WO2015088104A1 - Composition pharmaceutique comprenant de la pravastatine et du valsartan - Google Patents

Composition pharmaceutique comprenant de la pravastatine et du valsartan Download PDF

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WO2015088104A1
WO2015088104A1 PCT/KR2014/001865 KR2014001865W WO2015088104A1 WO 2015088104 A1 WO2015088104 A1 WO 2015088104A1 KR 2014001865 W KR2014001865 W KR 2014001865W WO 2015088104 A1 WO2015088104 A1 WO 2015088104A1
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pravastatin
valsartan
composition
pharmaceutically acceptable
acceptable salt
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PCT/KR2014/001865
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Korean (ko)
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고광곤
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가천대학교 산학협력단
(의료)길의료재단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61P3/08—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

Definitions

  • the present invention relates to a pharmaceutical composition comprising pravastatin and valsartan, and more particularly, to a pharmaceutical composition for treating cardiovascular disease containing pravastatin and valsartan as an active ingredient and having no side effects of diabetes.
  • hyperlipidemia refers to an abnormally increased state of lipids such as cholesterol and triglycerides in plasma.
  • Hyperlipidemia especially hypercholesterolemia, causes arterial thrombosis, leading to arteriosclerosis, in which lipids build up along the blood vessels, which decreases blood flow and causes cardiovascular diseases such as ischemic heart disease, angina pectoris, myocardial infarction, and cerebral infarction. This is an important issue.
  • arteriosclerosis can be prevented and cardiovascular disease can be prevented.
  • hyperlipidemia include, for example, hypercholesterolemia, familial abnormal beta-lipoproteinemia, diabetes abnormal dyslipidemia, nephrotic dyslipidemia, and familial complex hyperlipidemia.
  • Hypercholesterolemia results in elevation of low density lipoprotein-cholesterol in serum and total cholesterol in serum. Low density lipoproteins carry cholesterol in the blood.
  • Familial aberrant beta-lipoproteinemia also known as type III hyperlipidemia, is characterized by the accumulation of beta VLDL (very low density lipoprotein), called ultralow density lipoprotein cholesterol particles, in serum. This symptom is also associated with the replacement of normal apolipoprotein E3 with abnormal heterozygous apolipoprotein E2.
  • Diabetic dyslipidemia results in a number of lipoprotein abnormalities, such as overproduction of VLDL-cholesterol, abnormal lipolysis of VLDL triglycerides, decreased LDL-cholesterol receptor activity, and frequent type III hyperlipidemia.
  • Nephrotic dyslipidemia is difficult to treat, with frequent examples of which include hypercholesterolemia and hypertriglyceridemia.
  • Familial complex hyperlipidemia is divided into a number of phenotypes of hyperlipidemia, namely type IIa, IIb, IV, V or hyperlipobeta-lipoproteinemia.
  • HMG-CoA reductase inhibitors have been used for decades for the treatment of such hyperlipidemia. These HMG-CoA reductase inhibitors are known to lower the total cholesterol and LDL-cholesterol in the human body and provide an effect of raising HDL-cholesterol levels in some individuals.
  • the conversion of HMG-CoA to mevalonate is an early step in the biosynthesis of cholesterol.
  • Inhibition of HMG-CoA reductase, which interferes with the production of mevalonate means that HMG-CoA reductase inhibitors lower their total cholesterol. Effect and LDL-cholesterol lowering effect (Grundi SM, N Engl J Med, 319 (1): 24-32, 25-26, 31 (1998)).
  • HMG-CoA reductase inhibitors examples include mevastatin (US Pat. No. 3,983,140), lovastatin (US Pat. No. 4,231,938), also called mevinolin, pravastatin (US Pat. Nos. 4,346,227 and 4,410,629), and lactones of pravastatin (US Patent 4,448,979), velostatin and simvastatin (US Pat. Nos. 4,448,784 and 4,450,171), called mysterolin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin.
  • mevastatin US Pat. No. 3,983,140
  • lovastatin also called mevinolin
  • pravastatin US Pat. Nos. 4,346,227 and 4,410,629
  • lactones of pravastatin US Pat. Nos. 4,448,979
  • velostatin and simvastatin US Pat. Nos. 4,448,784 and 4,450
  • Angiotensin-II-receptor blockers have been commercialized as antihypertensive drugs over the last few years and have shown rapid growth.
  • Angiotensin-II is not only a potent vasoconstrictor but also an oxidative and inflammatory substance, a thrombus formation, and hypertension, as well as worsening of cardiovascular diseases such as arteriosclerosis, heart failure, angina pectoris, myocardial infarction, kidney failure, and stroke, and complications of diabetes. It plays a pivotal role in the back.
  • angiotensin-II-receptor blockers cause vasodilation by blocking the activation of angiotensin-II AT1 receptors, reduce the secretion of vasopressin, and reduce the production and secretion of aldosterone, thereby lowering blood pressure.
  • angiotensin-II-receptor blockers are effective in the prevention and treatment of cardiac cerebrovascular disease, additional heart failure, cardiomyopathy, angina pectoris, myocardial infarction, renal failure, stroke associated with various symptoms of diabetes, antiplatelet action, atherosclerosis prevention, It is also known that aldosterone inhibits harmful effects and prevents aggravation of circulatory diseases.
  • angiotensin-II-receptor blockers examples include losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan and the like.
  • hyperlipidemia About 60% of patients with hypertension are hyperlipidemia, and hypertension and hyperlipidemia are proven to be closely related to each other. If hypertension and hyperlipidemia are administered to cardiovascular patients, heart failure, angina, myocardial infarction and heart failure, kidney failure, stroke, etc. It is known to reduce the incidence and death of complications.
  • the present inventors have studied medicament for the treatment of cardiovascular disease, and as a result, when treating a combination of hyperlipidemia treatment pravastatin and hypertension valsartan, there is no problem of lowering the drug efficacy as known in the prior art and there is no synergy between the two drugs.
  • the cardiovascular disease can be treated more effectively than the case of using pravastatin or valsartan alone, and also effectively prevent the side effects of diabetes.
  • An object of the present invention is to provide a pharmaceutical composition for treating cardiovascular diseases comprising pravastatin and valsartan as an active ingredient.
  • an object of the present invention to provide a pharmaceutical composition for treating cardiovascular diseases comprising pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient and can prevent side effects of diabetes.
  • Another object of the present invention comprises a) a first composition comprising pravastatin or a pharmaceutically acceptable salt thereof as an active ingredient and b) a second composition comprising valsartan or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to administer to the subject a pharmaceutical composition comprising pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, or pravastatin or a pharmaceutically acceptable salt thereof.
  • a method for treating cardiovascular disease and preventing diabetes side effects comprising administering to a subject a composition comprising a salt and a composition comprising valsartan or a pharmaceutically acceptable salt thereof simultaneously, sequentially or in reverse order. To provide.
  • Still another object of the present invention is to provide a use for treating cardiovascular disease without side effects of diabetes in the composition comprising pravastatin, or a pharmaceutically acceptable salt thereof and valsartan, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating cardiovascular disease comprising pravastatin and valsartan as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating cardiovascular disease, which includes pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient and can prevent side effects of diabetes.
  • the present invention comprises a) a first composition comprising pravastatin or a pharmaceutically acceptable salt thereof as an active ingredient and b) a second composition comprising valsartan or a pharmaceutically acceptable salt thereof as an active ingredient,
  • a kit for treating cardiovascular diseases which can prevent side effects of diabetes.
  • the present invention also provides a method of administering a pharmaceutical composition comprising pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, or pravastatin or a pharmaceutically acceptable salt thereof.
  • a method of treating a cardiovascular disease and preventing a side effect of diabetes comprising administering to a subject a composition comprising a composition comprising the composition and valsartan or a pharmaceutically acceptable salt thereof simultaneously or sequentially or in reverse order. .
  • the present invention provides a use for treating cardiovascular disease without side effects of diabetes mellitus of a composition comprising pravastatin, or a pharmaceutically acceptable salt thereof and valsartan, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the kit comprising the pharmaceutical composition comprising pravastatin and valsartan as an active ingredient, and the first composition comprising pravastatin and the second composition comprising valsartan, are used to treat hypolipidemia and hyperlipidemia by synergistic action of pravastatin and valsartan.
  • pravastatin and valsartan By simultaneously exhibiting the effect, not only provides a superior cardiovascular disease treatment effect compared to the single component, it can prevent side effects of diabetes can be effectively used for cardiovascular disease treatment.
  • FIG. 1 shows the rate of change (right) of the high sensitivity CRP (hsCRP) level and the rate of change of blood flow-mediated vasodilation response (FMD) after the treatment of pravastatin alone, combination of pravastatin and valsartan, and valsartan alone from each pre-treatment value.
  • This graph shows the left side. The mean (left) or median (right) is shown with the SEM.
  • FIG. 2 shows the rate of change of adiponectin level (A), the rate of change of insulin level (B), and the rate of change of QUICKI (C) after each treatment with pravastatin alone, in combination with pravastatin and valsartan, and valsartan alone. It is a graph. Mean values are presented along with median (A, B) or SEM.
  • the present invention provides a pravastatin, or a pharmaceutically acceptable salt thereof (hereinafter, referred to as pravastatin unless otherwise indicated) and valsartan, or a pharmaceutically acceptable salt thereof (hereinafter, Unless otherwise stated, the present invention provides a pharmaceutical composition for treating cardiovascular diseases, which includes valsartan) as an active ingredient and can prevent side effects of diabetes.
  • HMG-CoA reductase inhibitors when a combination of these HMG-CoA reductase inhibitors and angiotensin-II receptor blockers is administered, it is known that competitive inhibition occurs between drugs, reducing the efficacy of drugs and increasing the risk of side effects. In addition, it is known that the inhibitory effect of angiotensin-II receptor blocker on insulin resistance is offset by the generation of insulin resistance by HMG-CoA reductase inhibitor.
  • the present inventors have developed a combination of an angiotensin-II receptor blocker with an HMG-CoA reductase inhibitor that can provide a superior therapeutic effect of cardiovascular disease as well as prevent side effects of cardiovascular disease without reducing such efficacy and risk of side effects.
  • the combination treatment of pravastatin, one of HMG-CoA reductase inhibitors, and valsartan, one of angiotensin-II receptor blockers can effectively treat cardiovascular diseases and diabetes, which is known as a side effect of statin drugs. It was confirmed for the first time that not only no side effects occurred but also prevent the occurrence of diabetes.
  • pravastatin is (3 R, 5 R) -3,5- dihydroxy -7 - ((1 R, 2 S, 6 S, 8 R, 8a R) -6- hydroxy- 2-methyl -8 - ⁇ [(2 S) -2- methyl-butanoyl] oxy ⁇ -1,2,6,7,8,8a- hexahydro-1-yl) - the acid of the formula and to It refers to an HMG-CoA reductase inhibitor having the structure I, and is mainly used for the treatment of hyperlipidemia such as dyslipidemia.
  • brasartan is N- (1-oxopentyl) -N-[[2 '-(1H-tetrazol-5-yl) [biphenyl-4-yl] methyl] -L-valine]
  • Angiotensin-II-receptor blocker having the chemical formula of Formula II and the following structural formula II, an anti-pressure agent that relaxes blood vessels by blocking the action of angiotensin II, which raises blood pressure by vasoconstrictive action, causes oxidants, inflammatory substances and thrombus formation.
  • cardiac cerebrovascular diseases such as heart failure, ischemic heart disease, stroke, kidney disease, and the like.
  • pharmaceutically acceptable salts means salts prepared according to conventional methods in the art, and such preparation methods are known to those skilled in the art.
  • the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
  • Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.
  • pravastatin and valsartan may be included in a ratio of about 1: 1 to 1:10 by weight, preferably in a ratio of 1: 2 to 1: 5, and more preferably May be included in a ratio of 1: 3 to 1: 4.
  • the content of pravastatin and valsartan contained in the pharmaceutical composition of the present invention is not particularly limited, but may be included in an amount of 0.0001 to 90% by weight, more preferably 0.01 to 50% by weight, based on the total weight of the final composition.
  • composition of the present invention may further comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a carrier or diluent that does not interfere with the biological activity and properties of the compound to be administered without stimulating the organism.
  • the kind of the carrier usable in the present invention is not particularly limited, and any carrier can be used as long as it is a conventionally used and pharmaceutically acceptable carrier in the art.
  • Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like. These may be used alone or in combination of two or more thereof.
  • compositions of the present invention may be prepared in various formulations depending on whether the desired mode of administration is oral or parenteral.
  • Non-limiting examples of formulations for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like. Can be mentioned.
  • oral dosage forms such as tablets or capsules, such as lactose, Saccharose, Sorbitol, Mannitol, Starch, Amylopectin, Cellulose or Gelatin, etc.
  • Binders such as dicalcium phosphate and the like; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, and the like.
  • the capsule formulation may further contain a liquid carrier such as fatty oil in addition to the above-mentioned materials.
  • Formulations for parenteral administration include, for example, injectable forms such as subcutaneous injection, intravenous injection or intramuscular injection; Suppository injection mode; Or it may be formulated for spraying, such as aerosols to enable inhalation through the respiratory tract, but is not limited thereto.
  • injectable formulations the compositions of the present invention may be mixed in water with stabilizers or buffers to prepare solutions or suspensions and formulated for unit administration of ampoules or vials.
  • a propellant or the like may be combined with the additives to disperse the dispersed concentrate or wet powder.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount
  • the term "pharmaceutically effective amount" of the present invention is used to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention
  • Sufficient amount means an effective dose level means the severity of the disease, the activity of the drug, the age, weight, health, sex, sensitivity of the patient to the drug, the time of administration of the composition of the invention used, the route of administration and the rate of excretion treatment Period of time, factors including drugs used in combination or coincidental with the compositions of the invention used, and other factors well known in the medical arts.
  • the pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
  • a preferred daily dosage of the pharmaceutical composition comprising pravastatin and valsartan of the present invention may be 0.5 mg / kg / day to 50 mg / kg / day, more preferably 1 mg / kg / day to 20 mg / kg May be / day.
  • Preferred frequency of administration of the pharmaceutical composition of the present invention may be once daily, but is not limited thereto.
  • cardiovascular disease refers to diseases occurring in the heart and major arteries, and examples of cardiovascular diseases include hypertension, heart failure, cardiomyopathy, ischemic heart disease (coronary artery disease), angina pectoris, myocardial infarction, arrhythmia, atherosclerosis (arteriosclerosis) ), Stroke, which is a cerebrovascular disease.
  • cardiovascular diseases include hypertension, heart failure, cardiomyopathy, ischemic heart disease (coronary artery disease), angina pectoris, myocardial infarction, arrhythmia, atherosclerosis (arteriosclerosis) ), Stroke, which is a cerebrovascular disease.
  • Blood pressure is the blood pressure measured at least two times more than 140 mmHg systolic blood pressure or more than 90 mmHg diastolic blood pressure.
  • Ischemic heart disease is a condition in which the heart muscle fails to function because oxygen as needed for the heart muscle is not supplied to the heart muscle for various reasons, and the most common cause is the coronary artery that supplies blood to the heart. ) Is narrowing or clogging.
  • Coronary artery disease is a disease caused by abnormalities in the coronary artery (cardiac artery), a blood vessel that supplies oxygen and nutrients to the heart muscle, and is generally referred to as coronary artery disease, and angina pectoris and myocardial infarction are typical examples.
  • Angina is a disease in which the internal diameter of the coronary arteries is narrowed by arteriosclerosis, which does not supply enough blood to the heart muscle.
  • angina is a blood vessel that is narrowed when the heart needs more nutrients and oxygen, such as when exercising. It can't supply this heart muscle, resulting in heart failure.
  • Myocardial infarction is a disease in which the myocardium is necrotic due to blockage of the coronary artery (cardiac artery) that supplies blood to the heart, and oil clots accumulated on the narrowed coronary artery wall by arteriosclerosis burst to meet blood and form a blood clot, A thrombus completely blocks the flow of blood, causing heart pain to become necrotic (rotating).
  • Atherosclerosis refers to a disease in which blood vessels become oily and the blood vessel walls become hard. Cholesterol deposits in the inner membrane of blood vessels and cell proliferation results in the formation of a deadly atherosclerosis. The inner surface of these vessels becomes gritty and the walls become thicker, and the inside diameter of the blood flowing narrows, which causes a problem in blood circulation. When the fibrous membranes around the atherosclerosis burst, blood clots form in the blood vessels. In addition, bleeding occurs inside the atherosclerosis, which causes the vessel's internal diameter to narrow rapidly or become blocked.
  • Cerebrovascular disease can be categorized into ischemic stroke and hemorrhagic stroke.
  • Ischemic stroke is caused by blood vessel disorders that are blocked by arteriosclerosis or blood clots. This occurs and the blood supply is blocked by the bleeding is a hemorrhagic stroke.
  • the hypercholesterolemia patients are divided into three groups, the first group is administered with pravastatin alone, the second group is administered with valsartan alone, and the third group is combined with pravastatin and valsartan as a result.
  • plasma hsCRP levels were significantly reduced compared to the treatment group alone, and blood flow-mediated dilation (FMD) was significantly increased to improve endothelial cell function.
  • plasma insulin levels were also significantly reduced compared to the treatment group alone, the Quantitative Insulin-Sensitivity Check Index (QUICKI) was increased compared to the treatment group alone, and plasma adiponectin level was significantly increased compared to the treatment group alone.
  • QUICKI Quantitative Insulin-Sensitivity Check Index
  • the present invention comprises a) a first composition comprising pravastatin as an active ingredient and b) a second composition comprising a valsartan as an active ingredient, the treatment of cardiovascular diseases that can prevent the side effects of diabetes mellitus
  • the first composition and the second composition may each be a pharmaceutical composition comprising pravastatin as an active ingredient and a pharmaceutical composition comprising valsartan as an active ingredient, and these pharmaceutical compositions may further contain a pharmaceutically acceptable carrier as described above. It can be included as.
  • the content of pravastatin and valsartan contained in each of the first and second compositions of the present invention is not particularly limited, but is 0.0001 to 90% by weight, and more preferably 0.01 to 50% by weight, based on the total weight of the final composition. It may be included as.
  • the kit of the present invention is not particularly limited in kind, and may be used as a kit commonly used in the art.
  • the kit of the present invention may be packaged in a form in which the first composition and the second composition are each contained in separate containers, or in one container divided into one or more compartments, wherein the first composition and the second composition May be packaged in the unit dose form of each single dose.
  • the first composition and the second composition in the kit may be administered separately in combination at an appropriate time according to the health condition of the subject to be administered and the like.
  • the weight ratio of pravastatin of the first composition and valsartan of the second composition included in the kit of the present invention may be about 1: 1 to 1:10, preferably 1: 2 to 1: 5, and more Preferably 1: 3 to 1: 4.
  • the preferred daily dosage of the first composition of the present invention may be 0.1 mg / kg / day to 10 mg / kg / day, more preferably 0.5 mg / kg / day to 5 mg / kg / day.
  • Preferred frequency of administration of the first composition of the present invention may be once daily.
  • the preferred daily dosage of the second composition of the present invention may be 0.5 mg / kg / day to 50 mg / kg / day, more preferably 2 mg / kg / day to 20 mg / kg / day. .
  • the preferred frequency of administration of the second composition of the present invention may be once daily.
  • the invention provides a method of administering a pharmaceutical composition comprising pravastatin and valsartan to a subject, or simultaneously or sequentially or in reverse order of a first composition comprising pravastatin and a second composition comprising valsartan. It provides a method for preventing or treating cardiovascular diseases and preventing side effects of diabetes, including administering to a subject.
  • the term "individual" means all animals, including humans at risk of or suffering from cardiovascular disease.
  • treatment refers to any action by which the composition of the present invention is administered to a subject to improve or benefit from cardiovascular disease.
  • prevention means any action that inhibits or delays the development of cardiovascular disease by administering the composition of the present invention to a subject.
  • administration refers to introducing the pharmaceutical composition of the present invention to a subject by any suitable method, and the route of administration may be administered through various routes, oral or parenteral, as long as the target tissue can be reached.
  • the method for preventing or treating the present invention specifically comprises administering a pharmaceutical composition comprising pravastatin and valsartan in a pharmaceutically effective amount to an individual at risk of or suffering from cardiovascular disease, or comprising pravastatin. Simultaneously administering the first composition and the second composition comprising valsartan in a pharmaceutically effective amount, respectively. Suitable once and / or total daily doses of the composition can be appropriately determined by one skilled in the art within the scope of sound medical judgment.
  • the first composition and the second composition are 1: 1 to 1:10, preferably 1: 2 to 1: 5, more preferably 1: 3 to 1, based on the weight of pravastatin and valsartan. It may be administered in a ratio of 1: 4.
  • the specific pharmaceutically effective amount of the composition for a particular subject may be determined by the type and extent of the reaction to be achieved as described above, the age, weight, general state of health, sex or diet of the subject, as well as the time of administration of the composition, administration It may be determined in consideration of the route and the ratio of the composition, the duration of treatment, and the like, and may vary according to various factors and similar factors well known in the medical field, including the components of the drug or other composition used simultaneously or simultaneously. Preferred dosages of the compositions are as described above.
  • the route of administration and mode of administration of the pharmaceutical composition, the first composition and the second composition of the present invention are not particularly limited and may be in accordance with any route of administration and mode of administration as long as the composition can reach the desired site of interest.
  • the pharmaceutical composition, the first composition and the second composition of the present invention may be administered by oral or parenteral administration.
  • parenteral administration for example, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration or topical administration may be used, but is not limited thereto.
  • the present invention provides the use of pravastatin, or a pharmaceutically acceptable salt and valsartan, or a composition comprising a pharmaceutically acceptable salt thereof as an active ingredient for treating cardiovascular disease without the side effects of diabetes mellitus. do.
  • Each treatment group received 40 mg of pravastatin and placebo, 40 mg of pravastatin, 160 mg of valsartan, 160 mg of valsartan and placebo daily for 2 months.
  • This experiment was designed as a randomized, blinded, placebo control with three treatment groups (two months each) and interchangeable (two washout periods of two months). Hidden assignments were made in collaboration with statisticians. 23 of the 48 patients had metabolic syndrome. The experiment was approved by the Gil Hospital Committee and agreed with all participants.
  • hsCRP levels were determined by latex aggregation (CRP-Latex (II) Denka-Seiken, Tokyo, Japan), plasma insulin levels were measured by immunoradiometric assay (INSULIN-RIABEAD II, SRL, Inc, Tokyo), HbA1c Analyzed by liquid chromatography analysis (VARIANT II TURBO®, BIO-RAD, Inc, Hercules, CA, USA) (Koh KK, Quon MJ, Han SH, et al.
  • Quantitative insulin sensitivity check index was calculated (Katz A, Nambi SS, Mather K, et al. J Clin Endocrinol Metab 2000; 85: 2402-2410, Chen H, Sullivan G, Quon MJ. Diabetes 2005; 54: 1914-1925).
  • Image analysis of the right brachial artery was performed with an ATL HDI 3000 ultrasound machine (ATL Philips, Bothell, WA, USA) equipped with a 10 MHz linear-array transducer (Koh KK, Quon MJ, Han SH, et al. Diabetes Care 2008).
  • the intrameasured error for repeated measurements of the maximum diameter of repetition was 0.01 ⁇ 0.06 mm, and the intrameasured error for repeated measurements of blood flow-mediated vasodilation response (FMD) percentage was 0.13 ⁇ 1.33%.
  • Valsartan alone or a combination of valsartan and pravastatin showed a significant decrease in blood pressure during cardiac contraction and dilation when compared to the baseline after 2 months of treatment. This decrease was significantly greater than that observed with pravastatin alone (P ⁇ 0.05 by ANOVA) (Table 1).
  • Pravastatin alone or a combination of valsartan and pravastatin showed a significant decrease in total cholesterol levels (P ⁇ 0.001), triglycerides (P ⁇ 0.05), LDL cholesterol (P ⁇ 0.001), and apolipoprotein B levels compared to the default values. . This reduction was significantly greater than that observed with valsartan alone (P ⁇ 0.05 by ANOVA) (Table 1).
  • the FMD percentages were significantly increased to 37 ⁇ 2%, 47 ⁇ 3%, and 32 ⁇ 2%, respectively (P ⁇ 0.001). This response was significantly increased (P ⁇ 0.001 by ANOVA; FIG. 1 and Table 1).
  • BMI body mass index
  • hsCRP hypersensitive C-reactive protein
  • ADP adiponectin
  • HbA1c glycated hemoglobin
  • Quantitative Insulin Sensitivity Check Index 1 / [log (insulin) + log (glucose)]
  • BMI body mass index
  • hsCRP hypersensitive C-reactive protein
  • ADP adiponectin
  • HbA1c glycated hemoglobin
  • Quantitative Insulin Sensitivity Check Index 1 / [log (insulin) + log (glucose)]

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant de la pravastatine ou son sel pharmaceutiquement acceptable et du valsartan ou son sel pharmaceutiquement acceptable comme principe actif. En outre, la présente invention concerne un kit pour le traitement d'une maladie cardiovasculaire qui prévient la survenue du diabète, comprenant a) une première composition comprenant de la pravastatine ou son sel pharmaceutiquement acceptable comme principe actif et b) une seconde composition comprenant du valsartan ou son sel pharmaceutiquement acceptable comme principe actif, et un procédé permettant de traiter une maladie cardiovasculaire tout en empêchant l'effet indésirable de survenue d'un diabète, comprenant une étape consistant à administrer une composition comprenant de la pravastatine et et du valsartan comme principes actifs à un individu, ou une étape consistant à administrer simultanément une composition comprenant de la pravastatine et une composition comprenant du valsartan à un individu.
PCT/KR2014/001865 2013-12-12 2014-03-07 Composition pharmaceutique comprenant de la pravastatine et du valsartan WO2015088104A1 (fr)

Applications Claiming Priority (2)

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KR1020130155030A KR101579656B1 (ko) 2013-12-12 2013-12-12 프라바스타틴과 발사르탄을 포함하는 약학 조성물
KR10-2013-0155030 2013-12-12

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WO2015088104A1 true WO2015088104A1 (fr) 2015-06-18

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KR101579656B1 (ko) 2015-12-22

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