KR20190043076A - Pharmaceutical composition comprising amlodipine, losartan and rosuvastatin for prevention and treatment of cardiovascular diseases accompanied by diabetes and formulated combination including the same - Google Patents

Abstract

Provided are: a pharmaceutical composition containing amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof for preventing or treating cardiovascular diseases accompanied by diabetes; and a composite formulation containing the same.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating cardiovascular diseases accompanied by diabetes mellitus including amlodipine, rozatan and rosuvastatin, and a combination preparation comprising the same, and formulated combination including the same}

The present invention relates to the prevention or treatment of cardiovascular diseases, and more particularly, to a pharmaceutical composition comprising amlodipine, rozatan and rosuvastatin for the prevention or treatment of cardiovascular diseases accompanied by diabetes mellitus, .

Cardiovascular disease is one of the major causes of death and is a multifactorial disease caused by the complex interactions of chronic diseases such as hypertension, dyslipidemia and diabetes, and various risks such as smoking and obesity. Many people are sick at the same time. According to the scale and treatment status jointly announced by the Korean Society of Hypertension, the Korean Diabetes Society, and the Korean Society of Atherosclerosis, patients with hypertension, diabetes, and dyslipidemia have experienced a decline in the past 10 years (2006 ~ 2016 ) From 340,000 to 1.41 million.

In particular, the prevalence of other cardiovascular diseases such as diabetes, hypertension and dyslipidemia is steadily increasing. For example, diabetic patients are twice as likely to have hypertension as compared with non-diabetic patients, (Nephrotic syndrome, retinopathy) and macrovascular complications are likely to trigger or worsen hypertension, and it is known that 60 to 70% of diabetic patients are hypertensive. Conversely, people with hypertension are also at increased risk for diabetes. Diabetes mellitus is also classified as a very high risk group in dyslipidemia. In 30% of diabetic patients, the concentration of triglyceride (TG) is increased and the death from cardiovascular disease is 2 to 4 times Respectively. In diabetic patients, a gradual increase in triglyceride and a gradual decrease in HDL cholesterol are found with abnormal glucose tolerance. According to the Third National Health and Nutrition Examination Survey (NHANES III), about 85% of patients with type 2 diabetes are LDL (low-density lipoprotein cholesterol) Cholesterol is more than 100 mg / dl, 42% is more than 200 mg / dl of triglycerides, and 62% is less than 45 mg / dl of HDL cholesterol. This increase in cardiovascular disease in diabetes is associated with both type 1 and type 2 diabetes.

Thus, diabetic patients are often accompanied by cardiovascular disease, whereas diabetic patients with the same or similar disease are likely to have a different pathophysiology or drug response from non-diabetic patients, There are many cases in which blood pressure or lipid concentration control fails or is poorly controlled. In addition, patients with cardiovascular disease with diabetes are required to take a large amount of various drugs, and therefore, they are not only troublesome and uncomfortable, but also often fail to take the medication, failing to achieve the desired therapeutic effect, and accordingly have a burden of social burden and medical expenses . Therefore, in order to treat cardiovascular diseases accompanied by diabetes, there is a need to develop therapeutic agents and combinations of customized cardiovascular diseases taking into consideration the characteristics of the patient's diseases and the accompanying diseases.

 Patent Document 1 discloses a preparation containing amlodipine and simvastatin, but does not disclose a preparation capable of effectively controlling blood pressure and lipid concentration in a diabetic patient group. Accordingly, the present inventors have developed a pharmaceutical composition exhibiting excellent therapeutic and prophylactic effects in cardiovascular diseases accompanied by diabetes, and a combination preparation containing the same, after repeated research and clinical studies.

Korean Patent Publication No. 10-2007-0068658

One aspect is to provide a pharmaceutical composition for the prevention or treatment of cardiovascular diseases accompanied by diabetes.

Another aspect is to provide a combination preparation for the prevention or treatment of cardiovascular diseases accompanied by diabetes.

Another aspect is to provide a method of preventing or treating cardiovascular disease associated with diabetes.

One aspect is pharmaceuticals for the prevention or treatment of cardiovascular diseases with diabetes, including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof. Lt; / RTI >

Another aspect relates to a method for the prevention or treatment of cardiovascular diseases with diabetes mellitus comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof Thereby providing a combined preparation.

Another aspect is the use of a composition comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof to treat a cardiovascular disease with diabetes mellitus . ≪ / RTI >

The pharmaceutical composition comprising amlodipine, rozatan, and rosuvastatin according to one aspect is excellent in blood pressure control and lipid-improving effect in cardiovascular diseases accompanied by diabetes, and particularly in hypertension and dyslipidemia together with diabetes The improvement of blood pressure and lipid is excellent in the patient. The pharmaceutical composition is administered in combination with amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, The treatment or prevention of hypertension and dyslipidemia with diabetes is superior to that of either one or two of them alone. In addition, the pharmaceutical composition effectively reduces the mean systolic blood pressure and the mean diastolic blood pressure in diabetic patients, effectively reduces the increased triglyceride (TG), and improves blood pressure normalization rate and lipolytic protein cholesterol (LDL-C) great.

The combined preparation according to one aspect of the present invention can improve convenience of taking and compliance with the patient and reduce drug costs. It is also useful for the prevention or treatment of cardiovascular diseases in patients with diabetes, in which a therapeutic agent for hypertension and a therapeutic agent for dyslipidemia should be used in combination.

Figure 1 shows the results of measuring the changes in the mean sitting systolic blood pressure (sitSBP) (mmHg) according to the drug administered to patients with diabetes mellitus (DM) and non-diabetes mellitus (non-DM) .
FIG. 2 shows the results of measurement of the changes in the sitting diastolic blood pressure (sitDBP) (mmHg) according to the drug administered in the diabetic and non-diabetic patients.

Hereinafter, the present invention will be described in more detail.

All technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art, unless otherwise defined. Also, preferred methods or samples are described herein, but similar or equivalent ones are also included in the scope of the present specification. Also, the numerical values set forth herein are considered to include the meaning of " about " unless explicitly stated. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety. As used herein, the term " about " means that the value referred to may vary to some extent. For example, the value may be changed to 10%, 5%, 2%, or 1%. For example, " about 5 " means to include any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05. As used herein, the terms " having, " " having, " " including, " or " including, And does not exclude the presence of additional features.

One aspect relates to a method of treating cardiovascular complications associated with diabetes, including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, There is provided a pharmaceutical composition for preventing or treating a related disease.

The term " cardiovascular diseases " includes not only direct diseases caused by various causes such as abnormalities of the circulatory system in the living body, dysfunctions, damages, but also secondary diseases derived from such direct diseases. For example, the cardiovascular disease may include hypertension, dyslipidemia, angina pectoris, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure, atherosclerosis, coronary heart disease, or myocardial infarction.

The term " blood pressure " refers to the pressure exerted by the blood flowing along the blood vessel to the wall of the blood vessel. Blood pressure is summarized as two measurements of systolic blood pressure and diastolic blood pressure of systolic blood pressure. The normal blood pressure at rest is 60 ~ 90mmHg when relaxed to 100 ~ 140mmHg when contracted, and when blood pressure is constantly 140 / 90mmHg or more, .

The term " hypertension " refers to a chronic disease whose blood pressure is above the normal range. Hypertension can be classified into essential hypertension (primary hypertension) and secondary hypertension. According to the Korean Standard Classification of Diseases (KCD), essential hypertension and secondary hypertension are diseases classified by different disease classification codes. Approximately 90% to 95% are classified as essential hypertension without a definite underlying medical cause, while the remaining 5% to 10% (secondary hypertension) are due to other health conditions affecting the kidneys, arteries, heart, or endocrine system . For example, the phenomenon of obesity, hyperlipidemia, diabetes and hypertension may be referred to as " metabolic syndrome " or " insulin resistance syndrome ". Hypertension can be accompanied by symptoms such as dizziness, headache, heart palpitations, dyspnea, and if the human body is in the long term hypertensive state, it can cause a lot of complications such as stroke, coronary heart disease, and renal failure. The term " complication " refers to the presence of other symptoms in a disease.

The term "Essential (primary) hypertension" (KCD classification code: I10) is the most common type of hypertension due to the complex interplay of genetic and environmental factors. In addition, essential hypertension is a common symptom of diabetes, and insulin resistance, which is part of the metabolic syndrome (or metabolic syndrome), can also cause hypertension. The term "secondary hypertension (KCD classification code: I15)" arises from a recognizable cause and is one of the common secondary causes of kidney disease, and includes Cushing's syndrome, hyperthyroidism, hypothyroidism, Syndrome, hyperaldosteronism, hyperparathyroidism, chromium-rich cell tumor, diabetes, sleep apnea, pregnancy, aortic coalescence, licorice and steroid drugs, and illegal drugs. Secondary hypertension was classified into two groups according to KCD classification code: renal vascular hypertension (I15.0), secondary hypertension due to other kidney disorders (I15.1), secondary hypertension secondary to endocrine disorders (I15.2), and other secondary hypertension I15.8), unspecified secondary hypertension (I15.9), and the like.

The diagnosis of hypertension may be that the sitting systolic blood pressure (sitSBP) is greater than 140 mmHg or the sitting diastolic blood pressure (sitDBP) is greater than 90 mmHg. According to the revised JNC VIII Guideline (2014), blood pressure normalization criteria for general patients (those not diabetic or chronic kidney disease patients) are below 150/90 mmHg for those over 60 years old and below 140/90 mmHg for those under 60 years , And blood pressure normalization criteria for diabetic patients or chronic kidney disease patients are below 140/90 mmHg at all ages.

The term " hyperlipidemia " refers to a condition in which many lipid ingredients are present in the blood, causing inflammation by accumulating in the blood vessel walls, resulting in cardiovascular diseases, and also referred to as dyslipidemia, do. Treatment of hyperlipidemia is mediated by medication along with improving lifestyle through exercise control and exercise and maintaining proper weight. Statin-based drugs are widely used for drug therapy. HMG-CoA It acts as a reducing enzyme inhibitor and inhibits the synthesis of cholesterol. It also reduces the level of LDL-cholesterol and also the level of triglycerides.

The LDL-cholesterol (LDL-C) plasma concentration ≥ 130 mg / dL, HDL-cholesterol (HDL-C) ) Blood concentration <60 mg / dL, triglyceride blood concentration ≥ 150 mg / dL, total cholesterol concentration> 200 mg / dL). The diagnostic criteria for dyslipidemia include the risk of dyslipidemia to be treated according to risk factors such as diabetes mellitus, smoking, hypertension, age, and family history of early coronary artery disease in the high risk group, high risk group, moderate risk group , And low-risk groups, and set therapeutic targets accordingly.

The cardiovascular disease may be accompanied by diabetes. The cardiovascular disease associated with diabetes is one of the symptoms of diabetes that occurs simultaneously with diabetes, diabetes as the primary disease, or a condition in which the cardiovascular disease first occurs and subsequently occurs as a sequela or complication of diabetes It says. For example, the diseases include cardiovascular diseases caused by drugs for the treatment of diabetes or diabetes, and may be sequelae or complications due to diabetes. In addition, for example, the disease includes a case in which diabetes further afflicts as one of sequelae or complications that arise after cardiovascular disease.

The term " diabetes mellitus (DM, or diabetes) " refers to a group of metabolic disorders in which high blood sugar levels persist for a long period of time. Diabetes can occur because the pancreas does not produce enough insulin or because the cells in the body do not respond appropriately to the insulin produced. Acute complications associated with diabetes include diabetic ketoacidosis, hyperglycemic hyperammonic non-ketotic coma, and the like. Serious long-term complications associated with diabetes include cardiovascular disease, stroke, chronic renal failure, diabetic ulcers, and diabetic retinopathy.

The term " glucose toxicity or glucotoxicity " refers to a phenomenon in which body cells that make and use insulin are damaged due to high blood glucose levels. Sugar toxicity resulting from prolonged hyperglycemia induces tissue-dependent insulin resistance and exacerbates cardiovascular disease, referred to as nephropathy, retinopathy, dyslipidemia, hypertension, hypertriglyceridemia, obesity, and metabolic syndrome, It can cause secondary complications. Heart disease caused by diabetes can be caused by sugar toxicity.

The term " insulin resistance " (IR) refers to the ability of cells to burn glucose effectively because of the insulin's ability to lower blood sugar. If insulin resistance is high, the body can produce too much insulin, which can lead to hypertension, hyperlipidemia, and diabetes. For example, type 2 diabetes does not notice the increase in insulin in muscle and adipose tissue, so insulin action does not occur. This insulin resistance is a pathophysiological phenomenon common to Type 2 diabetes and unexplained essential hypertension. In patients with high plasma insulin levels, the probability of developing hypertension is significantly increased compared to those with low insulin levels And long-term insulin therapy may increase the risk of hypertension. Heart disease due to diabetes can occur due to insulin resistance.

Several mechanisms have been suggested as to how insulin resistance in diabetics increases blood pressure. For example, insulin produces nitric oxide (NO), a blood vessel relaxation substance, through the nitric oxide pathway, which relaxes blood vessels. By resistance to this insulin response, the blood vessel relaxes well The blood pressure may increase. In addition, blood pressure increases due to sympathetic stimulation effect, high vascular smooth muscle hypertrophy, sodium and fluid retention due to high insulin concentration in the blood. Hyperglycemia in diabetic patients stimulates the renin-angiotensin system (RAS) and contributes to increased blood pressure. In addition, insulin is associated with increased secretion of endothelin-1 and plasminogen activator inhibitor-1 (PAI-1), increased production of reactive oxygen species, nuclear factor kappa B B: NF-κB) inhibition, platelet aggregation inhibition, and the like, are known to affect blood pressure directly or indirectly. In addition, insulin resistance and hyperinsulinemia promote atherosclerosis and thus, secondary blood pressure may be involved.

The cardiovascular diseases with diabetes include those suffering from diabetes due to sequelae or complications of cardiovascular diseases due to direct or indirect causes due to abnormality, dysfunction or damage of the circulatory system in vivo.

In addition, the cardiovascular disease accompanied by the above-mentioned diabetes may be a cardiovascular disease caused by &quot; diabetes &quot;, &quot; sugar toxicity &quot;, or &quot; insulin resistance &quot;, or an endocrine disorder caused by a cardiovascular disease . The cardiovascular disease with diabetes may be, for example, hypertension, dyslipidemia (hyperlipidemia), angina pectoris, arterial spasm, heart arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure or myocardial infarction. The cardiovascular disease with diabetes can be clinically distinguished from a disease that is not accompanied by diabetes alone and pathophysiologically. In one embodiment, the cardiovascular disease with diabetes may exhibit different drug responses when the same amount of the same drug as the cardiovascular disease without diabetes is administered, for example, in a non-diabetic patient group, In the case of diabetic patients, it may be a failure of treatment not controlled by normal blood pressure or normal lipidemia.

In one embodiment, the cardiovascular disease with diabetes is selected from the group consisting of hypertension, dyslipidemia, angina pectoris, arterial spasm, heart arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction, Can be referred to. According to one embodiment, the cardiovascular disease accompanying diabetes may be a disease in which hypertension and dyslipidemia together with diabetes occur simultaneously.

In one embodiment, the cardiovascular disease associated with diabetes,

(1) fasting plasma glucose ≥ 126 ㎎ / dL for more than 8 hours,

(2) a symptom of at least one of the following: diarrhea, obesity, next, hunger, and unexplained weight loss, and at the same time a plasma glucose of ≥ 200 mg / dL,

(3) Plasma blood glucose ≥ 200 ㎎ / dL after 2 hours according to 75 g oral glucose tolerance test, and

(4) Hemoglobin A1c (HbA1c) ≥ 6.5%

, And at the same time

(a) Left systolic blood pressure (sitSBP) ≥ 140 mmHg,

(b) Left-sided diastolic blood pressure (sitDBP) ≥ 90 mmHg,

(c) LDL-cholesterol (LDL-C) blood levels ≥ 130 mg / dL,

(d) HDL-cholesterol (HDL-C) plasma concentration <60 mg / dL,

(e) Triglyceride blood concentration ≥ 150 mg / dL, and

(f) Total cholesterol concentration> 200 mg / dL

Or a disease that satisfies any one or more of the following conditions.

The above (a) to (f) may be modified in accordance with the revision of the guidelines for the diagnosis of hypertension or dyslipidemia.

Fasting plasma glucose (FPG) for 8 hours or more in the above (1) refers to the blood glucose level measured in the fasting state at least 8 hours after the meal.

The diarrhea, obesity, next hunger, and unexplained (unexplained) weight loss of (2) above refer to one of the typical symptoms of diabetes. These symptoms can also be caused by fatigue, blurred vision, and slow wound healing. Random plasma glucose refers to the blood glucose level measured regardless of the last meal time.

The oral glucose tolerance test (OGTT) described in (3) above was fasted for at least 8 hours before the test, and blood glucose was measured at 2 hours after ingesting 75 g of glucose solution in the fasted state .

The glycated hemoglobin (HbA1c) of the above (4) is a value indicating the concentration of glycated hemoglobin which is caused by the reaction of glucose with the hemoglobin in the blood of the patient, and is a measure of the average blood glucose level of 3 months. In 2010, the American Diabetes Association (ADA) adopted more than 6.5% of glycated hemoglobin as a diagnostic criteria for diabetes. The method of marking glycosylated hemoglobin can be roughly classified into standardization through NGSP comparison method in the United States and standardization through IFCC reference method in Europe. The NGSP method separates Hb into individual subtypes (HbA1a, HbA1b, and HbA1c) by chromatography and expresses HbA1c in%. The IFCC method measures HbA1c in which the sugar is bound to valine at the N-terminal of Hb and is expressed in mmol / mol. For example, 6.5% of glycated hemoglobin by the NGSP method corresponds to 48 mmol / mol of glycated hemoglobin by the IFCC method. The above items (1) to (4) may be changed in accordance with the revision of the guidelines on diabetes diagnosis.

For example, in the case of diabetic patients, the pharmaceutical composition according to one embodiment corresponds to the risk category C, so that the concentration of low density lipoprotein cholesterol (LDL-C) in the blood is not less than 100 mg / dL, not more than 250 mg / dL, and may be administered to a diabetic patient having a blood triglyceride concentration of less than 400 mg / dL.

The diabetes can be classified into type 1 diabetes, type 2 diabetes, and gestational diabetes. "Diabetes mellitus type 1, type 1 diabetes (T1DM)" is caused by insufficient insulin production, and "insulin-dependent diabetes mellitus (IDDM or juvenile diabetes)" or " "And the specific cause of this is unknown. &Quot; Diabetes mellitus type 2, type 2 diabetes (T2DM) " starts with insulin resistance that cells do not adequately respond to insulin, insulin deficiency may develop as the disease progresses, and " Non-insulin dependent diabetes mellitus (NIDDM) " or " adult diabetes ". It is known to be predominantly caused by excessive weight and insufficient exercise. Pregnancy Diabetes is the third type and occurs when a pregnant woman without a history of diabetes develops to hyperglycemia. Hypertension may be a risk factor for nephropathy in diabetic patients. The longer the duration of diabetes, the greater the risk of developing hypertension. In a cardiovascular disease associated with diabetes according to one embodiment, diabetes may be type 2 diabetes.

Such diabetes may increase the risk of accompanying cardiovascular diseases such as hypertension, dyslipidemia, angina pectoris, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction, or other metabolic diseases in patients suffering from diabetes. In addition, the risk of accompanying diabetes or other metabolic diseases may increase in patients with the cardiovascular disease.

The cardiovascular disease accompanying diabetes may be a disease in which one or more of cardiovascular diseases selected from hypertension and dyslipidemia and diabetes are simultaneously suffered. In one embodiment, the cardiovascular disease associated with diabetes may be hypertension or dyslipidemia with diabetes. In one embodiment, the cardiovascular disease associated with diabetes may be " diabetic hypertension " or " diabetic dyslipidemia ".

Diabetes can alter cardiovascular or cardiac function and structure independently of normal hypertension. The term " diabetic hypertension " refers to hypertension accompanied by diabetes mellitus, including hypertension and diabetes at the time of drug treatment, or diabetes earlier than hypertension or diabetes later than hypertension. The mechanism by which hypertension occurs or changes in diabetic hypertension due to diabetes may be due to, for example, insulin resistance. Insulin resistance causes loss of insulin-induced vasodilatation, increased sodium and water in the body due to hyperinsulinemia, and activation of the sympathetic nervous system. In addition, increased diabetes mellitus due to lowered renal function may cause increased blood pressure. Diabetes increases atherosclerosis in the large blood vessels or coronary arteries, which can lead to abnormal physiological conditions and may reduce drug sensitivity. This can lead to new hypertension, exacerbation of symptoms of hypertension, or impaired drug treatment effects on existing hypertensive drugs.

Previous studies on diabetic hypertension have shown that the ACE inhibitors perindopril and the thiazide-based diuretic, indapamide, reduce mortality and the incidence of macrovascular and microvascular disease . However, the ACE inhibitor is contraindicated in patients with angioedema and bilateral renal artery stenosis. It is a contraindication to decrease glomerular filtration rate (GFR) of 30% or more, increase creatinine, decrease or stop the hyperkalemia, Care must be taken because it should be monitored periodically. In addition, high doses of thiazide diuretics may result in elevated blood glucose levels, inhibiting insulin secretion, increasing insulin resistance, and worsening blood glucose control.

A pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof according to one embodiment inhibits hypertension progression, inhibits microvascular / macrovascular complications in diabetic patients, protects the cardiovascular system, inhibits diabetic nephropathy It inhibits deterioration of renal function in patients, dilates peripheral blood vessels, and increases blood flow to improve insulin sensitivity. Also, a pharmaceutical composition comprising losartan or a pharmaceutically acceptable salt thereof according to one embodiment dilates peripheral blood vessels and increases blood flow to improve insulin sensitivity.

The term " diabetic dyslipidemia " refers to dyslipidemia which occurs as a complication of diabetes. The diabetic dyslipidemia may be due to insulin resistance due to diabetes. Insulin resistance is often associated with dyslipidemia and its mechanism is unclear, but its association with lipoprotein metabolism is well known. Or, for example, hypertriglyceridemia observed in relatively well-controlled type 2 diabetes can be attributed to an increase in the concentration of free fatty acids in the portal vein as a result of intraperitoneal fat accumulation, which is considered to be one of the causes of diabetes mellitus. Liver free fatty acids are esterified in the liver to become triglycerides and increase the production of very low density lipoproteins. In patients with poorly controlled diabetes, hyperlipidemia (LDL-cholesterol) is commonly seen in addition to very low-density lipoprotein (LDL) cholesterol. In this case, Low-density lipoprotein cholesterol also decreases.

The characteristics of the above-mentioned diabetic dyslipidemia can be summarized as 1) increase of blood triglyceride, 2) decrease of HDL cholesterol, and 3) chemical denaturation of LDL. Specifically, 1) hypertriglyceridemia is common in diabetes, which may be the result of over-production of VLDL-triglyceride (VLDL-TG) in liver and decreased elimination in peripheral tissues. In diabetes, insulin deficiency or insulin resistance increases the release of free fatty acids in adipose tissue, leading to an increase in free fatty acid inflow into the liver, thereby increasing the synthesis of VLDL in the liver. On the other hand, in lipid tissues and muscles, the activity of lipoprotein lipase, which is involved in the degradation of VLDL-TG, is decreased due to insulin deficiency and insulin resistance, and the elimination of VLDL-TG is decreased, thereby increasing blood triglyceride. In addition, the diabetes mellitus often has a decreased HDL concentration, especially a decrease in HDL2, and its precise mechanism is unknown. The current mechanism is presumably due to the decrease of lipoprotein lipase activity, the possibility that VLDL and kilo-micron metabolic disturbance may occur, resulting in the failure of conversion of HDL3 to HDL2, and the increase of liver lipase activity involved in metabolizing HDL And an increase in one HDL metabolism. 3) There is no definite conclusion regarding the increase of LDL concentration in diabetic patients. However, it has been reported that there is a change in the composition of LDL in relation to the occurrence of atherosclerosis. These include oxidation of LDL due to glycation of LDL and reduction of antioxidant capacity in the blood due to hyperglycemia.

Traditional methods of drug therapy for dyslipidemia include niacin, nicotinic acid, fibrates, and estrogen. Niacin is a drug that inhibits lipolysis in adipose tissue, but its duration of action is so short that it can cause a rebound increase in free fatty acids and hyperglycemia, limiting its use in the treatment of diabetic hyperlipemia. Nicotinic acid preparations are often selected when the action time is long, the lipolytic action is stronger, the reaction of free fatty acids increases, and the side effects of hyperglycemia are low, especially when TG is increased. However, side effects such as severe redness may occur. Fibrate derivatives may be the first choice if triglycerides alone or in combination with triglycerides and cholesterol are present, but in 2005 the CHMP Substance Monitoring Subcommittee reassessed that there was insufficient evidence for long-term cardiovascular risk As a result, they concluded that the fibrate derivative is not the first choice for the treatment of dyslipidemia. A pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof according to one embodiment comprises a high intensity statin drug and is useful for the treatment and / or prophylaxis of atherosclerotic cardiovascular diseases, cardiovascular diseases with diabetes The blood pressure and lipid concentration control effect is excellent.

The pharmaceutical composition according to one embodiment is a pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmacologically acceptable salt thereof as a customized therapeutic agent for diabetic patients in a cardiovascular disease accompanied by such diabetes mellitus 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salts.

&Quot; amlodipine " refers to an amlodipine of the 3-ethyl 5-methyl 2 - [(2- aminoethoxy) methyl] -4- (2- chlorophenyl) -6- 5-dicarboxylate], which is a calcium channel blocker, induces diuretic action by relaxing the calcium ion channel on the myocardial and vascular smooth muscle surface by relaxing the vascular smooth muscle and relaxing the imported arterioles of the kidney to increase the glomerular filtration rate Indicating a blood pressure lowering effect. In particular, amlodipine is a third-generation CCB that is slowly absorbed when administered orally and has a long half-life of about 35 to 40 hours, exhibiting a gentle blood pressure lowering effect for a long period of time and alleviating side effects such as orthostatic hypotension and preventing systolic hypertension and stroke It is effective and useful for angina due to coronary artery dilation.

&Quot; losartan " refers to 2-butyl-4-chloro-l - [{2 '-( lH-tetrazol-5-yl) It has been developed for the first time among the angiotensin receptor antagonist components and it has antihypertensive effect by selectively and competitively antagonizing the receptor of angiotensin II which is a strong vasoconstrictor, , Ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), or to prevent progression of heart failure after myocardial infarction.

 &Quot; Rosuvastatin " refers to the compound [(E) -7- [4- (4- fluorophenyl) -6-isopropyl- 2- [methyl (methylsulfonyl) amino] pyrimidin- - (3R, 5S) -3,5-dihydroxyhept-6-enoic acid], acting as an HMG-CoA reductase inhibitor as a statin drug, inhibits the synthesis of cholesterol in the liver , Increases the number of low density lipoprotein (LDL) receptors on the surface of hepatocytes, and lowers plasma cholesterol and lipoprotein levels by promoting uptake and degradation of LDL. It also reduces the LDL production and the number of LDL particles, while at the same time it alters the quality of the circulating LDL particles in a beneficial direction. In addition to treatment of hypercholesterolemia, hyperlipoproteinemia or atherosclerosis, cardiovascular diseases such as stroke, myocardial infarction . &Lt; / RTI &gt;

The pharmaceutical composition according to one embodiment of the present invention is excellent in blood pressure control and lipid-improving effects especially in diabetic patients, and particularly has superior effect of lowering systolic blood pressure and improving lipid in diabetic patients. The excellent blood pressure lowering and lipid-lowering effects in the diabetic patients compared to the non-diabetic patients using the pharmaceutical composition including amlodipine, rosatane, and rosuvastatin are not predicted in the technical field of the conventional therapeutic agents for hypertension or dyslipidemia It is a new effect that did not succeed.

In one embodiment, the composition comprising amlodipine, rozatan, and rosuvastatin exhibits a 1.4-fold reduction in mean systolic blood pressure (mean sit SBP) in the diabetic group relative to the non-diabetic group when observed 8 weeks after administration, ) (Test Example 1). From this, it was confirmed that the composition comprising amlodipine, rozatan and rosuvastatin effectively reduced the mean systolic blood pressure in diabetic patients.

In one embodiment, the composition comprising amlodipine, rosatane, and rosuvastatin exhibits a reduction in mean sitting diastolic blood pressure (mean sit DBP) of about 1.2 times (about 1.18 fold) in diabetic patients compared to non- ) (Test Example 2). From these results, it was confirmed that the composition containing amlodipine, rosatan and rosuvastatin effectively reduced the mean left diastolic blood pressure in diabetic patients.

In one embodiment, the composition comprising amlodipine, rozatan, and rosuvastatin is administered in combination with amlodipine and rozatan only when observed 8 weeks after administration, or when the composition contains only rosigandan and rosuvastatin alone, TG) was effectively reduced (Test Example 3 (1) (2)).

In one embodiment, the composition comprising amlodipine, rozatan and rosuvastatin has increased modulation of triglyceride (TG) in the diabetic group, especially when observed 8 weeks after administration. Specifically, when the administration of rosatan and rosuvastatin was compared with the administration of amlodipine, rozatan and rosuvastatin, the addition of amlodipine to non-diabetic patients However, TG was not well controlled by the addition of amlodipine, rather than the reduction of triglyceride (TG), but rather the administration of roszatan and rosuvastatin alone. In comparison, administration of the above composition containing amlodipine, rozatan and rosuvastatin in the diabetic patients showed that the reduction rate of triglyceride (TG) was about 1.9 times higher than that of rosigastone and rosuvastatin alone (About 1.93 times). From this, it was confirmed that administration of a composition containing amlodipine, rozatan, and rosuvastatin in the diabetic patient group increased triglyceride (TG) reduction rate, thereby increasing the effect of TG regulation (Test Example 3 (3)).

In one embodiment, the composition comprising amlodipine, rozatan, and rosuvastatin is administered at a rate of 4 to 8 weeks after administration of amlodipine and rosigadmin alone, or a blood pressure normalization rate that is higher than when rosigadin and rosuvastatin alone are administered (Test Example 4 (1)). In addition, the above compositions comprising amlodipine, rozatan and rosuvastatin showed high blood pressure normalization rates for cardiovascular risk group C and excellent blood pressure normalization rates in both cardiovascular risk groups A, B, and C (Test Example 4 (2)). In addition, the composition comprising amlodipine, rozatan and rosuvastatin showed a higher blood pressure normalization rate than either amlodipine and rozatan alone or rosigandan plus rosuvastatin alone in patients with diabetes (test Example 4 (3)). From these results, it was confirmed that the composition containing amlodipine, rosatan, and rosuvastatin showed excellent blood pressure normalization rate and showed a high blood pressure normalization rate even in patients with diabetes.

In one embodiment, the composition comprising amlodipine, rozatan, and rosuvastatin is administered at a 4 or 8 week time period after administration of amlodipine and rosatane alone, or a combination of low-density lipoprotein Cholesterol (LDL-C) therapeutic goal and blood pressure normalization rate (Test Example 5 (1)). In addition, the above composition comprising amlodipine, rozatan and rosuvastatin showed a higher LDL-C therapeutic achievement rate than patients receiving both amlodipine and rosatan alone or rosatan and rosuvastatin alone in diabetic patients Blood pressure normalization rate (Test Example 5 (2)). From these results, it was confirmed that the composition comprising amlodipine, rosatane and rosuvastatin showed excellent achievement rate of LDL-C and blood pressure normalization rate, and showed high goal achievement rate and blood pressure normalization rate even in patients with diabetes.

In one embodiment, the pharmaceutical composition may be used in the prevention or treatment of diseases in which hypertension and dyslipidemia together with diabetes are simultaneously present. The pharmaceutical composition may be a composition for preventing or treating diabetic hypertension or diabetic dyslipidemia. In one embodiment, the pharmaceutical composition may be a composition for preventing or treating diabetic hypertension.

According to the Guideline for Hypertension Therapeutics, the efficacy of hypertension treatment is generally evaluated as the primary endpoint of changes in post-treatment systolic blood pressure before and after treatment, and the change in post-treatment diastolic blood pressure Secondary evaluation items are evaluated. In addition, the degree of hypertension treatment response was defined as the normalization rate of blood pressure (systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg after completion of treatment) and blood pressure response rate (systolic blood pressure 20 mmHg or more relative to baseline and diastolic blood pressure 10 mmHg (Food and Drug Administration, Food and Drug Safety Assessment, 2015.12).

In one embodiment, the pharmaceutical composition may be about 1.3 times more, for example, about 1.36 times more, or about 1.4 times more, the left systolic blood pressure than in cardiovascular diseases not accompanied by diabetes. The pharmaceutical composition is about 1.3 times or more, such as about 1.36 times or more, or about 1.4 times or more, such as about 1.3 times, 1.36 times, about 1.4 times, about 1.45 times, or about 1.3 times as long as the non- Or about 1.5 times the left systolic blood pressure. In one embodiment, the amount of the left ventricular systolic blood pressure change in the diabetic patient group relative to the non-diabetic patient group of the pharmaceutical composition is about 1.3 times or more, about 1.2 times to 2.5 times, about 1.3 times or 2.5 times, About 1.35 times or more and 1.5 times or less, or about 1.3 times or more and 1.5 times or less.

In one embodiment, the pharmaceutical composition may be a pharmaceutical composition for lowering left ventricular systolic pressure in a diabetic patient.

In one embodiment, the amount of decrease in left systolic blood pressure (mean +/- SD) of the pharmaceutical composition is 20.48 +/- 17.95 mmHg in the diabetic group and 15.04 +/- 10.86 mmHg in the non-diabetic group after 8 weeks of administration of the drug compared to the basal value. In one embodiment, the maximum value of the decrease in the left systolic blood pressure after 8 weeks of administration of the drug compared to the base value may be 52.00 mmHg and 38.30 mmHg in the diabetic and non-diabetic patients, respectively.

In one embodiment, the pharmaceutical composition may be to reduce the left ventricular diastolic blood pressure by about 1.2 times or more, such as about 1.10 times or more, or about 1.18 times more than in a cardiovascular disease not accompanied by diabetes. The pharmaceutical composition may be administered in an amount of about 1.2 times or more, for example, about 1.10 times, or about 1.18 times or more, for example, about 1.10 times, 1.15 times, or about 1.20 times as much as the diastolic blood pressure Can be greatly reduced.

In one embodiment, the pharmaceutical composition may be a composition for preventing or treating diabetic hypertension and diabetic dyslipidemia. In another embodiment, the pharmaceutical composition may be a composition for preventing or treating diabetic hypertension.

A cardiovascular disease that can be prevented or treated by the pharmaceutical composition may be one that meets one or more of the following criteria. The following criteria may be altered by revising guidelines for the diagnosis of hypertension or dyslipidemia (JCCP Guideline and JNC 8 Report, J Lipid Atheroscler 2015; 4 (1): 61-92).

(a) Left systolic blood pressure (sitSBP) ≥ 140 mmHg

(b) Left-sided diastolic blood pressure (sitDBP) ≥ 90 mmHg

(c) LDL-cholesterol (LDL-C) Blood concentration ≥ 130 mg / dL

(d) HDL-cholesterol (HDL-C) blood levels <60 mg / dL

(e) Triglyceride blood concentration ≥ 150 mg / dL

(f) Total cholesterol concentration> 200 mg / dL

According to the Clinical Practice Guidelines, normal blood glucose is less than 100 mg / dL in fasting plasma glucose, less than 140 mg / dL in plasma glucose 2 hours after 75 g oral glucose tolerance, fasting plasma glucose is 100 to 125 mg / dL in fasting plasma glucose, Is a plasma glucose of 140-199 mg / dL 2 hours after oral administration of 75 g.

The subject group to which the pharmaceutical composition exhibits blood pressure control and lipid-improving effects may be a diabetic patient group, and may be, for example, an individual exhibiting one or more of the following conditions. In addition, the following criteria may be met according to recognized diabetes diagnostic criteria in the art to which the invention pertains, for example the American Diabetes Association (ADA) 2016 guidelines, and amendments to these guidelines Can be changed accordingly.

(1) 8 hours or more fasting plasma glucose ≥ 126 ㎎ / dL

(2) a symptom of at least one of diarrhea, obesity, next, hunger and unexplained weight loss, and at the same time a plasma glucose level of ≥ 200 mg / dL

(3) 75 g 2 hours after oral glucose tolerance test Plasma glucose ≥ 200 ㎎ / dL

(4) Hemoglobin A1c (HbA1c) ≥ 6.5%

In one embodiment, the amlodipine or pharmaceutically acceptable salt thereof in the total amount of the pharmaceutical composition is from 5 mg to 10 mg when converted to amlodipine free base form, and losartan or a pharmaceutically acceptable salt thereof is in the form of losartan free acid And 45 mg to 100 mg when converted, and rosuvastatin or a pharmaceutically acceptable salt thereof may be 5 mg to 20 mg when converted to the rosuvastatin free acid form. In one embodiment, the pharmaceutical composition may be for administration once a day.

In one embodiment, the amlodipine or pharmaceutically acceptable salt thereof in the pharmaceutical composition may be 5 to 10 mg, for example 5 mg, as amlodipine. The losartan or pharmaceutically acceptable salt thereof in the composition may be from 45 to 100 mg, for example, 50 mg or 100 mg as losartan. Rosuvastatin or a pharmaceutically acceptable salt thereof in the composition may be 5-20 mg, for example 5 mg, 10 mg or 20 mg as rosuvastatin. The dose can be appropriately adjusted in consideration of symptoms, age, race, and sex.

In another embodiment, the pharmaceutical composition comprises amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof in a ratio of 1:10 to 20: 1 to 4 Range. &Lt; / RTI &gt;

In one embodiment, the pharmaceutical composition comprises a fixed dose combination formulation comprising amlodipine of the aforementioned amount or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, (fixed-dose combination formulation).

In one embodiment, the pharmaceutical composition may be administered once to several times a day, for example once or three times, depending on the dose, preferably 5 mg amlodipine, 100 mg roza tan and 20 mg rosuvastatin May be administered once a day.

The pharmaceutical composition comprising 5 mg of amlodipine, 100 mg of rosatane, and 20 mg of rosuvastatin is administered once a day to keep patient convenience and adherence to medication constant, and to provide an optimal pharmacological clinical Effect can be provided.

In one embodiment, the pharmaceutical composition may be administered for 4 weeks or 8 weeks, or more, or less, taking into consideration the pathological condition of the subject to be treated and the severity thereof. The pharmaceutical composition comprises, when administered in the same composition and amount, for example, amlodipine or a pharmaceutically acceptable salt thereof in an amount of 5 mg in terms of amlodipine free base form, and the losartan or a pharmaceutically acceptable salt thereof, In terms of the free acid form, in an amount of 100 mg, and the daily dosage of rosuvastatin or a pharmaceutically acceptable salt thereof in terms of rosuvastatin free acid in an amount of 20 mg , It is possible to further reduce left ventricular systolic blood pressure in patients with diabetes compared with non-diabetic patients.

Pharmaceutically acceptable salts of amlodipine, rozatan, or rosuvastatin in such pharmaceutical compositions refer to salts prepared according to methods conventional in the art, and such methods of preparation are well known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene- Sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, besylic acid, camsylic acid and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as calcium and magnesium.

The pharmaceutically acceptable salt of amlodipine is formed from an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, a hydrochloride, a hydrobromide, a sulfate, a phosphate, an acetate, a maleate , Fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate, but are not limited thereto. Preferably, for example, amlodipine besylate salt or camsylate salt can be used. In addition, the amlodipine includes amlodipine racemate and (S) -amlodipine. The pharmaceutically acceptable salt of losartan is preferably, for example, potassium losartan, but not limited thereto. Examples of pharmaceutically acceptable salts of rosuvastatin include rosuvastatin calcium salt and rosuvastatin magnesium salt, but the present invention is not limited thereto.

In one embodiment, the pharmaceutical composition may include amlodipine camsylate, losartan potassium, and rosuvastatin calcium.

In one embodiment, the amlodipine or a pharmaceutically acceptable salt thereof, rosetan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, may be administered simultaneously or sequentially.

In one embodiment, the amlodipine or a pharmaceutically acceptable salt thereof, losartan, or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, may be administered in one single formulation, &Lt; / RTI &gt; The amlodipine or a pharmaceutically acceptable salt thereof, roza tan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof may be present in a single dosage form, . The single dose or individual dosage forms may be in the form of tablets or capsules. For example, they may be administered by different routes when they are administered in the form of individual doses. If the administration of the active ingredient is sequential or separate, the delay in administering the second ingredient should preferably not impair the beneficial effects of, for example, combination therapy. In this context, sequential administration may also (but not be limited to) include, for example, alternating administration of the active ingredient.

The dosage of the pharmaceutical composition according to one embodiment may vary depending on the age, sex, body weight, pathological condition and severity of the subject to be treated, route of administration, or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of those skilled in the art.

The pharmaceutical composition may be in the form of a sterile aqueous or oily solution or suspension for oral administration such as tablets, capsules, aqueous or oily suspensions, ointments or dispersible powders or granules, parenteral administration such as intravenous, subcutaneous, , A form suitable for topical use such as a cream, a gel or ointment, or a suppository for rectal administration. In one embodiment, the composition is in a form suitable for oral administration, for example, as a tablet or capsule.

In one embodiment, the pharmaceutical composition comprises at least one other cardiovascular disease prevention or treatment selected from a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and an HMG-CoA reductase inhibitor And may further comprise a pharmaceutical agent. The one or more other medicines for the prevention or treatment of cardiovascular diseases may be administered in combination with the above pharmaceutical composition.

The calcium channel blockers may include, for example, nifedipine, felodipine, verapamil, and the like in addition to amlodipine. The angiotensin receptor antagonist (ARB) may include, for example, telmisartan, valsartan, candesartan, ivesartan, olmesartan and the like in addition to rosantan. The HMG-CoA reductase inhibitor may include, for example, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin and the like in addition to rosuvastatin. The pharmaceutical composition may further include a thiazide-based diuretic agent such as a diuretic agent, for example, hydrochlorothiazide, chlorothiazide, chlortalidone, indapamide, metolazone, polythiazide, For example, a combination therapy using two or more drugs in the treatment of hypertension may be employed to enhance the blood pressure lowering effect, and at the same time to reduce complementary side effects of each drug. For example, the combination of calcium channel blocker (CCB) and angiotensin II receptor blocker (ARB) can be expected to have both vasodilatation and body fluid control.

Another aspect is the use of a medicament for the prevention or prophylaxis of cardiovascular disease in diabetic patients with diabetes mellitus comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, Thereby providing a combined preparation for treatment.

The combined preparation according to this aspect may be useful for the treatment of patients with hypertension and dyslipidemia. These hypertension and dyslipidemia are the single risk factors of cardiovascular disease, respectively, and treating two diseases at the same time has a great clinical effect. The combination preparation also improves the ease of administration and compliance of patients who are to be administered concurrently with amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof. And the drug cost can be reduced. In particular, considering the fact that most of the patients with the disease are elderly patients after middle age, and many of them are taking the drugs at the same time, the effect of increasing the compliance of the medicines is more remarkable when the combination preparation is administered.

The dose of amlodipine or a pharmaceutically acceptable salt thereof, rosetan or a pharmaceutically acceptable salt thereof, or rosuvastatin or a pharmaceutically acceptable salt thereof contained in the combination preparation is as mentioned in the pharmaceutical composition.

In one embodiment, the combination preparation comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount of 5 to 10 mg, and comprises losartan or a pharmaceutically acceptable salt thereof in an amount of 50 to 100 mg, Statin or a pharmaceutically acceptable salt thereof in an amount of 5 to 20 mg. For example, the combined preparation may contain the three active ingredients in amounts of 5 mg, 50 mg, and 5 mg, respectively; 5 mg, 50 mg, 10 mg; 5 mg, 50 mg, 20 mg; 5 mg, 100 mg, 5 mg; 5 mg, 100 mg, 10 mg; Or 5 mg, 100 mg, 20 mg. In one embodiment, the combined preparation may be in the form of a tablet, a capsule, or a caplet. The combination preparation may be in a bilayer or a three-layered form.

The combination preparation comprises, for example, amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixing portion, wherein the rosatan or its pharmaceutically acceptable salt Wherein the first mixing portion and the second mixing portion are physically separated from each other. For example, each of the first mixing portion and the second mixing portion may further include a pharmaceutically acceptable additive.

In addition, the combined preparation may contain, for example, amlodipine or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof in the first layer, wherein the rosatan or a pharmaceutically acceptable salt thereof As shown in FIG. For example, each of the first layer and the second layer may further include a pharmaceutically acceptable additive.

A pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof according to the above embodiment, or a combination preparation comprising the same, And dyslipidemia were excellent.

In the clinical trial, patients who received amlodipine 5 mg, rosatan 100 mg, and rosuvastatin 20 mg (A5 + L100 + R20) were more than 8 weeks old with lipidemia (LDL-C, total cholesterol, HDL (Average rate of change in triglyceride, triglyceride, rate of NCEP ATP III LDL-C) and hypertension (mean sitDBP, sitSBP change, JNC VII blood pressure normalization rate) were superior to those in diabetic patients, Regulatory and lipid-improving effects, and the effect of reducing left ventricular systolic blood pressure was excellent.

Another aspect is the use of a composition comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof to treat a cardiovascular disease with diabetes mellitus . &Lt; / RTI &gt;

In one embodiment, the amlodipine or a pharmaceutically acceptable salt thereof, rosatane, or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, contained in the composition, is in a form suitable for the treatment or prophylaxis of the individual or patient And can be administered by various administration methods, whether oral or parenteral, depending on the purpose. The administration method should be determined in consideration of various related factors such as the patient's body weight, age, race, sex, health condition, diet, administration time, administration method, disease severity, etc., And the dose is not intended to limit the scope of the invention in any way. Physicians having ordinary skill in the relevant art can readily determine and prescribe dosages of the compounds used as needed. For example, a physician may start the dose of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved .

As used herein, the term " treatment " is used as a concept that includes treatment, improvement, amelioration or management of disease. The term " treating " or &quot; treating &quot; as used herein refers to inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or expressing a pathology or symptom of the disease, condition, And / or preventing further development of the symptoms, ameliorating the disease, or reversing the pathology and / or symptoms, such as reducing the severity of the disease.

As used herein, the term " preventing " or " prevention " refers to the prevention of a disease, for example a disease, condition or disorder in a subject that may be predisposed to the disease, To prevent a condition or disorder.

The term "individual" or "patient" as used herein refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and humans .

The use of the terms "having," "having," "including," or "including may refer to the presence of a feature (eg, a component such as a numerical value or a component) And does not exclude the presence of additional features.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

[Example]

Example 1: Selection of test subjects and administration of clinical test drugs

1. Selection of subjects

The subjects were selected based on the following selection criteria.

1) Adults aged 19 to 75 years

2) Patients who meet the following conditions at the screening of the first visit

① blood pressure standard: sitDBP ≥ 90 mmHg

② Lipid criteria: LDL-C ≤ 250 mg / dL, TG <400 mg / dL

3) After 4 weeks of treatment lifestyle change (TLC), patients who meet the following conditions at the second visit

① blood pressure standard: 80 mmHg ≤ sitDBP <110 mmHg

② Lipid criteria: When classified as A, B, C according to the risk of cardiovascular disease, patients with the following conditions

Coronary heart disease (CHD) Risk factor (CHD)

1) Current smoker

2) taking blood pressure medicine

3) Low HDL-C (<40 mg / dL) ^†

4) Early coronary heart disease Family history: Parents, siblings, and siblings Men with coronary artery disease under 55 years of age or under 65 years of age

5) Age (male 45 years old or older; female 55 years old or older)

^{† In the} case of HDL-C ≥ 60 mg / dL, one should be deducted from the total number of risk factors by considering it as a protective factor.

^* CHD equivalent risk factors

Coronary artery disease, diabetes mellitus (HbA1c ≥ 6.5%, but diabetes mellitus, regardless of HbA1c criteria), or other clinical forms of atherosclerosis (eg, peripheral artery Disease, abdominal aortic aneurysm, symptomatic carotid artery disease, etc.)

Specifically, when the risk factors for coronary heart disease (CHD) were 0 to 1, it was classified into group A. In addition, cases with two or more CHD risk factors were classified as group B. In addition, cases with CHD / CHD equivalent risk factors or risk of developing cardiovascular disease within 10 years exceeded 20% were classified as group C. The detailed classification according to LDL-C or TG condition is shown in the above table.

In addition, subjects who were not suitable for clinical trials were excluded from the subjects according to the pre-set criteria.

2. Preparation and preparation of clinical trial medicines

(1) Manufacture of pharmaceutical preparations for testing

Tablets containing amlodipine 5 mg, losartan 100 mg and rosuvastatin 20 mg were prepared as test drugs to be administered to the selected subjects, and the test drugs were prepared.

Specifically, amlodipine camsylate, rosuvastatin calcium, lactose hydrate, microcrystalline cellulose and crospovidone were mixed and sieved, and then magnesium stearate was added and finally mixed in a mixer to prepare a mixture of amlodipine and rosuvastatin. In addition, potassium losartan, microcrystalline cellulose, and crospovidone were mixed and formulated, and the pressure was increased to form granules, followed by addition of magnesium stearate and final mixing to prepare losartan granules. A complex two-layer tablet composed of the above-prepared amlodipine and rosuvastatin mixed portion and rosacean granule portion was prepared.

(2) Preparation of medicines for comparison

As a control drug, 5 mg of Amodipine ^TM (5 mg as amlodipine), 100 mg of Coza ^TM (100.0 mg as losartan), and 20 mg of Crestor ^TM tablet (20 mg as rosuvastatin) were prepared.

3. Assignment of subject

Phase III trials were conducted on the selected subjects based on the following protocol. First, the Therapeutic Lifestyle Change (TLC) was conducted on the subjects at the first visit for 4 weeks. During this TLC period, conventional hypertension treatment and dyslipidemia treatment were wash-out and rosaran monoglyceride monotherapy was performed. After 4 weeks of TLC, blood pressure and fasting serum lipids were checked again at the 2nd visit and randomly assigned to three groups of eligible subjects.

Test group: Tablets containing 5 mg of amlodipine, 100 mg of rosatane and 20 mg of rosuvastatin (A5 + L100 + R20)

Control 1: 5 mg of amlodipine and losartan 100 mg (5 mg tablet Amodipine ^TM and ^TM wishes information 100 mg) (A5 + L100) treated group

Control 2: losartan 20 mg to 100 mg, and rosuvastatin (Crestor ^TM and wishes ^TM tablet 100 mg tablet 20 mg) (+ R20 L100) treated group

A full analysis set (FAS) was administered to subjects who received at least one dose of the clinical trial drug after randomization, and who had undergone the primary efficacy evaluation at least once before the clinical trial was completed. Respectively.

The Per protocol set (PPS) was the subject who completed the clinical trial according to the clinical trial plan among the FAS subjects, and the subjects who were in the protocol deviations were PPS .

The main analytical group FAS of the clinical study included 143 subjects who had not undergone the primary efficacy evaluation after randomization. The subjects were divided into A5 + L100 + R20 group, A5 + L100 group, And 43 patients in the L100 + R20 group. In the FAS, 131 subjects who completed clinical trials according to the clinical trial protocol were included in the PPS. Forty patients in the A5 + L100 + R20 group, 41 patients in the A5 + L100 group and 40 patients in the L100 + R20 group were included in the PPS. The number of subjects excluded from the PPS was 12, and the reasons for exclusion were those who were dropped out, taking medication for concomitant medication, and drug dispensing errors for clinical trials.

There was no significant difference in FAS between the groups except for body weight when the homogeneity between the groups was compared between demographic data such as sex, age, height, weight, smoking ability, and drinking power. In addition, compliance with medication compliance was 95% or more in all groups.

4. Administration of Clinical Trials

Phase III clinical trials were conducted on the selected test subjects by administering the prepared test drug and reference drug according to the protocol. Specifically, in the A5 + L100 + R20 administration group (test group), the above-mentioned test drug (amlodipine 5 mg, rosatan 100 mg and rosuvastatin 20 mg tablets) was administered once a day once a day. A5 + L100 treated group (control group 1) Amodipine ^TM and wishes ^TM define a once a day by 1 tablets administered and, L100 + R20 group (control group 2) wishes to test product ^TM information and Crestor ^TM tablet 20 mg 1 day One dose each was administered once. The clinical trial drug assigned to the test group and the control group was administered for 8 weeks. During the period of administration of the 8 week clinical trial drug, the subjects visited the laboratory every 4 weeks and conducted a safety and efficacy evaluation. In addition, the results of the friability test were analyzed according to the following evaluation criteria.

 5. Evaluation Criteria

(1) Evaluation of effectiveness

In the case of continuous variables among primary and secondary efficacy evaluation variables, the rate of change or the amount of change was calculated as follows.

1) Primary efficacy endpoint

(1) Amlodipine / Losartan / Rosuvastatin (A5 + L100 + R20) group and Amlodipine / Losartan group (A5 + L100) The change in LDL-C of control group 1

② Mean changes in sitDBP of amlodipine / rozatan / rosuvastatin treated group and rosatan / rosuvastatin treated group after 8 weeks compared to baseline

2) Secondary efficacy assessment variables

① Changes in LDL-C of amlodipine / rosatane / rosuvastatin treated group and amlodipine / rozatlan treated group after 4 weeks compared to baseline

② Changes in LDL-C of amlodipine / rosatane / rosuvastatin treated group and rosatan / rosuvastatin treated group after 4 weeks and 8 weeks compared to baseline

③ Changes in TC, HDL-C, and TG of amlodipine / rosatane / rosuvastatin treated group, rosatane / rosuvastatin treated group, amlodipine / rozatan treated group after 4 weeks and 8 weeks compared to baseline

④ Mean change in sitDBP (mmHg) of amlodipine / rozatan / rosuvastatin treated group and rosatan / rosuvastatin treated group after 4 weeks compared to baseline

⑤ Mean changes in sitDBP (mmHg) of amlodipine / rozatan / rosuvastatin treated group and amlodipine / rozatan treated group after 4 weeks and 8 weeks compared to baseline

⑥ Mean sitSBP (mmHg) change of amlodipine / rozatan / rosuvastatin treated group, rozatan / rosuvastatin treated group, amlodipine / rozatan treated group after 4 weeks and 8 weeks compared to baseline

⑦ At 4 weeks and 8 weeks, the LDL-C treatment goal achieved according to the NCEP ATP III guideline of amlodipine / rozatan / rosuvastatin, rosatane / rosuvastatin, and amlodipine /

⑧ After 4 and 8 weeks, blood pressure normalization rate according to JNC VII guideline of amlodipine / rozatan / rosuvastatin treated group, rosatan / rosuvastatin treated group, amlodipine / rozatan treated group

⑨ After 4 weeks and 8 weeks, amlodipine / rosatane / rosuvastatin treated group, rosuvastatin / rosuvastatin treated group, amlodipine / rozatan treated group's LDL-C according to NCEP ATP III guidelines and blood pressure according to JNC VII Guideline Percentage of subjects who reached normalization

(2) Safety evaluation

1) Adverse reaction

2) Signs of vitality

3) Laboratory test (general blood test, serum biochemical test, urinalysis)

4) Physical examination

5) Electrocardiogram (ECG)

6) Hormone test, etc.

 6. Statistical analysis methods and standards

 The results obtained on the basis of the clinical test evaluation standard were statistically analyzed in the following manner. Statistical analysis was carried out according to the 'Intend to Treat Principle' when evaluating the efficacy of clinical trials. Demographic and baseline characteristics were analyzed by FAS, FAS was used as the main analysis group and PPS was used as the secondary analysis group for statistical analysis. For the safety evaluation, statistical analysis was performed on the safety analysis set.

All statistical tests were performed on both sides at a significance level of 5%. The statistical analysis was performed by applying the Last Observation Carried Forward (LOCF) method when missing values were found for the primary and secondary efficacy evaluation variables. The LOCF method was not applied to the safety evaluation variables, Statistical analysis was performed according to the data.

(1) Analysis of effectiveness evaluation

1) Primary efficacy assessment

Covariance analysis (ANCOVA) was performed with covariance corrected LDL-C at baseline for comparison of amlodipine / rosatan / rosuvastatin treated group versus amlodipine / rozatan treated group for the difference in LDL-C change after 8 weeks compared to baseline , And the number of subjects, arithmetic mean, standard deviation, median, minimum, and maximum values for LDL-C at each time point in each treatment group.

In addition, covariance analysis (ANCOVA) was performed with covariance corrected sitDBP at baseline for comparison between amlodipine / rozatan / rosuvastatin treated group and rosatan / rosuvastatin treated group for the difference in sitDBP change after 8 weeks compared to baseline The number of test subjects, arithmetic mean, standard deviation, median, minimum, and maximum values of sitDBP at each time point in each treatment group were presented.

2) Secondary efficacy assessment

After 4 weeks and 8 weeks compared to the baseline values except for the primary efficacy endpoint, the test group, amlodipine / rozatan / rosuvastatin, and LDL-C, TC, HDL-C and TG, The covariance analysis (ANCOVA) was performed with covariance corrected for each efficacy variable at baseline for comparison between rosacain / rosuvastatin treated group and amlodipine / rozatan treated group. In each administration group, Number, arithmetic mean, standard deviation, median, minimum, and maximum.

At 4 and 8 weeks after the administration of the clinical trial drug, the LDL-C therapeutic target achievement rate according to the NCEP ATP III guideline, the blood pressure normalization rate according to the JNC VII guideline, and the LDL-C target rate according to the NCEP ATP III guideline Cochran-Mantel-Haenszel (CMH) test with a cardiovascular risk category as the stratum for the percentage of subjects who achieved and normalized blood pressure according to the JNC VII guideline ) test) was performed to compare the test group and the control group. In addition, Pearson's chi-square test or Fisher's exact test was performed for each cardiovascular risk group and compared between groups.

(2) Safety assessment analysis

1) Adverse reaction

All the investigated adverse events were listed as pre-existing AEs prior to randomization and treatment emergent adverse events (TEAEs). For TEAEs, the number and severity of serious adverse events, causality, and causality with the drug for each trial were presented.

2) Other safety evaluation variables

A shift table was presented for each of the treatment groups for normal, clinically insignificant abnormalities (NCS) and clinically significant abnormalities (CS), and McNemar's test was performed for clinical trials A statistical significance test was performed on changes in each treatment group before and after the administration of medicines. In addition, for continuous variables, the number of subjects, arithmetic mean, standard deviation, median, minimum, and maximum values were presented for each time point.

Test Example 1: Measurement of the decrease (mean mmHg) of the mean systolic blood pressure (mean sitSBP) in the diabetic patients relative to the non-diabetic patients

(A5 + L100) (group A), amlodipine 5 mg and rosarthan 100 mg (group A5 + L100) (control group 1) after 8 weeks of baseline (Mean sit-SBP) change (mmHg) of the left-systolic blood pressure (mean systolic blood pressure) The test group and the control group each include a diabetes mellitus (DM) patient group and a non-diabetes mellitus (non-DM) patient group. The results are shown in Table 1 and Fig.

[Table 1]

As shown in Table 1 and FIG. 1, when the (A5 + L100 + R20) administration group and the (A5 + L100) administration group were compared, the (A5 + L100 + R20) The change in sitSBP (mmHg) was greater. From this, it can be seen that when amlodipine 5 mg, rozatan 100 mg and rosuvastatin 20 mg are administered, the effect of decreasing the mean systolic blood pressure is significantly larger than when 5 mg of amlodipine and 100 mg of rosatin alone are administered.

In addition, these effects were observed in both diabetic (DM) and non-diabetic (DM) patients, and the mean changes in sitSBP (A5 + L100 + R20) mmHg) was significantly increased in patients with diabetes (DM). The effect of 5 mg of amlodipine, 100 mg of rosatane, and 20 mg of rosuvastatin significantly reduced the mean systolic blood pressure of patients with diabetes compared with 5 mg of amlodipine and 100 mg of rosatin alone And it can be seen that it is remarkably large. In addition, the results of the PPS group were similar to those of all the subjects (FAS).

(A5 + L100 + R20) than in the (A5 + L100) group in both diabetic and non-diabetic patients. In addition, changes in sitSBP (mean ± SD) at the time of (A5 + L100 + R20) administration and at the time of (A5 + L100) administration in the non-diabetic patients were -15.04 ± 10.86 mmHg and -13.42 ± 14.42 mmHg, (Mean ± SD) at the time of administration of (A5 + L100 + R20) and (A5 + L100) in diabetic patients were -20.48 ± 17.95 mmHg and -13.30 ± 15.03 mmHg, respectively, In the treatment group. Specifically, (A5 + L100) treated group had a similar effect of reducing sitSBP, ie, systolic blood pressure, in the diabetic and non-diabetic patients, but the change of sitSBP in the non-diabetic patients (mean ± SD) (Mean ± SD) was greater in diabetic patients than in non-diabetic patients, indicating that systolic blood pressure was reduced by about 1.4 times (about 1.36 times) in patients with diabetes compared with non-diabetic patients.

Test Example 2: Measurement of the Average Situ Diastolic Blood Pressure (Mean Sit DBP) Reduction Rate (mmHg) in the Diabetic Patients vs. Non-Diabetic Patients

(A5 + L100) (group A), amlodipine 5 mg and rosarthan 100 mg (group A5 + L100) (control group 1) after 8 weeks of baseline (Mean change in diastolic blood pressure (mmHg)) were measured. The test group and the control group include diabetic patients and non-diabetic patients, respectively. The results are shown in Table 2 and FIG.

[Table 2]

(A5 + L100 + R20) treated group (A5 + L100 + R20) treated group and the (A5 + L100) treated group as shown in Table 2 and FIG. 2 The change in siDBP (mmHg) was increased. The results showed that when 5 mg amlodipine, 100 mg rozatan, and 20 mg rosuvastatin were administered, the effect of reducing the mean diastolic blood pressure was greater than when 5 mg amlodipine and 100 mg roszan alone were administered.

These effects were also observed in patients with diabetes mellitus (DM) and those with non-DM (non-DM) patients. The mean changes in sitDBP (A5 + L100 + R20) mmHg) in diabetic (DM) patients. Specifically, diabetic patients had a diastolic blood pressure reduction of about 1.2 times (about 1.18 times) compared with non-diabetic patients.

It was found that the effect of reducing the mean diastolic blood pressure was greater in the diabetic patients than when 5 mg of amlodipine, 100 mg of rosarane, and 20 mg of rosuvastatin were administered, have. In addition, the results of the PPS group were similar to those of all the subjects (FAS).

From the results of Tables 1 and 2 and FIGS. 1 and 2, it can be seen that the blood pressure reduction effect is further increased in both diastole and systole by administering amlodipine, rosatan, and rosuvastatin together. In addition, the effect of such blood pressure reduction was more prominent in diabetic patients. In addition, the effect of blood pressure reduction was further increased in mean systolic blood pressure, especially in diabetic patients, effectively reducing mean systolic blood pressure.

Test Example 3: Measurement of change rate of triglyceride after 4 weeks and 8 weeks compared to baseline

For the comparison of the changes in triglyceride (TG) after 4 and 8 weeks compared to the baseline values, we compared each of the efficacy parameters at baseline for the comparison between the test group A5 + L100 + R20, the control group L100 + R20 and the A5 + Covariance analysis (ANCOVA) was performed. The percent change of triglyceride (TG) was measured 4 weeks and 8 weeks after the baseline values of the A5 + L100 + R20, L100 + R20, and A5 + L100 groups estimated from the covariance analysis. Also, the rate of change of triglyceride (TG) in the diabetic patients group was measured relative to the non-diabetic group.

(1) Analysis of all analyzed groups (FAS)

The percent change (%) of triglyceride (TG) versus baseline at 4 and 8 weeks after drug administration was measured for all analytes (FAS).

The mean (LS mean) triglyceride (Tg) change rates of the A5 + L100 + R20 group and the A5 + L100 group were 4.31 ± 4.60% and 4.78 ± 4.98%, respectively, , The A5 + L100 + R20-treated group had a higher rate of change of triglyceride (TG) than the A5 + L100-treated group, and this difference was statistically significant (p <0.0001) . In addition, the minimum mean squares (LS Mean) of the changes in triglyceride (TG) were -28.92 ± 4.04% and -17.43 ± 4.53%, respectively, after 4 weeks of the baseline values in the A5 + L100 + R20 and L100 + 0.0622).

In addition, the least mean squares (LS Mean) of the changes in triglyceride (TG) after 8 weeks compared to the baseline values of the A5 + L100 + R20 and A5 + L100 groups estimated by the covariance analysis were -21.77 ± 5.03% and 2.21 ± 5.45 %, The change rate of triglyceride (TG) was greater in A5 + L100 + R20 treated group than in A5 + L100 treated group and statistically significant (p = 0.0018).

(2) Analysis of PPS subjects who complied with the plan

The percent change in triglyceride (TG) versus the baseline value was estimated at 4 weeks and 8 weeks after the administration of the drug to the subjects who complied with the protocol (PPS), and the results are shown in Tables 3 and 4 Respectively.

Table 3 below shows the percent change in triglyceride (TG) versus baseline at 4 weeks after drug administration in the protocol-adapted clinical trial subjects (PPS).

[Table 3]

As shown in Table 3, the least mean squares (LS Mean) of the changes in triglyceride (TG) after 4 weeks compared to the baseline values of the A5 + L100 + R20 and A5 + L100 administration groups estimated by the covariance analysis were -30.64 + 4.46 , And 0.80 ± 4.93%, respectively. The A5 + L100 + R20 group had a higher rate of change of triglyceride (TG) than the A5 + L100 group, and this difference was statistically significant (p <0.0001). In addition, the least mean squares (LS Mean) of the changes in triglyceride (TG) after 4 weeks of the baseline values of the A5 + L100 + R20 and L100 + R20 groups were -28.62 ± 4.23% and -15.64 ± 4.74% Was statistically significant (p = 0.0444).

Table 4 below shows the percent change in triglyceride (TG) versus baseline at 8 weeks after drug administration in the protocol-adapted clinical trial subjects (PPS).

[Table 4]

As shown in Table 4 above, the least mean squares (LS Mean) of the changes in triglyceride (TG) after 8 weeks from the baseline values of the A5 + L100 + R20 and A5 + L100 administration groups estimated by the covariance analysis were -23.06 + 4.82 %) And -3.11 ± 5.33%, respectively. The A5 + L100 + R20 group showed a higher rate of change of triglyceride (TG) than the A5 + L100 group (p = 0.007).

As shown in Table 3 and Table 4, the A5 + L100 + R20 administration group showed a significant difference in the rate of change of triglyceride compared to the L100 + R20 administration group and the A5 + L100 administration group. When amlodipine 5 mg, rosatan 100 mg and rosuvastatin 20 mg were administered, administration of rosigadin 100 mg and rosuvastatin 20 mg alone or administration of amlodipine 5 mg and rosigadin 100 mg were more effective than administration of triglyceride (TG), and showed statistically significant differences.

(3) Analysis of change in triglyceride (TG) in diabetic patients versus non-diabetic patients

The percent change (%) of triglyceride (TG) versus baseline at 8 weeks after the administration of (A5 + L100 + R20) or (L100 + R20) drug in patients with diabetes mellitus was measured and is shown in Table 5 below.

[Table 5]

As shown in Table 5, when comparing the DM group and the non-DM group with diabetes, the DM group with diabetes (A100 + R20) + R20) treated group showed a greater decrease in the percentage change of triglyceride (TG).

Specifically, the change in triglyceride (TG) (mean ± SD) (%) at the time of administration of (L100 + R20) and (A5 + L100 + R20) was -23.60 ± 40.89 and -16.98 ± 39.39 (Tg) change (mean ± SD) at the time of administration of (L100 + R20) and (A5 + L100 + R20) in the diabetic patients group was lower than that of the patients who did not increase the decrease rate by the addition of amlodipine ) Were -14.41 ± 34.98 and -27.75 ± 21.03, respectively, which showed a marked increase in the rate of decrease with the addition of amlodipine. From this, it was confirmed that the effect of TG control was increased by increasing the decrease rate of triglyceride (TG) according to administration of (A5 + L100 + R20) in diabetic patients compared with non-diabetics.

Test Example 4: Measurement of blood pressure normalization rate according to JNC VII guideline

The Cochran-Mantel-Haenzel (CMH) test was conducted at baseline and after 8 weeks of administration of the drug for clinical trials, with baseline cardiovascular risk-stratified groups on the blood pressure normalization rate according to the JNC VII guidelines. In addition, Pearson's chi-square test or Fisher's exact test was performed for each cardiovascular risk group. The classification according to the cardiovascular risk classification is as described above in this specification. When the risk factors of CHD are 0 to 1, it is classified into the group A, and the risk of CHD is 2 or more, A group with a risk of developing a relational disease of 10 to 20% was classified as a group B, and a group with a CHD / CHD equivalent risk factor or a risk of developing a cardiovascular disease within 10 years exceeded 20% .

(1) Analysis of blood pressure normalization rate in all subjects (FAS)

The standard of blood pressure normalization according to JNC VII guideline is based on 'sitSBP / sitDBP <140/90 mmHg' for cardiovascular risk group A and B, 'sitSBP / sitDBP <130/80 mmHg' for group C . The results are shown in Tables 6 and 7, respectively. Percentages in Tables 6 and 7 below are based on subjects in each drug treatment group. A) Pearson's chi-square test with respect to the p-value; b) Fisher's exact test; c) Cochran-Mantel-Haenzel test.

[Table 6]

Table 6 above shows the rate at which blood pressure normalization was achieved in all the subjects of the 4th week (FAS) according to the cardiovascular risk category.

As shown in Table 6, the blood pressure normalization rate of each group of cardiovascular risk groups after 4 weeks of drug administration was 60.00% (group A5 + L100 + R20) in the risk factor 0-1 group 3/5 patients), and 66.67% (2/3 patients) in the A5 + L100 group and 33.33% (1/3 patients) in the L100 + R20 group. In the group with two or more risk factors (risk factor ≥ 2) and with a risk of developing cardiovascular disease within 10 years, the group receiving A5 + L100 + R20 received 61.11% (11/18), A5 + L100 The risk of developing CHD / CHD-equivalent risk factors or cardiovascular disease within 10 years was more than 20%. (6/31) in the A5 + L100 + R20 group, 7.69% (2/26) in the A5 + L100 group and in the L100 + R20 group in the CHD / CHD risk equivalents Showed a normalization rate of 0.00% (0/27).

After four weeks of administration of the clinical trial drug, blood pressure normalization ratios according to the JNC VII Guideline were 37.04% (20/54) for A5 + L100 + R20, 28.26% (13/46) for A5 + L100, And 9.30% (4/43 patients) in the administration group. There was a statistically significant difference in blood pressure normalization rate between the A5 + L100 + R20 group and the L100 + R20 group (p = 0.0017).

[Table 7]

Table 7 above shows the percentage of blood pressure normalization achieved in all the subjects of the 8th week (FAS) according to the cardiovascular risk category.

In Table 7, the blood pressure normalization rate of each cardiovascular risk group after 8 weeks of drug administration was 80.00% (4/5), A5 + L100 + 66.67% (2/3) of L100 - treated group and 66.67% (2/3) of L100 + R20 treated group showed normalization rate. A5 + L100 + R20 treated group had 77.78% (14/18), A5 + L100 treated group had a risk factor ≥ 2, and the risk of cardiovascular disease was less than 20% The risk of cardiovascular disease within 10 years was more than 20%, or the risk of CHD / CHD equivalent risk factor was higher than that of CHD / CHD group (64.71%, 11/17) and L100 + R20 group (30.77% Group showed 29.03% (9/31) of A5 + L100 + R20 treated group, 19.23% (5/26) of A5 + L100 treated group and 3.70% (1/27) of L100 + R20 treated group .

(2) Analysis of blood pressure normalization rate according to cardiovascular risk classification

The distribution of the cardiovascular risk groups in the subjects of this study was group A (7.69%), group B (48.33%) and group C (84.7%). . Considering that blood pressure normalization criteria for group A and group B were less than sitSBP / sitDBP 140/90 mmHg, while group C blood pressure normalization criteria were less than sitSBP / sitDBP 130/80 mmHg, risk factors 0 - 1 (CHD / CHD risk equivalents or 10-year risk> 20%) and group C (CHD / CHD risk equivalents or 10% risk> 20%

In group A and group B, the A5 + L100 + R20 group received 60.87% (14/23) and the A5 + L100 group L100 + R20 administration group showed normalization rate of 25.00% (4/16), Group C showed 19.35% (6/31) of A5 + L100 + R20 administration group and A5 + The rate of normalization of group C was relatively lower than that of groups A and B, showing that 7.63% (2/26) of L100 administration group and 0.001% (0/27) of L100 + R20 administration group showed normalization rate I could.

In group A and B, the A5 + L100 + R20-treated group was 78.26% (18/23), and the A5 + L100-treated group L100 + R20 treated group showed a normalization rate of 37.50% (6/16). In group C, A5 + L100 + R20 treated group showed 29.03% (9/31) 19.23% (5/26) of L100 - treated group and 3.70% (1/27) of L100 + R20 treated group showed normalization rate.

As a result, the blood pressure normalization rate was relatively lower in group C than in group A and B, suggesting that it is difficult to control blood pressure because group C has a high mean baseline blood pressure. Overall, the A5 + L100 + R20 treated group showed better blood pressure normalization rates than the A5 + L100 treated group or the L100 + R20 treated group in both cardiovascular risk group A, B and C groups.

(3) Analysis of blood pressure normalization rate in diabetic patients

The ratio of achieving normalization of blood pressure at 8 weeks after administration of (A5 + L100 + R20), (A5 + L100), or (L100 + R20) drug in patients with diabetes was analyzed and shown in Table 8 below.

[Table 8]

As shown in Table 8, 21.43% (3/14) of A5 + L100 + R20, 18.75% (3/16) of A5 + L100 and L100 + R20 of diabetic group % (0/12) normalization rate. From these results, it was confirmed that administration of A5 + L100 + R20 drug showed higher blood pressure normalization rate than that of A5 + L100 or L100 + R20 in patients with diabetes.

Test Example 5: Measuring the percentage of subjects achieving the LDL-C therapy goal according to the NCEP ATP III guidelines and reaching blood pressure normalization according to the JNC VII guidelines

Cochran-Mantel-Haenszel (CMH) test for the proportion of subjects who achieved LDL-C treatment goals according to the NCEP ATP III guidelines 4 weeks or 8 weeks after administration of the drug for clinical trial and whose blood pressure was normalized according to the JNC VII guidelines To compare the treatment groups. In addition, Pearson's chi-square test or Fisher's accuracy test was performed to compare LDL-C therapy goals and blood pressure normalization rates among the treatment groups.

(1) Analysis of LDL-C and blood pressure normalization rate in all subjects (FAS)

After 4 weeks of administration of the clinical trial drug, the percentage of subjects who reached the LDL-C treatment goal according to the NCEP ATP III guidelines and whose blood pressure was normalized according to the JNC VII guideline was 35.19% (19 / L100 + R20 treated group was higher than that of the other two treatment groups, while the A5 + L100 treated group was 0.00% (0/46) and the L100 + R20 treated group was 9.30% (4/43) (A5 + L100 + R20 vs. A5 + L100: p <0.0001, A5 + L100 + R20 vs. L100 + R20: p = 0.0028), and the difference was statistically significant.

In addition, the ratio of subjects who achieved LDL-C therapy and normalized blood pressure after 8 weeks of clinical drug administration was 48.15% (26/54) in the A5 + L100 + R20 group and 8.70% in the A5 + L100 group (4/46), and L100 + R20 treated group showed 16.28% (7/43). The proportion of A5 + L100 + R20 treated group was higher than the other two treatment groups and statistically significant (A5 + L100 + R20 vs. A5 + L100: p <0.0001, A5 + L100 + R20 vs. L100 + R20: p = 0.0007). All three groups achieved LDL-C treatment goals at 8 weeks after 4 weeks of administration of the drug, and the percentage of subjects whose blood pressure was normalized was higher.

From the above results, it was confirmed that the A5 + L100 + R20 administration group was more effective than the A5 + L100 administration group or the L100 + R20 administration group in the treatment of dyslipidemia and hypertension.

(2) LDL-C therapy goal attainment and blood pressure normalization rate analysis in diabetic patients

In the patients with diabetes (A5 + L100 + R20), (A5 + L100), or (L100 + R20) after 8 weeks of drug administration, the percentage of subjects who achieved LDL- Are shown in Table 9 below.

[Table 9]

As shown in Table 9, 21.43% (3/14) of A5 + L100 + R20, 18.75% (3/16) of A5 + L100 and L100 + R20 of diabetic patients % (0/12) normalization rate. From these results, it was confirmed that administration of A5 + L100 + R20 drug to patients with diabetes attained higher LDL-C target and blood pressure normalization rate than A5 + L100 or L100 + R20 administration.

[Explanation of Abbreviations]

A5: amlodipine (A) 5 mg

L100: losartan (L) 100 mg

R20: 20 mg of rosuvastatin (R)

sitDBP: sitting diastolic blood pressure

sitSBP: sitting systolic blood pressure

DM: diabetes mellitus patients

Non-DM: Non-diabetic patients

LDL-C: low-density lipoprotein cholesterol

TG: triglyceride

Hb1Ac: glycated hemoglobin (hemoglobin (Hb) A1c)

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

The use of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cardiovascular diseases &Lt; / RTI &gt; The method according to claim 1, wherein the prevention or treatment of a disease that simultaneously affects one or more of cardiovascular diseases selected from the group consisting of hypertension, dyslipidemia, angina pectoris, heart arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction &Lt; / RTI &gt; The cardiovascular disease according to claim 1,
(1) fasting plasma glucose ≥ 126 ㎎ / dL for more than 8 hours,
(2) a symptom of at least one of the following: diarrhea, obesity, next, hunger, and unexplained weight loss, and at the same time a plasma glucose of ≥ 200 mg / dL,
(3) Plasma blood glucose ≥ 200 ㎎ / dL after 2 hours according to 75 g oral glucose tolerance test, and
(4) Hemoglobin A1c (HbA1c) ≥ 6.5%
, And at the same time
(a) Left systolic blood pressure (sitSBP) ≥ 140 mmHg,
(b) Left-sided diastolic blood pressure (sitDBP) ≥ 90 mmHg,
(c) LDL-cholesterol (LDL-C) blood levels ≥ 130 mg / dL,
(d) HDL-cholesterol (HDL-C) plasma concentration <60 mg / dL,
(e) Triglyceride blood concentration ≥ 150 mg / dL, and
(f) Total cholesterol concentration> 200 mg / dL
Or a pharmaceutically acceptable salt thereof. [Claim 2] The pharmaceutical composition according to claim 1, wherein the cardiovascular disease accompanied by diabetes is a disease in which one or more of cardiovascular diseases selected from hypertension and dyslipidemia and diabetes mellitus are simultaneously present. The pharmaceutical composition according to claim 1, which is used for preventing or treating diabetic hypertension. The pharmaceutical composition according to claim 1 or 5, wherein the left systolic blood pressure is further reduced by at least 1.3 times as compared with a cardiovascular disease not accompanied by diabetes. The pharmaceutical composition according to claim 1, wherein the amlodipine or pharmaceutically acceptable salt thereof in the total amount of the pharmaceutical composition is 5 mg to 10 mg in terms of amlodipine free base form, and losartan or a pharmaceutically acceptable salt thereof is in the form of losartan free acid And the pharmaceutically acceptable salt thereof is from 45 mg to 100 mg, and the rosuvastatin or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg in terms of the rosuvastatin free acid form. The pharmaceutical composition according to claim 1, which is administered once a day. The pharmaceutical composition according to claim 1, wherein the amlodipine or pharmaceutically acceptable salt thereof in the total amount of the pharmaceutical composition is 5 mg when converted into amlodipine free base form, and losartan or a pharmaceutically acceptable salt thereof is converted into losartan free acid form And wherein the rosuvastatin or a pharmaceutically acceptable salt thereof is at a daily dosage of 20 mg as converted to the rosuvastatin free acid form. The pharmaceutical composition according to claim 1, comprising amlodipine camsylate, losartan potassium, and rosuvastatin calcium. The pharmaceutical composition according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof, rosatane or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially. [Claim 2] The method according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof are administered in one single form containing it, Wherein the pharmaceutical composition is administered in multiple formulations, including separately. The pharmaceutical composition according to claim 1, which is used for the prevention or treatment of one or more other cardiovascular diseases selected from a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and an HMG-CoA reductase inhibitor &Lt; / RTI &gt; The use of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cardiovascular diseases Or a pharmaceutically acceptable salt thereof. The combined preparation according to claim 14, which is formulated in the form of a tablet, a capsule, or a caplet.

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