WO2006119692A1 - Medicament pour le traitement de l’hypertension - Google Patents

Medicament pour le traitement de l’hypertension Download PDF

Info

Publication number
WO2006119692A1
WO2006119692A1 PCT/CN2006/000888 CN2006000888W WO2006119692A1 WO 2006119692 A1 WO2006119692 A1 WO 2006119692A1 CN 2006000888 W CN2006000888 W CN 2006000888W WO 2006119692 A1 WO2006119692 A1 WO 2006119692A1
Authority
WO
WIPO (PCT)
Prior art keywords
calcium
group
containing component
pharmaceutical composition
antihypertensive
Prior art date
Application number
PCT/CN2006/000888
Other languages
English (en)
Chinese (zh)
Inventor
Jidao Peng
Lisheng Liu
Jinping Su
Jiaxiu Yang
Original Assignee
Cp Drug Development Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cp Drug Development Co., Ltd. filed Critical Cp Drug Development Co., Ltd.
Publication of WO2006119692A1 publication Critical patent/WO2006119692A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition for treating hypertension. Background technique
  • Hypertension is one of the most common cardiovascular diseases with increased systemic arterial pressure, often accompanied by various complications such as stroke, myocardial infarction, heart failure, coronary heart disease, and diabetes.
  • the systolic blood pressure of adults over 18 years old is greater than or equal to 140mmHg and (or) the diastolic blood pressure is greater than or equal to 90mmHg.
  • a large number of studies have shown that increased systolic blood pressure is more harmful than increased diastolic blood pressure.
  • the survey shows that the prevalence of hypertension in adults in China is 18.8%.
  • the estimated number of patients in the country is 160 million, an increase of more than 70 million compared with 1991.
  • the prevalence of hypertension in rural areas has increased rapidly, and the gap between urban and rural areas is not obvious.
  • the incidence of hypertension in China has the characteristics of 'high three low', that is, the prevalence rate, disability rate, and mortality rate are high, while the awareness rate, medication rate, and control rate are low. Therefore, how to effectively control blood pressure has become a common concern of the medical community.
  • One of the focuses is to effectively control blood pressure.
  • hypertension In general, patients with hypertension have a shorter life span than normal people by 15-20 years. 95% of hypertensive patients are primary hypertension, and the causes are mostly related to abnormal levels of renin, parathyroid hypertension (PHF), and vitamin D in patients.
  • PHF parathyroid hypertension
  • antihypertensive drugs there are many types of antihypertensive drugs, and commonly used drugs include calcium channel antagonists, alpha receptor blockers, 'beta blockers, renin-angiotensin system modulators (including angiotensin I converting enzyme). Inhibitors and angiotensin II receptor blockers) and diuretics.
  • antihypertensive drugs should start with small doses. Patients with mild hypertension can choose an antihypertensive drug, and more severe patients often need two different types of antihypertensive drugs. However, patient compliance is poor, and it is best to use a combination of the two drugs. The same class of antihypertensive drugs are generally not used in combination. Blood pressure should be measured frequently during the course of medication to observe the effect of medication.
  • calcium antagonists were first introduced into antihypertensive therapy.
  • calcium antagonists have become one of the major drugs for the treatment of hypertension.
  • Calcium antagonists reduce the number of open calcium channels in myocardium and smooth muscle cell membranes, Blocking Ca 2+ into the cells, thus relaxing the smooth muscle, reducing vascular resistance, lowering blood pressure, and also protecting the target organs such as heart and kidney. It is especially suitable for elderly hypertension, systolic hypertension, hypertension with hyperlipidemia, obesity or electrolyte imbalance, hypertension with heart, brain and renal vascular complications, and pregnancy-related hypertension. It is widely used in China.
  • Alpha-receptor blockers selectively block peripheral vascular alpha-receptors, inhibit norepinephrine release, relax vascular smooth muscle, reduce peripheral vascular resistance, dilate small arteries, and lower blood pressure.
  • Alpha-blockers may be beneficial for hyperlipidemia and impaired glucose tolerance, can reverse left ventricular hypertrophy, improve insulin resistance, and significantly improve dysuria in patients with prostatic hypertrophy.
  • Prazosin not only lowers blood pressure, but also reduces blood viscosity, maintains normal blood, brain and kidney blood flow supply, does not affect glomerular filtration, and is especially effective in hypertensive patients with renal insufficiency.
  • Beta blockers are first-line drugs widely used in the treatment of hypertension, 'applicable to hypertensive patients with sympathetic hyperactivity or angina pectoris and tachyarrhythmia. This class of drugs blocks ⁇ -receptors, reduces myocardial contractility, reduces cardiac output, reduces myocardial oxygen consumption, inhibits renin secretion, and slows heart rate and lowers blood pressure. Beta blockers are very effective in patients with hypertension complicated with coronary heart disease, especially in patients with acute coronary syndrome and myocardial infarction. They are considered to be the "best drug" for secondary prevention of coronary heart disease, beta blocker It is also a strong indication for blood pressure combined with heart failure and diabetes. The combination of ⁇ -blockers and diuretics and calcium antagonists has a good antihypertensive effect.
  • Renin-angiotensin system (RAS) modulators include angiotensin I converting enzyme inhibitors (ACE I ) and angiotensin II receptor blockers.
  • ACE I angiotensin I converting enzyme inhibitors
  • Angll angiotensin II
  • This kind of medicine not only has a good antihypertensive effect, but also has a good influence on the onset of hypertension and some associated diseases. It can be used as a hypertensive patient with diabetes, left ventricular hypertrophy, left heart dysfunction and acute myocardial infarction.
  • angiotensin II receptor blockers The greatest advantage of angiotensin II receptor blockers is that they retain the advantages of angiotensin-converting enzyme inhibitors, while overcoming most of their shortcomings, with no allergic reactions to cough.
  • Diuretic hypotension began in 1948, diuretics reduced blood pressure by reducing extracellular fluid volume and cardiac output; vascular resistance decreased after long-term administration. According to the results of large-scale clinical trials in the world, it is proved that the antihypertensive effect of diuretics is positive, and can enhance the effects of other antihypertensive drugs.
  • Several high-pressure treatment principles committees in Europe and the United States recommend non-complexed hypertensive patients, with diuretics as the drug of choice. Diuretics are especially effective in elderly, obese hypertensive patients.
  • Novel antihypertensive drugs also include endothelin receptor antagonists, neuropeptide Y inhibitors, atrial natriuretic peptides and endopeptidase inhibitors; imidazole receptor agonists, serotonin receptor antagonists, K+ channel openers , calcitonin gene-related peptide (CGRP) and the like.
  • endothelin receptor antagonists neuropeptide Y inhibitors, atrial natriuretic peptides and endopeptidase inhibitors
  • imidazole receptor agonists imidazole receptor agonists
  • serotonin receptor antagonists serotonin receptor antagonists
  • K+ channel openers calcitonin gene-related peptide (CGRP) and the like.
  • CGRP calcitonin gene-related peptide
  • CN1562369 A discloses a pharmaceutical composition for treating hypertension comprising a certain weight ratio of a calcium ion antagonist, a diuretic, an aldosterone antagonist or the like.
  • Antihypertensive drugs according to the general recommended dose, typical with placebo, mean blood pressure is 160/95mmHg, usually single drug treatment reduces systolic blood pressure 7-15mmHg and diastolic blood pressure 4-10mHg; combined with other antihypertensive drugs, It can lower blood pressure by 8-15%, that is, the systolic blood pressure drops by 12-24mmHg and the diastolic blood pressure drops by 8-12mmHg.
  • Route 1 shows that the main pathogenic factors affect a small number of target organs leading to cytopathological activities leading to pathological symptoms. However, other organs or cells in the body are unaffected and the cells are normal. The response of "pathological defects” and "normal” tissues to different pathogenic factors is a key focus of therapeutic drug design and development.
  • Pathway 2 represents the current state of treatment of most western medicines, and such drugs act on one or several pathological tissues.
  • biochemical or physiological abnormalities of the body have been clearly explained, and the designed drugs improve clinical symptoms by changing one or several diseased tissues.
  • a large amount of medication is required.
  • These drugs have strong pharmacological activities and also have an effect on other normal tissues, thus causing side effects.
  • Route 3 represents a more desirable state of medication. If the main cause of the disease is known, the disease can be inhibited by the design of the drug or the physiological activity can be directly produced, so that the diseased tissue returns to normal, and the disease symptoms are controlled. Drug-induced pathogenic factors have an effect on healthy tissues, and normal healthy tissues are not affected by pathogenic factors. Therefore, the side effects of drugs are less. In theory, this is an ideal way to develop new drugs. However, the following problems exist: First, most of the diseases, the main pathogenic factors are unknown; secondly, most of the diseases have more complications; third, even if the cause is known, it is almost impossible to suppress all the causes by one chemical component.
  • Antihypertensive drugs have developed greatly over the past 50 years. However, hypertension is a disease with an uncertain cause, and the effect of one or several drugs on a cause or mechanism of action is low, usually a drug. The cure rate of the object is about 40-50%, and the prognosis is poor. In recent years, although there are many new antihypertensive drugs with low efficacy and few side effects, the blood pressure control rate can only reach 50-60%. Therefore, a new treatment mode is gradually applied to the clinic, and the compound antihypertensive drug preparation is an internationally recognized treatment direction. Many years of research by the inventors have shown that nearly 70% of hypertensive patients require a combination of drugs.
  • Another object of the present invention is to provide the use of the composition for the preparation of a medicament for the treatment of hypertension.
  • the present invention provides a pharmaceutical composition for treating hypertension characterized by comprising one or two different antihypertensive drugs and a calcium-containing component and a pharmaceutically acceptable excipient.
  • the antihypertensive agent is selected from the group consisting of a calcium antagonist, an alpha receptor blocker, a beta blocker, a renin-angiotensin system modulator, and a diuretic.
  • the calcium antagonist is selected from the group consisting of nifedipine, amlodipine, felodipine, lacidipine, nitrendipine, nicardipine, nimodipine, nisoldipine, nigodipine, isradipine, verapamil Rice and diltiazem.
  • the calcium antagonist is preferably nifedipine or nitrendipine.
  • the alpha receptor blocker is selected from the group consisting of prazosin (prazosin), terazosin, doxazosin, trimazolazine, phenoxybenzamine and phentolamine.
  • the ⁇ receptor blocker is preferably prazosin.
  • the beta blocker is selected from the group consisting of nadolorol, acebutolol, labetalol, metoprolol, bisoprolol, esmolol, propranolol (propranolol), and alt. Lol (aminoacylamine), carvedilol.
  • the beta receptor blocker is preferably atenolol.
  • the renin-angiotensin system modulator is selected from the group consisting of captopril, enalapril, benazepril, fosinopril, lisinopril, quinapril Lime, ramipril, perindopril, cilazapril, losartan, valsartan, telmisartan, irbesartan, candesartan.
  • the renin-angiotensin system modulator is preferably enalapril.
  • the diuretic is selected from the group consisting of furosemide (furosemide), uric acid, bumetanide, tolathiamide, hydrochlorothiazide (hydrochlorothiazide), chlorothiazide, indapamide, chlorthalidone, metolazone, Quinoxazine, triamterene, amiloride, spironolactone, acetazolamide.
  • the diuretic is preferably furosemide or hydrochlorothiazide.
  • Calcium-containing component refers to various calcium substances available for human body, which are selected from shells, keels, calcium chloride, calcium carbonate, calcium sulphate, calcium citrate, calcium lactate, calcium gluconate or L-threonate.
  • the calcium-containing component is preferably calcium gluconate and/or calcium citrate.
  • the ratio of the two types of antihypertensive drugs to the calcium-containing component is 0-50 by weight: 0-50: 10-2000, excellent ratio is 0-30: 0-30: 15-1000, more preferably 0-20: 0-20: 20-500, wherein different types of antihypertensive drugs are different in content It is 0 and the calcium-containing component is calculated as Ca 2+ .
  • the pharmaceutical composition includes one type of antihypertensive drug and one facial component
  • the antihypertensive drug does not include a diuretic
  • the ratio of the antihypertensive drug to the calcium-containing component is by weight. 1 : 10-2000, preferably 1:15-1000, and the crane is 1:20-500, wherein the calcium-containing component is calculated as Ca 2+ . '
  • composition for treating hypertension of the present invention contains an appropriate amount of excipients, wherein the excipients are sucrose, lactose, galactose, maltose, mannitol, sorbitol, starch, corn starch, dextrin.
  • composition of the present invention can be formulated into any of the pharmaceutically acceptable dosage forms, and tablets or capsules for oral administration are preferred. '
  • the invention also relates to the use of the composition in the manufacture of a medicament for the treatment of hypertension. It has been reported that high doses of calcium can produce a hypotensive effect. However, this finding could not be successfully repeated throughout the study. In addition, the antihypertensive effect of dietary calcium is quite clear in patients with low renin levels and salt sensitivity, and calcium antagonists have a good effect on such patients. This seems to be a very very sharp conclusion. Many experts in this field of research tried to find a reasonable explanation and did not succeed.
  • compositions of the present invention provide a solution to the above problems.
  • the present invention uses a spontaneously hypertensive rat (SHR) to test the antihypertensive effect of a combination of calcium and calcium antagonists, and the clinical effect of a combination of calcium + calcium antagonist and calcium + alpha receptor blocker in clinical patients. Observed. The result is as follows:
  • Calcium enhances the antihypertensive effect of low dose calcium antagonists or alpha receptor blockers
  • the core of the invention is the special role of calcium in the treatment of hypertension.
  • Calcium inhibits renin levels, has parathyroid activity, reduces circulating levels of parathyroid hypertensive factor (PHF) and physiological activity of 1,25-dihydroxy-vitamin D 3 in patients; antihypertensive drugs can inhibit Symptoms of high blood pressure, reduce damage to target organs.
  • PHF parathyroid hypertensive factor
  • antihypertensive drugs can inhibit Symptoms of high blood pressure, reduce damage to target organs.
  • calcium enhances the blood pressure lowering effect of low-dose antihypertensives, achieving the goals shown in FIG. DRAWINGS
  • Figure 1 shows an experimental study of the blood pressure lowering effect of calcium-enriched nifedipine.
  • Figure 2 shows an experimental study of the hypotensive effect of calcium-enhanced furosemide.
  • Figure 3 shows an experimental study of the hypotensive effect of calcium-enhanced hydrochlorothiazide.
  • Figure 4 shows a statistical table of experimental data for the effect of cadherin on human systolic blood pressure (SBP).
  • Figure 5 is a graph showing the experimental data of the effect of calcium plus prazosin on human systolic blood pressure (SBP).
  • Figure 6 shows a statistical table of experimental data for the effect of calcium accelerated urine on human systolic blood pressure (SBP).
  • Figure 7 is a graph showing the experimental data of the effect of calcium hydrochlorothiazide on human systolic blood pressure (SBP).
  • FIG 8 shows three ways in which the usual drugs are treated in the prior art.
  • Figure 9 shows the specific role of calcium in the treatment of hypertension, the goal achieved.
  • BEST MODE FOR CARRYING OUT THE INVENTION The following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the pharmaceutical composition of the present invention is separately prepared into tablets or capsules by the following methods and ratios -
  • Preparation Method 1 The fine powder of the active ingredient in the pharmaceutical composition and the appropriate amount of the auxiliary materials are uniformly mixed, and the tablet is dry-pressed according to a conventional method.
  • Preparation Method 2 The fine powder of the active ingredient in the pharmaceutical composition and the appropriate amount of the auxiliary material are uniformly mixed, and the method is wet granulation or powder according to a conventional method. Fill the capsule directly. The capsule weighs 100-1000mg.
  • Example 1 The fine powder of the active ingredient in the pharmaceutical composition and the appropriate amount of the auxiliary materials are uniformly mixed, and the tablet is dry-pressed according to a conventional method.
  • Granulation tablets The tablet may be coated with sugar, film or uncoated, and the tablet weight is 100-1 OOOmg
  • Preparation Method 2 The fine powder of the active ingredient in
  • Example 2 Nifedipine 5.0 mg, calcium citrate 1000 mg, starch 180 mg, sucrose 15 mg.
  • Example 3 Nitrendipine 5.0mg, calcium gluconate 2000 mg, starch 380 mg, dextrin 15 mg.
  • Wca 2+ indicates the amount of calcium used
  • W HF represents the amount of calcium component in the formulation
  • Mca 2+ /M H F*100% indicates the percentage of calcium in the calcium-containing component.
  • Figure 1 is an animal experiment result based on nifedipine + calcium group
  • Figure 2 is based on animal experiment results of furosemide + calcium group
  • Figure 3 is based on animal experiment results of hydrochlorothiazide + calcium group
  • Figure 4 is based on nitrendipine
  • Figure 5 is a human observation effect based on the prazosin + calcium group
  • Figure 6 is a human observation effect based on the furosemide + calcium group
  • Figure 7 is based on the hydrochlorothiazide + calcium group. Human body observation effect.
  • Animal test is based on animal experiment results of furosemide + calcium group
  • Figure 3 is based on animal experiment results of hydrochlorothiazide + calcium group
  • Figure 4 is based on nitrendipine
  • Figure 5 is a human observation effect based on the prazosin + calcium group
  • Figure 6 is a human observation effect based on the furosemide + calcium group
  • Figure 7 is based on the hydroch
  • SHR is an animal model with a genetic background that is most suitable for studying human essential hypertension.
  • the SHR was randomly divided into 3 groups. A certain amount of the test sample and distilled water were taken according to the body weight of the rat.
  • the nifedipine group was 10 mg/kg, qd; the nifedipine + calcium group was nifedipine 10 mg/kg, qd + mother-of-pearl ultrafine powder 500 mg/kg, qd; the control group was distilled water 7.5 ml/kg, qd.
  • Rats were dosed in a conscious state through a gastric tube and blood pressure was measured three times per week. After 1 month of observation, the blood pressure of both groups was significantly decreased, and there was no significant difference in the blood pressure drop between calcium and calcium.
  • nifedipine group was 3.33mg kg, qd; nifedipine + calcium group was nifedipine 3.33mg/kg, qd + mother-of-pearl ultrafine powder 500mg/kg, qd; control group was distilled water 7.5ml/ Kg, qd, continued to observe for one month, the blood pressure of the calcium-added group was significantly lower than that of the uncalcified group, and the two reached 15 mmHg.
  • the results are shown in Figure 1. The results showed that: adding calcium can enhance the nifedipine at lower doses. Lowering blood pressure. Depressurization test of furosemide: 'SHR was randomly divided into 3 groups during the test.
  • a certain amount of the test sample and distilled water were taken according to the body weight of the rat.
  • the furosemide group was 35m ⁇ kg/d; the furosemide+calcium group was furosemide 35mg/kg/d + mother-of-pearl ultrafine powder 2000mg/kg/d; the control group was distilled water 7.5ml/kg/d.
  • the rats were fed with a stomach tube in an awake state, and the blood pressure was measured three times a week or according to actual conditions. When the blood pressure dropped to a certain level and no longer decreased, the administration was stopped and the recovery of blood pressure was further observed and collected. Blood pressure values are calculated.
  • Antihypertensive test of hydrochlorothiazide During the test, SHR was randomly divided into 3 groups, and the test sample and distilled water were taken according to the body weight of the rat. At the beginning of the test, the hydrochlorothiazide group was 4 mg/k g .qd; the hydrochlorothiazide + ⁇ group was Hydrochlorothiazide 4mg/kg.qd + mother-of-pearl ultrafine powder 500mg/kg.qd ; control group was distilled water 7.5ml/kg.qd, the rats were fed with smear through the stomach tube, blood pressure was measured three times per week or according to Actual measurement, when the blood pressure drops to a certain level and no longer drops, stop the administration and further observe the recovery of blood pressure, collect blood pressure values and calculate.
  • Patients with hypertension with moderate to moderate blood pressure of 140-180/90-109 mmHg were selected from the community clinic. The gender was not limited, and the age was over 35 years old. Secondary hypertension, sputum blood pressure combined with heart and kidney failure, serum creatinine ⁇ 3mg / dl, history of allergies to ACEI, pregnant women and patients who can not cooperate with doctors are not selected, daily calcium tablets are not selected. The test was emptied for two weeks before the start of the test, and continuous administration was observed for four weeks. The designated drugs were taken orally once a day, blood pressure and heart rate were reviewed weekly during the treatment period, blood pressure and heart rate were recorded three times in the right upper arm, and the patient was asked for adverse reactions.
  • Figure 4 Human observational study of calcium-enhanced rennetine lowering blood pressure. The patients were randomly divided into two groups. The observation group A1 and the control group A2 each had 25 patients. The dose of group A1 was nitrendipine 5 mg/d + calcium gluconate 2000 mg/d (corresponding to calcium 178.6 mg/d), while the A2 group was 5 mg/d nitrendipine.
  • Figure 4 is a graph of the effect of drugs on systolic blood pressure (SBP) in patients.
  • SBP systolic blood pressure
  • the systolic blood pressure of the observation group was significantly lower than that of the control group.
  • the effective rate of the observation group was 80%, and the effective rate was 20%; while the effective rate of the control group was 64%, and the effective rate was 36%.
  • FIG. 5 Human-observed study of calcium-enhanced prazosin-lowering blood pressure. The patients were randomly divided into two groups, and the observation group D1 and the control group D2 each had 25 patients. The D1 group dose was prazosin 0.5 mg/d + calcium gluconate 2000 mg/d (corresponding to calcium 178.6 mg/d), while the D2 group was prazosin 0.5 mg/d.
  • Figure 5 shows the statistical effect of the drug on the patient's contraction pressure (SBP). The statistical results showed that compared with the control group and the observation group, the contraction pressure of the observation group was significantly lower than that of the control group.
  • the effective rate of the observation group was 88%, the effective rate was 8%, and the ineffective rate was 4%; while the effective rate of the control group was 64%, the effective rate was 32%, and the ineffective rate was 4%.
  • FIG. 6 Human observational study of calcium-enhanced furosemide lowering blood pressure. The patients were randomly divided into two groups. The observation group C1 and the control group C2 each had 25 patients. The dose of group C1 was furosemide 5 mg/d + calcium gluconate 2000 mg/d (corresponding to calcium 178.6 mg/d), while the C2 group furosemide was 5 mg/d.
  • Figure 6 is a graph of the effect of drugs on systolic blood pressure (SBP) in patients. The statistical results showed that: at the low dose of furosemide, compared with the control group and the observation group, the systolic blood pressure of the observation group was significantly lower than that of the control group.
  • SBP systolic blood pressure
  • FIG. 7 Human observational study of calcium-enhanced hydrochlorothiazide hypotensive effect. The patients were randomly divided into two groups, and the observation group F1 and the control group F2 each had 25 patients. The dose of F1 group was hydrochlorothiazide 6.25 mg/cl + calcium gluconate 2000 mg/d (corresponding to calcium 178.6 mg/d), while the F2 group hydrochlorothiazide was 6.25 mg/d.
  • Figure 7 shows the statistics of the effects of drugs on patients' systolic blood pressure (SBP).
  • SBP systolic blood pressure
  • the systolic blood pressure of the observation group was significantly lower than that of the control group.
  • the effective rate of the observation group was 92%, and the effective rate was 8%.
  • the effective rate of the control group was 72%, the effective rate was 24%, and the ineffective rate was 4%.
  • composition of the present invention is compared with a separate diuretic and a novel antihypertensive drug as follows - Diuretic New antihypertensive drug
  • the present invention has low efficacy and high efficacy
  • Patent non-protection period can apply for side effects significantly low low

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L’invention concerne une composition médicinale permettant de traiter l’hypertension. La composition contient un ou deux médicaments antihypertenseurs, un composant contenant du calcium et l’auxiliaire pharmacologiquement acceptable, l’antihypertenseur étant choisi à partir d’antagoniste de calcium, de bloqueur de récepteur alpha, de bloqueur de récepteur béta, de régulateur et diurétique de système rénine-angiotonine, le composant contenant du calcium a la teneur en calcium pouvant être apportée au corps humain. Les deux médicaments antihypertenseurs et le composant contenant du calcium entrant dans la composition ont un rapport en poids allant de 0 à 50 : 0 à 50 : 10 à 2000, où la teneur des différents médicaments antihypertenseurs n’est simultanément pas 0, le composant contenant du calcium est calculé en tant que Ca+. Cette composition médicinale peut réduire la pression sanguine en diminuant rapidement le volume sanguin, le composant contenant du calcium pouvant bloquer le niveau de pression d’admission dans le corps, et accroître la dépressurisation des médicaments antihypertenseurs.
PCT/CN2006/000888 2005-05-08 2006-04-30 Medicament pour le traitement de l’hypertension WO2006119692A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200510068319.9 2005-05-08
CNB2005100683199A CN100389830C (zh) 2005-05-08 2005-05-08 一种治疗高血压的药物组合物

Publications (1)

Publication Number Publication Date
WO2006119692A1 true WO2006119692A1 (fr) 2006-11-16

Family

ID=35304591

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/000888 WO2006119692A1 (fr) 2005-05-08 2006-04-30 Medicament pour le traitement de l’hypertension

Country Status (2)

Country Link
CN (1) CN100389830C (fr)
WO (1) WO2006119692A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011528670A (ja) * 2008-07-24 2011-11-24 ルナン ファーマシューティカル グループ コーポレーション 高血圧と代謝症候群の治療に用いられる医薬組成物及びその使用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20120542A1 (es) * 2006-06-27 2012-05-14 Novartis Ag Formas de dosificacion solidas de valsartan, amlodipina e hidroclorotiazida y metodo para elaborarlas
CN102058872B (zh) * 2009-11-17 2013-12-25 北京万全阳光医学技术有限公司 一种含有赖诺普利和苯磺酸氨氯地平的药物组合物及其制备方法
CN102462844A (zh) * 2010-11-05 2012-05-23 四川滇虹医药开发有限公司 一种替利洛尔的药物组合物及其制备方法
CN104758290A (zh) * 2015-03-09 2015-07-08 西安力邦肇新生物科技有限公司 一种复方降压组合物及其应用
CN104758932B (zh) * 2015-03-09 2018-07-31 西安汉丰药业有限责任公司 一种美托法宗复方制剂及其应用
CN107753488A (zh) * 2017-10-26 2018-03-06 郭裴哲 一种治疗高血压肥胖患者的药物组合物及其制备方法
CN114569600B (zh) * 2022-04-19 2023-08-08 佳木斯大学 一种用于防治高血压的药物组合物及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1562369A (zh) * 2004-03-29 2005-01-12 王德山 一种治疗高血压的药物组合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1562369A (zh) * 2004-03-29 2005-01-12 王德山 一种治疗高血压的药物组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIN G.: "The effect on hypertension patient serum PTH calcium formulation for oral administration and judgement of depressurization therapeutic effect", MEDICAL THEORY AND PRACTICE, vol. 11, no. 3, 1998, pages 104 - 105 *
ZHOU C. ET AL.: "The effect on hypertension patient red blood cell membrane ATP enzymatic activity of calcium formulation for oral administration and judgement of depressurization therapeutic effect", PJCCPVD, vol. 2, no. 1, 1994, pages 7 - 10 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011528670A (ja) * 2008-07-24 2011-11-24 ルナン ファーマシューティカル グループ コーポレーション 高血圧と代謝症候群の治療に用いられる医薬組成物及びその使用

Also Published As

Publication number Publication date
CN1686549A (zh) 2005-10-26
CN100389830C (zh) 2008-05-28

Similar Documents

Publication Publication Date Title
WO2006119692A1 (fr) Medicament pour le traitement de l’hypertension
AU2001278045B2 (en) Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of congestive heart failure
CN101584700A (zh) 一种药物组合物
WO2006105726A1 (fr) Composition pour le traitement de l’hypertension
EP0910375B1 (fr) Composition a base d'enalapril et de losartan
JPH11507012A (ja) 心臓血管系病気の処置におけるアンギオテンシン変換酵素阻害薬と副作用軽減量のアルドステロン拮抗薬との組合わせ治療
WO2013152641A1 (fr) Préparation composée constituée de chlorhydrate de lercanidipine et de losartan potassique et son procédé de préparation
CN101167723A (zh) 缬沙坦分散片及其制备方法
SK19332001A3 (sk) Použitie antagonistov kortizolu v liečení srdcového zlyhania
CN1301545A (zh) 一种复方降血压药
CN110755429A (zh) 一种复方降压药组合物、其制剂及其用途
CN103721259A (zh) 血管紧张素ⅱ受体阻断剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物
CN115243774B (zh) 含氨氯地平、氯噻酮和阿米洛利的药物组合物
CN101987200B (zh) 含有降压肽和醛固酮受体拮抗剂的治疗高血压的复方药物
CN113226374B (zh) 含氨氯地平、氯噻酮和醛固酮受体拮抗剂的药物组合物
JP2003521496A (ja) Ａｃｅ阻害剤−バソプレッシンアンタゴニストの組み合わせ
CN106310271A (zh) 一种治疗慢性心力衰竭的药物组合物
JP2023501344A (ja) ｓＧＣ刺激剤による糖尿病性腎症の処置
UA146879U (uk) Фармацевтична композиція
Chinali et al. HYPOKALEMIA BLUNTS LEFT VENTRICULAR MASS REGRESSION IN HYPERTENSIVE PATIENTS DURING LOSARTAN-OR ATENOLOL-BASED TREATMENT: THE LIFE ECHO-SUBSTUDY: 9D. 06
UA146315U (uk) Фармацевтична композиція
White et al. THE NEW ANGIOTENSIN RECEPTOR BLOCKER AZILSARTAN MEDOXOMIL HAS SIGNIFICANTLY GREATER 24-HOUR BLOOD PRESSURE LOWERING EFFICACY TO BOTH OLMESARTAN AND VALSARTAN: 9D. 05
KR19980702100A (ko) 심장혈관질환의 치료를 위한 안지오텐신 전환 효소 억제제, 부작용-감소된 양의 알도스테론 길항제 및 이뇨제의 조합 치료요법
Azizi et al. BLOOD PRESSURE AND POTASSIUM EFFECTS OF THE NEW DIRECT ALDOSTERONE SYNTHASE INHIBITOR, LCI699, IN PATIENTS WITH PRIMARY ALDOSTERONISM: 9D. 03
Krämer et al. THE NON-PEPTIDE AT2-RECEPTOR AGONIST COMPOUND 21 AMELIORATES HYPERTROPHY AND FIBROSIS IN UREMIA-ASSOCIATED CARDIOMYOPATHY: 9D. 04

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

NENP Non-entry into the national phase

Ref country code: RU

WWW Wipo information: withdrawn in national office

Country of ref document: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06722433

Country of ref document: EP

Kind code of ref document: A1