, acrylic resin .
  • the present invention creatively introduces an insulin sensitizer for the treatment of diabetes, based on the existing antihypertensive regimen.
  • the ketone or its pharmaceutically acceptable salt has achieved a very good synergistic antihypertensive effect.
  • Calcium ion antagonist (CCB) A combination of amlodipine or a pharmaceutically acceptable salt thereof with the HMG-CoA reductase inhibitor rosuvastatin or a pharmaceutically acceptable salt thereof, the insulin sensitizer pioglitazone or a pharmaceutically acceptable salt thereof A good synergistic antihypertensive effect has been achieved in experimental research and clinical observation.
  • the incidence of adverse reactions and the degree of adverse reactions of the pharmaceutical compositions of the present invention are significantly reduced.
  • the invention combines the triple treatment scheme of antihypertensive drug + hypoglycemic drug + lipid-lowering drug, and achieves a remarkable synergistic effect in the treatment of hypertension, comprehensively combined, synergistically reducing blood pressure, significantly reducing the dosage, and making the defect
  • the incidence of the reaction and the degree of adverse reactions were significantly reduced.
  • the pharmaceutical composition of the present invention has a wide range of application.
  • the invention is suitable for various types of hypertensive patients because of its synergistic mechanism, and is especially suitable for patients with stroke-type hypertension and those with hypertension and kidney damage.
  • it has a good effect on hypertension, coronary heart disease, angina pectoris, peripheral vascular disease, senile hypertension, gestational hypertension, and refractory hypertension.
  • composition of the present invention has achieved a very good effect on the metabolic syndrome with high incidence in the society today! detailed description
  • amlodipine represents amlodipine or a pharmaceutically acceptable salt thereof
  • levamlodipine represents levamlodipine or a pharmaceutically acceptable salt thereof
  • the weight of the pharmaceutically acceptable salt of amlodipine is in terms of amlodipine.
  • the weight of pioglitazone hydrochloride is based on pioglitazone.
  • Preparation process Weigh the prescribed amount of rosuvastatin calcium, amlodipine, pioglitazone hydrochloride, starch, dextrin and mix well. In addition, an appropriate amount of 50% ethanol is added to the mixed powder, uniformly mixed, and the soft material is made into a wet granule by a 18-mesh nylon sieve, dried at about 60 Torr, and the dry granule moisture should be controlled to be less than 1.5%. The 20 mesh sieve is granulated, and then mixed with magnesium stearate, and tableted.
  • Preparation process The prescribed amount of rosuvastatin calcium, levamlodipine, pioglitazone hydrochloride, microcrystalline cellulose, and micro-silica gel are crushed and sieved through a 100 mesh sieve, and directly filled into capsules.
  • Magnesium stearate 2g Preparation process a: rosuvastatin calcium over 100 mesh sieve, mannitol, lactose, microcrystalline cellulose over 80 mesh sieve, weigh prescription amount of rosuvastatin calcium, mannitol, lactose, micro The crystalline cellulose was uniformly mixed, and granulated with a solution of 6% povidone (PVP) in 95% ethanol, dried at 60 ° C, sieved to dry the particles in a 16-mesh sieve, and a prescribed amount of magnesium stearate was added to the dry granules.
  • PVP povidone
  • Micronized silica gel 5g Preparation process b: Amlodipine and pioglitazone hydrochloride over 100 mesh sieve, pregelatinized starch and mannitol over 80 mesh sieve, weigh prescription amount of amlodipine, pioglitazone hydrochloride and pregelatinized starch, mannitol mixture Uniformly, 6% PVP 95% ethanol solution was added to prepare granules, dried at 60 ° C, 16 mesh sieved dry granules, and a dry amount of micro-silica gel was added to the dry granules.
  • pellet components of the above two preparation processes a and b were punched by a double laminator to obtain a two-layer sheet.
  • Preparation process of magnesium stearate 6g Prescription amount of rosuvastatin calcium, levamlodipine and pioglitazone hydrochloride over 100 mesh, carboxymethylcellulose calcium, cross-linked polyvinylpyrrolidone, microcrystalline cellulose over 80 mesh Sieve, mix well, add appropriate amount of 10% starch slurry to granulate, add magnesium stearate and then compress.
  • Preparation process Weigh the prescribed amount of rosuvastatin calcium, amlodipine, pioglitazone hydrochloride, starch, dextrin, and sucrose powder. In addition, an appropriate amount of 80% ethanol is added to the mixed powder, and the mixture is uniformly mixed, and the soft material is made into a wet granule through a 18-mesh nylon sieve, dried at about 60 ° C, and sieved into a 20-mesh sieve to obtain a pellet.
  • Preparation process rosuvastatin calcium, levamlodipine, pioglitazone hydrochloride, microcrystalline cellulose as filler, croscarmellose sodium and polyvinylpyrrolidone as disintegrants are weighed according to the prescription amount.
  • the 5% PVP 60% ethanol solution is a binder, and the micro-powder silica gel is a glidant, which is granulated by a fluidized bed in one step, and then tableted.
  • Micronized silica gel 100g Preparation process: The prescription amount of rosuvastatin calcium, levamlodipine, pioglitazone hydrochloride and the prescribed amount of hydroxypropylmethylcellulose, lactose are uniformly added to the binder polyvinylpyrrolidone granules, Dry at 40 ° C - 80 ° C, dry the granules, add the prescription amount of lubricant micro-silica gel to the dry granules, mix well, and shape the stamping sheet.
  • Example 8 Capsule
  • Spontaneously hypertensive rats 48 males, were provided by the New Drug Pharmacology Center of Shandong New Times Pharmaceutical Co., Ltd., weighing (300 ⁇ 20) g, and after adaptive feeding for one week, they were randomly divided into 6 groups, 8 in each group.
  • Model control group the same volume of normal saline was administered by gavage
  • Pyridine group lmg/ (kg.d) pioglitazone
  • Ammonia + Rui group 2mg / (kg.d) amlodipine + lmg / (kg.d) rosuvastatin calcium;
  • Pyridinium group lmg/(kg.d) pioglitazone + lmg/ (kg.d) rosuvastatin calcium;
  • Ammonia group 2mg / (kg.d) amlodipine
  • composition group of the present invention 2 mg / (kg.d) amlodipine + lmg / (kg.d) pioglitazone + lmg / (kg.d) rosuvastatin calcium;
  • Each group was administered by intragastric administration once a day for 10 weeks.
  • the diet, survival and behavior of the animals were observed daily, body weight was measured daily, and the amount of the drug was adjusted according to the body weight.
  • the animals were sacrificed, and the left ventricular mass was measured by cardiac measurement to calculate the left ventricular index.
  • the temperature is controlled at 18 ° C - 22 ° C, the temperature is 45% - 65%, indoor natural light.
  • the tail artery pressure was measured in the awake state of the rats using a BP-2006A intelligent non-invasive sphygmomanometer (provided by Beijing Soft Long Co., Ltd.). Blood pressure was measured at the first week, the third week, and the sixth week after administration, and was measured 5 times between 2 hours and 5 hours after the intragastric administration, and the mean value was taken as the blood pressure of the sample.
  • Medicament of the present invention is 153 ⁇ 13.7 149 ⁇ 7.1 140 ⁇ 16.2 ⁇ '* # 135 ⁇ 7.6 ""# Composition group
  • the medicament of the invention 303 ⁇ 14 0.75 ⁇ 0.15 ⁇ '* # 2.48 + 0.25 ⁇ ⁇ * #
  • Spontaneously hypertensive rats 48 males, were provided by the New Drug Pharmacology Center of Shandong New Times Pharmaceutical Co., Ltd., weighing (300 ⁇ 20) g, and after adaptive feeding for one week, they were randomly divided into 6 groups, 8 in each group.
  • Model control group the same volume of normal saline was administered by gavage
  • Pyridin group 2 mg / (kg.d) pioglitazone administered by intragastric administration;
  • Left ammonia + rui group intragastric administration of lmg / (kg.d) levamlodipine + lmg / (kg.d) rosuvastatin calcium; pyr + ruin group: 2mg / (kg.d) pioglitazone by intragastric administration + lmg/ (kg.d) rosuvastatin calcium;
  • Left ammonia group intragastric administration of lmg / (kg.d) levamlodipine;
  • the pharmaceutical composition group of the present invention intragastric administration of lmg / (kg.d) levamlodipine + 2mg / (kg.d) pioglitazone + lmg / (kg.d) rosuvastatin calcium;
  • All groups were administered by intragastric administration once a day, and all rats in this experiment were fed with high-sugar and high-fat diet for 6 months. During the experiment, the diet, survival and behavior of the animals were observed daily, body weight was measured weekly, and the amount of the drug was adjusted according to the body weight.
  • glycine-glacial acetic acid buffer pH 3.0: Weigh 22.72 g of glycine, dilute it to 1000 ml with 10% glacial acetic acid solution, add NaN 3 100 mg, and seal at room temperature for 1 year.
  • bromophenol blue (1.924mmol / L) stock solution Accurately weigh 257, 36mg BPB, dissolved in anhydrous ethanol to 200ml,
  • the refrigerator can be stable for 1 year at 4 °C.
  • bromophenol blue (0.231mmol / L) color developer take 60ml BPB stock solution, add 2.5ml Triton X-100, with The glycine-glacial acetic acid buffer was diluted to 500 ml and sealed at room temperature for 1 year.
  • Rats were housed in metabolic cages at 4, 8, 12 and 16 weeks, and urine was collected overnight for 12 hours to accurately record urine volume. Take 4ml, sodium azide treatment, centrifuge (2000r / min) lOmin, take the supernatant and put a 20 ° C refrigerator to store urine albumin to be tested. Store the stored rat urine 2tnl, add 1ml of each coloring agent, mix (prevent the generation of air bubbles), and measure the absorbance A at 600nm with an ultraviolet spectrophotometer. Table 3 Effect of the pharmaceutical composition of the present invention on urinary microalbumin in spontaneously hypertensive rats Soil S) Group n Absorbance A (600 nm)
  • composition group of the invention 8 0.411 ⁇ 0.158"
  • the 'Even's blue dye 60 mg/kg was injected through the femoral artery, and after 30 minutes, 0.9% physiological saline was used as the perfusate, and the perfusion was used.
  • the perfusion pressure was 13. 3 kPa, until the effluent was clear. After that, it was infused with 4% paraformaldehyde saline for 10 min, and fixed in situ (pressure as above).
  • the Even's blue colored carotid artery segment was taken and placed in formalin solution for further fixation.
  • the anterior, middle and posterior sections were taken for paraffin embedding, and non-continuous sections were 8 ⁇ 10 layers.
  • HE staining was performed, and 3 randomly selected.
  • the vascular section was input into a computer image processing system, and computer image measurement was performed to calculate the maximum intima thickness, the media thickness, and the intima/media thickness ratio.
  • the drug group of the present invention 0.062 soil 0. 014 ⁇ " # 1.102 ⁇ 0. 243 ⁇ '* #
  • Control group 28 males and 16 females, aged 62-71 years old, body mass index ( ⁇ ) 25. 5-30;
  • the experimental group 24 males and 20 females, aged 60-70 years old, body mass index ( ⁇ ) 24. 5-31;
  • Blood lipid analysis including total cholesterol TC, high-density lipoprotein cholesterol HDL (:), glycated hemoglobin (HbA) C), fasting blood glucose (FBG), fasting insulin (FINS), and fibrinogen (Fg) were performed before treatment. Detection.
  • NCEP- ⁇ National Cholesterol Education Program Adult Treatment Group
  • the patients in the control group were treated with pioglitazone, 15 mg each time, once a day.
  • the experimental group was administered according to the active ingredient distribution ratio of the common tablets of Preparation Example 1 5 mg of amlodipine, 7. 5 mg of pioglitazone and 5 mg of rosuvastatin calcium.
  • the above indicators were reviewed.
  • the hexokinase method was used to detect blood glucose
  • the esterase method was used to detect blood lipids.
  • the fibrinogen was detected by the coagulation method and the household substrate method
  • the HbAlC was detected by a chromatography column method, and the fasting insulin was irradiated by chemiluminescence.
  • the pharmaceutical composition of the present invention has significant differences in FBG, FINS, HbAlC, TC/HDLC, and Fg in the treatment of metabolic syndrome, and the pharmaceutical composition group of the present invention and the pioglitazone single-use group after the treatment. Comparing FBG, FINS, HbAlC, TC/HDLC, and Fg, there were significant differences, indicating that the pharmaceutical composition of the present invention is effective in the treatment of metabolic syndrome, and the effect is obvious.

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Description

用于治疗高血压和代谢综合症的药物组合物及其应用 技术领域
本发明涉及医药领域，特别涉及一种药物组合物及其用于制备治疗高血压或代谢综合征
背景技术
高血压病是最常见的心血管疾病之一， 又与造成人类死亡的主要疾病如冠心病、脑血管 疾病等密切相关， 我国高血压病的发病率虽然不如西方国家高， 但却呈逐年升高趋势， 随着 人们生活水平的不断提高和环境的恶化， 患有高血压、 高血脂、 高胆固醇类的心血管病人也 在不断增加， 据有关资料报道截至 2003年年底， 我国高血压患者己达 1. 5亿人， 并以每年 500万人的速度增加。 世界各国均十分重视高血压病从发病机理以致临床防治的研究。 高血 压病主要损害人体血管。 它能促使动脉管壁变硬， 管腔变狭窄即平时所说的 "动脉硬化" ， 高血压病若合并糖尿病， 则会加速、 加重血管损害， 使病情迅速恶化， 应该积极治疗。
氨氯地平（Amlodipine)为钙离子阻滞剂， 能阻滞钙离子跨膜进入心肌和血管平滑肌细 胞， 从而具有抗高血压的作用。氨氯地平有左旋和右旋两种同型异构体， 左旋体钙离子活性 是右旋体的 1000倍，是消旋体的两倍。氨氯地平对血管平滑肌的选择性作用大于硝苯地平， 对心肌缺血患者可增加心输出量及冠脉流量， 增加心肌供氧及减低耗氧， 改善运动能力。 此 外， 氨氯地平还可能激活 LDL受体， 减少脂肪在动脉壁累积及抑制胶原合成， 因而具有抗 动脉硬化作用。氨氯地平抗高血压作用的机制是直接松弛血管平滑肌， 缓解心绞痛的确切机 制还未完全肯定， 但它可以扩张外周小动脉和冠状动脉， 减少总外周血管阻力， 解除冠状动 脉痉挛， 降低心脏的后负荷， 减少心脏能量消耗和对氧的需求， 从而缓解心绞痛。
瑞舒伐他汀钙（Rosuvastatin Calcium) 由日本盐野义公司 （大阪 Shionogi公司）研 制开发， 属于合成类他汀药物， 1998年 4月转让给英国阿斯利康公司。 瑞舒伐他汀是一种 选择性 3-羟基 3-甲基异戊二酰辅酶 A (HMG-CoA)还原酶抑制剂， 可用来治疗动脉粥样硬化、 血脂过高、 家族性血胆甾醇过多以及相似的疾病。 瑞舒伐他汀钙的分子式如下：
Figure imgf000002_0001
从目前己有的临床验证结果和与同类他汀类产品的比较两方面来看，瑞舒伐他汀钙都不 愧被称为"超级他汀"， 其降脂效果非常好， 是迄今为止的最强效的降脂药物。
中国发明专利申请 CN200510094723.3公开了一种含有 5%-40%重量份苯磺酸氨氯地 平和 5%-40%重量份瑞舒伐他汀钙的药物组合物及其制备方法。
中国发明专利申请 CN200610028434.8公开了一种含有治疗有效量的氨氯地平和治疗 有效量的瑞舒伐他汀钙的药物组合物及其制备方法。
上述两个专利申请中氨氯地平和瑞舒伐他汀的联合应用虽然能够在抗高血压的同时进 行降脂治疗，但心血管疾病是高血压患者的高发疾病，仅仅在治疗高血压的同时降脂是不够 的， 长期高血压可能导致心血管系统、 肾脏等重要器官的损害， 所以说， 降压治疗不仅要将 血压降至靶目标水平， 而且要纠正同时存在的心血管疾病等危险因素， 并选用合适药物， 改 善代谢紊乱及患者的预后， 因此，寻找一种在治疗高血压疾病的同时有效控制与其相关的心 血管疾病的发生，更好的改善高血压患者的生存预后的多药联合治疗方式巳成为临床治疗中 亟需解决的问题。 发明内容
本发明的目的在于提供一种在治疗高血压或者代谢综合征的同时能够有效控制与其相 关的心血管疾病的发生， 更好的改善高血压患者的生存预后的新药物组合物。在降压治疗将 血压降至靶目标水平时， 纠正同时存在的心血管疾病等危险因素， 并改善代谢紊乱及患者的 预后， 提高高血压患者的生存率。
本发明提供了一种药物组合物， 该药物组合物含有如下活性成分：
1. 氨氯地平或其可药用盐；
2. 吡格列酮或其可药用盐； 和
3. 瑞舒伐他汀或其可药用盐。
在本发明的一个实施方案中， 氨氯地平可药用盐选自氨氯地平的苯磺酸盐、 马来酸盐、 盐酸盐、 甲酸盐、 乙酸盐、 氢溴酸盐、 天冬酸盐、 甲磺酸盐、 硫酸盐或酒石酸盐。
在本发明的一个实施方案中， 氨氯地平是氨氯地平的左旋体或左旋体和右旋体的混合 物。
在本发明的一个实施方案中， 本发明的药物组合物中的氨氯地平或其可药用盐、吡格列 酮或其可药用盐、瑞舒伐他汀或其可药用盐的重量比为 1 : 0.1〜18:0.1~16，其中氨氯地平可药 用盐的重量以氨氯地平计， 吡格列酮可药用盐的重量以吡格列酮计， 瑞舒伐他汀可药用盐的 重量以瑞舒伐他汀计。 · 优选地， 氨氯地平或其可药用盐、 吡格列酮或其可药用盐、 瑞舒伐他汀或其可药用盐的 重量比为 1 : 0.1~9:0.1~8，其中氨氯地平可药用盐的重量以氨氯地平计，吡格列酮可药用盐的 重量以吡格列酮计， 瑞舒伐他汀可药用盐的重量以瑞舒伐他汀计。
更优选地， 氨氯地平或其可药用盐、 吡格列酮或其可药用盐、 瑞舒伐他汀或其可药用盐 的重量比为 1 : 0.1〜4.5:0.1~4， 其中氨氯地平可药用盐的重量以氨氯地平计， 吡格列酮可药用 盐的重量以吡格列酮计， 瑞舒伐他汀可药用盐的重量以瑞舒伐他汀计。
在本发明的一个实施方案中，本发明的药物组合物中的吡格列酮可药用盐优选为盐酸吡 格列酮。
在本发明的一个实施方案中，本发明的药物组合物中的瑞舒伐他汀可药用盐优选为瑞舒 伐他汀钙。
本发明根据临床对于高血压治疗的最新研究进展情况和高血压患者的疾病发展趋势，创 造性地在现有降压方案中引入用于治疗糖尿病的胰岛素增敏剂吡格列酮，取得了非常好的治 疗效果。实验证明本发明药物组合物不但在降压方面有相当明显的优势， 而且还能有效减少 长期高血压导致心血管系统、 肾脏等重要器官的损害， 有效纠正同时存在的心血管疾病等危 险因素， 改善代谢紊乱情况和患者的预后情况， 在治疗并控制高血压所引起的各种心脑血管 并发症方面取得了很好的协同作用和意想不到的效果。本发明通过对大鼠心肌肥厚、颈动脉 内中膜厚度的测定表明本发明提供的药物组合物能够逆转心肌肥厚，有效的控制心血管疾病 的发生， 证明了其在防治心血管疾病方面的优势。 同时， 本发明还通过对大鼠尿微量白蛋白 的测定说明了本发明药物组合物对肾脏有一定的保护作用，可以有效减缓高血压患者肾脏的 损伤。
经过大量实验研究证实氨氯地平的左右旋体混合物及其可药用盐， 氨氯地平的苯磺酸 盐、 马來酸盐、 盐酸盐、 甲酸盐、 乙酸盐、 氢溴酸盐、 天冬酸盐、 甲磺酸盐、 硫酸盐和酒石 酸盐中的一种与吡格列酮或其可药用盐和瑞舒伐他汀或其可药用盐联合应用也能够逆转大 鼠心肌肥厚， 且降压作用明显， 而且能有效减少长期高血压导致心血管系统、 肾脏等重要器 官的损害， 有效纠正心血管疾病等危险因素， 还能够降低尿微量白蛋白、 保护高血压对肾脏 的损害。 同时能够改善代谢紊乱情况， 对代谢综合征患者治疗具有一定的疗效。
因此，本发明提供了本发明的药物组合物在用于制备治疗高血压或代谢综合征的药物的 应用。
本发明还提供了本发明的药物组合物治疗高血压或代谢综合征的方法，其包括给所需治 疗的患者施用有效量的本发明的组合物。
本发明还提供了可用于治疗高血压或代谢综合征的上述药物组合物。 · 代谢综合征是指多种代谢异常同时存在于一个人身上的病理现象， 包括肥胖（尤其是腹 型肥胖）、 胰岛素抵抗、 糖调节受损、 糖尿病、 高血压、 血脂紊乱、 微量白蛋白尿或高尿酸 血症等等。 本发明药物组合物能有效降低代谢综合征患者的总胆固醇 TC、 高密度脂蛋白胆 固醇 HDLC、 糖化血红蛋白 （HbAlC)、 空腹血糖 (FBG)、 空腹胰岛素 (FINS)及纤维蛋白原（Fg) 含量， 有效控制相关的心血管疾病， 降低病残率和病死率。
有效量是指，本发明药物组合物的施用量能够使该组合物在患者体内产生所需疗效的剂 本发明的药物组合物根据药物的性质和患者用药方便的需要， 制备成固体药物制剂， 如 片剂、 胶囊、 颗粒剂、 丸剂、 滴丸等。 其中片剂包括普通片、 包衣片、 糖衣片、 薄膜衣片、 肠溶衣片、 泡腾片、 咀嚼片、 多层片、 崩解片、 分散片、 舌下片、 口含片、 植入片、 溶液片、 缓释片等。 本发明采用固体药物制剂具有携带、 使用方便， 给药途径简单、 易行的优点， 易 于为患者接受。
在本发明的一个实施方案中， 本发明药物组合物的形式为片剂、 胶囊或颗粒剂， 但并不 限于这几种剂型。
本发明的药物组合物按照通常的制剂技术配制， 可以使用以下添加剂按常规技术制备： 赋形剂 （例如乳糖、 蔗糖、 葡萄糖、 甘露糖醇、 山梨糖醇、 淀粉、 糊精、 结晶纤维素、 阿拉 伯胶、 葡聚糖等）， 润滑剂 （硬脂酸镁、 硬脂酸钙、 滑石粉、 微粉硅胶、 硼酸、 十二垸基硫 酸钠等）， 粘合剂 （羟丙基纤维素、 羟丙基甲基纤维素、 聚乙烯吡咯烷酮、 聚乙二醇等）， 崩 解剂 （低取代羟丙基纤维素、 羧甲基纤维素、 羧甲基淀粉、 交联聚乙烯吡咯烷酮等）， 乳化 剂 （膨润土、 氢氧化镁、 氢氧化铝、 十二烷基硫酸钠等）， 稳定剂 （对羟基苯甲酸甲酯、 苯 甲醇、 苯乙醇、 苯酚、 山梨酸、 脱氢乙酸等）， 矫味剂（蔗糖、 香料、 阿斯巴甜、 环糊精等）， 稀释剂等。
此外， 还可以结合患者的需求将本发明的药物组合物制备成缓释片， 从而能够高效、 安 全地调节血压，缓慢释放维持较为平稳的血药浓度和更长的作用时间，并具有毒副作用减小、 服用更加方便的优点。
本发明中的药物组合物制备的缓释片以纤维素衍生物或乙烯基聚合物为缓释基质，这些 缓释基质可以是甲基纤维素、 羟甲基纤维素、 羟乙基纤维素、 羟丙基纤维素、 羟丙基甲基纤 维素、 羧甲基纤维素、 羧乙基纤维素、 微晶纤维素、 淀粉、 聚乙烯吡咯垸酮、 丙烯酸树脂其 中的一种或几种的混合。
本发明药物组合物的优势体现在下列几个方面：
一、本发明创造性地在现有降压方案的基础上引入用于治疗糖尿病的胰岛素增敏剂吡格 列酮或其可药用盐， 取得了非常好的协同降压效果。 钙离子拮抗剂 （CCB ) 氨氯地平或其可 药用盐与 HMG- CoA还原酶抑制剂瑞舒伐他汀或其可药用盐、胰岛素增敏剂吡格列酮或其可药 用盐的联合应用在实验研究和临床观察中取得了很好的协同降压作用。
二、 本发明药物组合物的不良反应的发生率和不良反应程度显著减轻。本发明由于联合 使用了降压药物 +降糖药物 +降脂药物的三联治疗方案，在治疗高血压方面取得了显著的协同 作用， 全面联合， 协同降压， 用药剂量显著减小， 同时使不良反应的发生率和不良反应程度 显著减轻。
三、 长期使用本发明药物组合物， 对高血压患者的长期生存率具有有益作用， 对患者的 预后产生积极的影响， 这也是本发明所解决的最具有意义的临床治疗问题。一般降压药物都 对高血压所引起的脑卒中、 肾脏损伤、 冠心病等并发症没有很好的预防和治疗作用， 但本发 明药物组合物能够在治疗高血压疾病的同时有效控制与其相关的心血管疾病的发生，更好的 改善高血压患者的生存预后， 在降压治疗将血压降至靶目标水平的同时， 纠正同时存在的心 血管疾病等危险因素， 并改善代谢紊乱及患者的预后， 提高高血压患者的生存率。
四、本发明药物组合物的适用范围广。本发明由于其协同作用机制适用于多种类型的高 血压患者， 尤其适用于卒中型高血压患者和高血压病合并肾脏损害者。另外对于高血压合并 冠心病心绞痛、周围血管疾病、老年高血压、妊娠期高血压、顽固性高血压都有很好的效果。
' ： b、 本发明的药物组合物对现在社会中发病率很高的代谢综合征取得了很理想的效果！ 具体实施方式
现通过如下实施例对本发明作进一步的阐述， 但本发明的应用范围并不限于下列实施 例， 对于本领域普通技术人员显而易见的改变和修饰也包括在本发明范围之内。对于本发明 记载的参考文献， 在此以引用方式将所述所有文献的全文并入本说明书中。
在以下实施例中氨氯地平表示氨氯地平或其可药用盐，左旋氨氯地平表示左旋氨氯地平 或其可药用盐， 氨氯地平可药用盐的重量均以氨氯地平计， 盐酸吡格列酮的重量以吡格列酮 计。 实施例 1 普通片剂
瑞舒伐他汀钙 10g
氨氯地平 10g
盐酸吡格列酮 15g 淀粉 140g
糊精 120g
50%乙醇 适量
硬脂酸镁 l.Og
制备工艺： 称取处方量的瑞舒伐他汀钙、 氨氯地平、 盐酸吡格列酮、 淀粉、 糊精混合均 匀。 另将适量的 50%乙醇加入于混合粉末中， 混合均匀， 制软材， 通过 18目尼龙筛制成湿 粒， 60Γ左右干燥， 干粒水分应控制在 1. 5%以下。 20目筛制粒， 再与硬脂酸镁混匀， 压片， 即得。
实施例 2 胶囊剂
瑞舒伐他汀钙 10g
左旋氨氯地平 10g
盐酸吡格列酮 10g
微晶纤维素 300g
微粉硅胶 12g
制备工艺： 将处方量的瑞舒伐他汀钙、 左旋氨氯地平、 盐酸吡格列酮、 微晶纤维素、 微 粉硅胶粉碎过 100目筛混匀， 直接填装胶囊即得。
实施例 3 双层片剂 瑞舒伐他汀钙 40g
甘露醇 10g
乳糖 40g
微晶纤维素 20g
6%PVP的 95%乙醇溶液 120g
硬酯酸镁 2g 制备工艺 a: 瑞舒伐他汀钙过 100 目筛， 甘露醇、 乳糖、 微晶纤维素过 80 目筛， 称取 处方量的瑞舒伐他汀钙、 甘露醇、 乳糖、 微晶纤维素混合均匀， 加入 6%聚维酮 （PVP) 的 95%乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒， 干颗粒中加入处方量的硬脂酸镁。 氨氯地平 10g
盐酸吡格列酮 45g
预胶化淀粉 50g
甘露醇 50g
6%PVP的 95%乙醇溶液 100g
微粉硅胶 5g 制备工艺 b: 氨氯地平和盐酸吡格列酮过 100 目筛， 预胶化淀粉、 甘露醇过 80 目筛， 称取处方量的氨氯地平、盐酸吡格列酮和预胶化淀粉、甘露醇混合均匀，加入 6%PVP的 95% 乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒， 干颗粒中加入处方量的微粉硅胶。
将上述两种制备工艺 a和 b的颗粒组分采用双层压片机冲压即得双层片。
实施例 4 分散片 瑞舒伐他汀钙 5g
左旋氨氯地平 10g
盐酸吡格列酮 5g
羧甲基纤维素钙 15g
交联聚乙烯吡咯垸酮 15g
微晶纤维素 HOg
10%淀粉浆 适量
硬脂酸镁 6g 制备工艺： 将处方量的瑞舒伐他汀钙、 左旋氨氯地平和盐酸吡格列酮过 100目筛， 羧甲 基纤维素钙、 交联聚乙烯吡咯烷酮、 微晶纤维素过 80目筛， 混匀后加入适量 10%淀粉浆制 粒， 加入硬脂酸镁后压片即可。
实施例 5 颗粒剂
瑞舒伐他汀钙 40g
氨氯地平 5g
盐酸吡格列酮 45g
淀粉 200g
糊精 50g 蔗糖粉 50g
80%乙醇 适量
制备工艺： 称取处方量的瑞舒伐他汀钙、 氨氯地平、 盐酸吡格列酮、 淀粉、 糊精、 蔗糖 粉混合均匀。 另将适量的 80%乙醇加入于混合粉末中， 混合均匀， 制软材， 通过 18目尼龙 筛制成湿粒， 60°C左右干燥， 20目筛整粒， 分装， 即得。
实施例 6 崩解片
瑞舒伐他汀钙 lg
左旋氨氯地平 10g
盐酸吡格列酮 lg
交联羧甲基纤维素钠 10g
微晶纤维素 100g
聚乙烯吡咯垸酮 20g
5 % PVP的 60 %乙醇溶液 适量
微粉硅胶 5g
制备工艺： 按处方量称取瑞舒伐他汀钙、 左旋氨氯地平、 盐酸吡格列酮， 以微晶纤维素 为填充剂， 交联羧甲基纤维素钠、 聚乙烯吡咯垸酮为崩解剂， 5%PVP的 60%乙醇溶液为黏 合剂， 微粉硅胶为助流剂， 用流化床一步制粒， 然后压片， 即得。
实施例 7 缓释片 瑞舒伐他汀钙 10g
左旋氨氯地平 10g
盐酸吡格列酮 5g
羟丙甲基纤维素 80g
聚乙烯吡咯烷酮 100g
乳糖 85g
微粉硅胶 100g 制备工艺： 将处方量的瑞舒伐他汀钙、 左旋氨氯地平、 盐酸吡格列酮和处方量的羟丙甲 基纤维素、 乳糖混合均匀加入粘合剂聚乙烯吡咯垸酮制粒， 在 40°C— 80°C下干燥， 整干颗 粒， 在干颗粒中加入处方量的润滑剂微粉硅胶， 混匀， 异型冲压片即可。 实施例 8 胶囊剂
瑞舒伐他汀钙 32g
左旋氨氯地平 2g
盐酸吡格列酮 36g
微品纤维素 300g
微粉硅胶 12g
制备工艺： 将处方量的瑞舒伐他汀钙、 左旋氨氯地平、 盐酸吡格列酮、 微晶纤维素、 微 粉硅胶粉碎过 100目筛混匀， 直接填装胶囊即得。 实施例 9 本发明药物组合物对自发性高血压大鼠血压和心肌肥厚的治疗效果
1.实验动物及实验分组
自发性高血压大鼠 48只，雄性，山东新时代药业有限公司新药药理中心提供，体重（300 ±20) g， 适应性饲养一周后， 随机分为 6组， 每组 8只。
模型对照组： 灌胃给予同体积生理盐水；
吡组： lmg/ (kg.d) 吡格列酮；
氨 +瑞组： 2mg/ (kg.d) 氨氯地平 + lmg/ (kg.d) 瑞舒伐他汀钙；
吡 +瑞组： lmg/ (kg.d) 吡格列酮 + lmg/ (kg.d) 瑞舒伐他汀钙；
氨组： 2mg/ (kg.d) 氨氯地平；
本发明药物组合物组: 2mg/ (kg.d) 氨氯地平 + lmg/ (kg.d) 吡格列酮 +lmg/ (kg.d) 瑞舒伐他汀钙；
各组均为灌胃给药， 每天一次， 共 10周。 实验过程中， 每日观察动物饮食、 存活情况 及行为活动， 每日测量体重， 根据体重调整药物用量。 10 周后处死动物， 取心脏测左室重 量， 计算左室指数。
2.实验方法和实验结果
2.1本发明药物组合物对自发性高血压大鼠血压的影响
温度控制在 18°C-22°C，温度 45%- 65%,室内自然光线。用 BP- 2006A智能无创血压计（北 京软隆有限公司提供）测量大鼠清醒状态下尾动脉压。 在给药后的第一周、 第三周以及第六 周分别测量血压， 均在灌胃给药后 2小时到 5小时之间测量 5次， 取其均值作为该样本的血 压。 表 1本发明药物组合物对自发性高血压大鼠血压的影响 （^±S， n = 8) (mmHg) 组别 治疗前 治疗后
第 1周 第 3周 第 6周
模型组 152±8.1 158±9.2 164±8.7 178±9.2
氨 +瑞组 150土 12.3 151±10.5 152±9.6* 150±7.0*
吡组 151±7.6 157±8.6 162±10.3 170±8.8
吡 +瑞组 149±9.4 156±8.9 160±9.2 165±11· 3*
氨组 150±9.0 152±9.5 154±11.4 156±10.9"
本发明药物 153±13.7 149±7.1 140±16.2··'*# 135±7.6""# 组合物组
#与模型组比较 ρ<0.05， ··与模型组比较 ρ<0.01；
τ与氨组比较 Ρ<0.05， '与吡 +瑞组比较 ρ<0.05，
#与氨 +瑞组比较 <0.05。
由以上结果可知， 瑞舒伐他汀、氨氯地平和吡格列酮复方组合对自发性高血压大鼠的降 压效果上取得了很好的协同作用。三种药物联合使用， 无论是在氨氯地平 +瑞舒伐他汀钙联 用的基础上加用吡格列酮， 还是在吡格列酮和瑞舒伐他汀钙联用的基础上加用氨氯地平， 都 在第 3周和第 6周的血压测量数据中取得了很好的协同作用。
2.2心脏重量、 左室重量、 体重及左室肥厚指数 （左室重量 /体重） 测定：
10%氯化钾 （2瞧 ol/L， 1ml/只） 处死大鼠后， 测体重， 取出心脏， 去除大血管及心脏 外结缔组织， 冲洗干净， 滤纸吸干后称量心脏重量； 再去除心房称左室重量， 计算左室重量 与体重比值。 表 2本发明药物组合物对自发性高血压大鼠心肌肥厚的影响 ±S， n=8) (g) 组别 体重 左室重量 左室重量 /体重 （ΧΚΓ3)
模型组 301 ±12 1.06+0.19 3.52±0.27
氨 +瑞组 304±13 0.91 ±0.16* 2.99±0.15··
吡组 298士 12 0.99±0.10 3.33±0.19
吡 +瑞组 308±14 0.97±0.13 3.15±0.28*
氨组 297 ±15 0.92±0.17 3.10±0.15"
本发明药物 303 ±14 0.75 ±0.15··'*# 2.48 + 0.25··τ*#
组合物组
与模型组比较 ρ<0.05， ββ与模型组比较 ρ<0.01; '与氨组比较 P<0.05， *与吡 +瑞组比较 <0.05，
#与氨 +瑞组比较 <0.05。 .
结果表明， 瑞舒伐他汀、氨氯地平和吡格列酮复方组合能有效逆转高血压大鼠左室心肌 肥厚， 三药联用对自发性高血压大鼠心肌肥厚的治疗取得了很好的协同作用。无论是在氨氯 地平 +瑞舒伐他汀钙联用的基础上加用吡格列酮，还是在吡格列酮和瑞舒伐他汀钙联用的基 础上加用氨氯地平， 都取得了很好的协同作用。 实施例 10本发明药物组合物对自发性高血压大鼠尿微量白蛋白和颈动脉内中膜厚度 的治疗效果
1.实验动物及实验分组
自发性高血压大鼠 48只，雄性，山东新时代药业有限公司新药药理中心提供，体重（300 ±20) g， 适应性饲养一周后， 随机分为 6组， 每组 8只。
模型对照组： 灌胃给予同体积生理盐水；
吡组： 灌胃给予 2mg/ (kg.d) 吡格列酮；
左氨 +瑞组： 灌胃给予 lmg/ (kg.d) 左旋氨氯地平 + lmg/ (kg.d) 瑞舒伐他汀钙； 吡 +瑞组： 灌胃给予 2mg/ (kg.d) 吡格列酮 + lmg/ (kg.d) 瑞舒伐他汀钙；
左氨组： 灌胃给予 lmg/ (kg.d) 左旋氨氯地平；
本发明药物组合物组： 灌胃给予 lmg/ (kg.d)左旋氨氯地平 + 2mg/ (kg.d) 吡格列酮 + lmg/ (kg.d) 瑞舒伐他汀钙；
各组均为灌胃给药， 每天一次， 同时本实验的所有大鼠给予高糖高脂饲料喂养， 共 6个 月。 实验过程中， 每日观察动物饮食、 存活情况及行为活动， 每周测量体重， 根据体重调整 药物用量。
2.实验方法和实验结果
2.1尿中微量白蛋白的测定：
试剂：
1、 10% (v/v) 的冰醋酸溶液 （PH2.8)。
2、 0.303mol/L甘氨酸-冰醋酸缓冲液（PH3.0): 称取 22.72g甘氨酸， 用 10%冰醋酸溶液 稀释成 1000ml, 加 NaN3100mg， 室温密封可稳定 1年。
3、 溴酚蓝（1.924mmol/L)贮存液： 精确称取 257、 36mgBPB, 用无水乙醇溶至 200ml，
4 °C冰箱可稳定 1年。
4、 溴酚蓝 (0.231mmol/L) 显色剂： 取 60mlBPB贮存液， 加入 2.5mlTriton X-100, 用 甘氨酸-冰醋酸缓冲液稀释至 500ml， 室温密封可保存 1年。
标本的采集和检测： 于第 4、 8、 12和 16周将大鼠分别放于代谢笼中饲养， 收集隔夜 12小时尿， 准确记录尿量。 取 4ml， 叠氮钠处理后， 离心 （2000r/min) lOmin, 取上清液置 一 20°C冰箱保存待测尿白蛋白。 量取储存的大鼠尿液 2tnl， 各加显色剂 lml， 混匀 （防止产 生气泡）， 用紫外分光光度计于 600nm下测定吸光度 A。 表 3 本发明药物组合物对自发性高血压大鼠尿微量白蛋白的影响 土 S) 组别 n 吸光度 A(600nm)
模型组 8 0·687±0.216
氨 +瑞组 8 0.603 ±0.232
吡组 8 0.568±0.125'
吡 +瑞组 8 0.575 ±0.161β
氨组 8 0.617±0.177
本发明药物组合物组 8 0.411 ±0.158"
#与模型组比较 ρ<0. 05, ··与模型组比较 ρ<0. 01.
结果表明， 瑞舒伐他汀、 氨氯地平和吡格列酮复方组合能够降低尿微量白蛋白、 保护高 血压对肾脏的损害， 取得了理想的效果， 在影响自发性高血压大鼠尿微量白蛋白方面， 三种 药物联合使用， 无论是在氨氯地平 +瑞舒伐他汀钙联用的基础上加用吡格列酮， 还是在吡格 列酮和瑞舒伐他汀钙联用的基础上加用氨氯地平， 都取得了很好的协同作用。
2. 2颈动脉内中膜厚度的测定
动物麻醉和固定后， 经股动脉注入 Even ' s蓝染料 （60mg/kg)， 30min后用 0. 9%生理 盐水为灌注液， 采用经心灌注法， 灌注压力 13. 3kPa， 至流出液清亮后， 改用 4%多聚甲醛 生理盐水灌注 10min， 进行原位固定 （压力同上）。 取 Even' s蓝着色颈动脉段， 放入福尔 马林液进一步固定后， 取前、 中、 后三部分进行石蜡包埋， 非连续切片 8〜10层， 行 HE染 色， 随机取 3个血管断面输入计算机图像处理系统， 进行计算机图像测量， 计算最大内膜厚 度、 中膜厚度、 内膜 /中膜厚度比值。 表 4 本发明药物组合物对自发性高血压大鼠内中膜厚度的影响 ±S ， n = 8 ) 最大内膜厚度 （mm ) 内膜 /中膜厚度比值
模型组 0.142±0. 031 2.432 ±0. 456
氨 +瑞组 0.094 ±0. 025· 1.683 ±0. 328·
吡组 0.130±0. 026 2.246 ±0. 361
吡 +瑞组 0.110±0· 028* 1.923 ±0. 422·
氨组 0. 116±0· 030* 2·125 ±0. 357*
本发明药物组 0.062土 0. 014··"# 1.102±0. 243··'*#
合物组
•与模型组比较 ρ<0. 05, ββ与模型组比较 ρ<0. 01；
'与氨组比较 Ρ<0. 01， *与吡 +瑞组比较 <0. 05，
#与氨 +瑞组比较 <0. 05。
结果表明， 瑞舒伐他汀、氨氯地平和吡格列酮复方组合能有效改善自发性高血压大鼠内 中膜厚度， '在影响自发性高血压大鼠颈动脉内中膜厚度方面有很好的协同作用。无论是在氨 氯地平 +瑞舒伐他汀钙联用的基础上加用吡格列酮，还是在吡格列酮和瑞舒伐他汀钙联用的 基础上加用氨氯地平， 都取得了很好的协同作用。 实施例 11 本发明药物组合物对代谢综合征患者的治疗效果
1.一般资料：
选取 2007年 5月到 2008年 5月在临沂人民医院治疗的代谢综合征患者 88例， 随机分 为对照组和实验组，
对照组： 男 28例， 女 16例， 年龄在 62-71岁， 体重指数 （ΒΜΙ ) 25. 5-30；
实验组: 男 24例， 女 20例， 年龄在 60-70岁， 体重指数 (ΒΜΙ ) 24. 5-31 ;
治疗前全部患者均进行血脂分析（包括总胆固醇 TC、 高密度脂蛋白胆固醇 HDL(：)、 糖化 血红蛋白 (HbA] C)、 空腹血糖 (FBG)、 空腹胰岛素（FINS)及纤维蛋白原 ( Fg) 检测。
入选标准根据 WH01999年 2型糖尿病、 高血压的诊断标准， 并参考 2000年美国国家胆 固醇教育计划成人治疗组（NCEP- ΑΤΡΙΠ)指南有关代谢综合征诊断标准， 选择符合代谢综合 征的患者， 并排除原发性高血压、 心衰 II级以上、 肝肾及血液系统疾病等。
2.治疗方案：
入选患者对照组服用吡格列酮， 15mg每次， 每日一次； 实验组服用按照制备实施例 1 普通片剂的活性成分配比服用氨氯地平 5mg、 吡格列酮 7. 5mg和瑞舒伐他汀钙 5mg， 每日一 次， 连续治疗 8周后， 复査上述指标， 其中应用己糖激酶法检测血糖， 酯酶法检测血脂， 应 用凝固法和户色底物法检测纤维蛋白原， 应用层析柱法检测 HbAlC， 用化学发光免疫法 空腹胰岛素。
统计学处理： 采用 SPSS软件， 显著性检验采用配对样本 t检验。
3.治疗结果 表 5治疗前后 Fg、 FINS, HbAlC、 TC/HDLC的变化 d土 S) 指标 治 疗 前 治 疗 后
对照组 实验组 对照组 实验组
FBG (mmol/L) 7.12±2· 06 7.08±2· 13 6.63±1.65 6.04±1.38'#
FINS (mlU/L) 32.4±7.21 31.6±8.32 25.68±5.34 19.48±5.10*#
HbAlC(%) 6.89±0.65 6.93 ±0.62 6.39±0.56 5.87±0.52 *
TC/HDLCC mmol/L) 4.11±1·26 4.08±1.22 3.75±0.84 3.32 ±0.67*
Fg (mg/dl) 419·6±89.62 425·0±84· 37 392.6±64.51 347.3 ±58.46'# 与治疗前实验组比较， ρ<0.05; #与治疗后对照组比较， ρ<0.05。
由表 5可知， 本发明药物组合物在治疗代谢综合征中 FBG、 FINS, HbAlC、 TC/HDLC, Fg 与治疗前比较均有显著性差异， 治疗后本发明药物组合物组与吡格列酮单用组比较 FBG、 FINS, HbAlC、 TC/HDLC, Fg 均有显著性差异， 说明本发明药物组合物在代谢综合征治疗中 疗效确切， 作用明显。

Claims

权利要求 、 一种药物组合物， 其特征在于， 所述药物组合物含有活性成分如下： 氨氯地平或其可药用盐； 吡格列酮或其可药用盐； 和 瑞舒伐他汀或其可药用盐。 、 如权利要求 1 所述的药物组合物， 其特征在于， 所述氨氯地平可药用盐选自氨氯地平 的苯磺酸盐、 马来酸盐、 盐酸盐、 甲酸盐、 乙酸盐、 氢溴酸盐、 天冬酸盐、 甲磺酸盐、 硫酸盐或酒石酸盐。 、 如权利要求 1 所述的药物组合物， 其特征在于， 所述氨氯地平是氨氯地平的左旋体或 左旋体和右旋体的混合物。 、 如权利要求 1 所述的药物组合物， 其特征在于氨氯地平或其可药用盐、 吡格列酮或其 可药用盐、 瑞舒伐他汀或其可药用盐的重量比为 1 : 0.1-18:0.1-16, 其中氨氯地平可药 用盐的重量以氨氯地平计， 吡格列酮可药用盐的重量以吡格列酮计， 瑞舒伐他汀可药 用盐的重量以瑞舒伐他汀计。 、 如权利要求 4所述的药物组合物， 其特征在于氨氯地平或其可药用盐、 吡格列酮或其 可药用盐、 瑞舒伐他汀或其可药用盐的重量比为 1 : 0.1-9:0.1-8, 其中氨氯地平可药用 盐的重量以氨氯地平计， 吡格列酮可药用盐的重量以吡格列酮计， 瑞舒伐他汀可药用 盐的重量以瑞舒伐他汀计。 、 如权利要求 5 所述的药物组合物， 其特征在于氨氯地平或其可药用盐、 吡格列酮或其 可药用盐、瑞舒伐他汀或其可药用盐的重量比为 1 : 0.1〜4.5:0.1~4，其中氨氯地平可药用 盐的重量以氨氯地平计， 吡格列酮可药用盐的重量以吡格列酮计， 瑞舒伐他汀可药用 盐的重量以瑞舒伐他汀计。 、 如权利要求 1-6任一所述的药物组合物， 其特征在于， 所述药物组合物的形式为片剂、 胶囊或颗粒剂。 、 如权利要求 1 -6任一所述的药物组合物在制备治疗高血压的药物中的应用。 、 如权利要求 1 -6任一所述的药物组合物在制备治疗代谢综合征的药物中的应用。 、 一种治疗高血压的方法， 其包括给所需治疗的患者施用有效量的如权利要求 1-6任 一所述的药物组合物。
1、 一种治疗代谢综合征的方法，其包括给所需治疗的患者施用有效量的如权利要求 1 -6 任一所述的药物组合物。
PCT/CN2009/000824 2008-07-24 2009-07-23 用于治疗高血压和代谢综合症的药物组合物及其应用 WO2010009619A1 (zh)

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