WO2019078592A1

WO2019078592A1 - Pharmaceutical composition for prevention or treatment of cardiovascular diseases accompanied by diabetes, including amlodipine, losartan, and rosuvastatin, and composite preparation including the same

Info

Publication number: WO2019078592A1
Application number: PCT/KR2018/012213
Authority: WO
Inventors: Jin A Jung; Hye Yung BAE
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2017-10-17
Filing date: 2018-10-17
Publication date: 2019-04-25
Also published as: CO2020001514A2; CN111511369A; ECSP20014155A; MX2020001681A; TW201922243A; CR20200096A; PH12020500295A1; KR20190043076A; EA202090165A1; NI202000017A; SG11202000622WA

Abstract

Provided herein are a pharmaceutical composition for the prevention or treatment of a cardiovascular disease accompanied by diabetes, and a composite preparation including the pharmaceutical composition. The pharmaceutical composition includes amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

Description

PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATMENT OF CARDIOVASCULAR DISEASES ACCOMPANIED BY DIABETES, INCLUDING AMLODIPINE, LOSARTAN, AND ROSUVASTATIN, AND COMPOSITE PREPARATION INCLUDING THE SAME

This application claims the benefit of Korean Patent Application Nos. 10-2017-0134809 and 10-2018-0112376, respectively filed on October 17, 2017 and September 19, 2018, in the Korean Intellectual Property Office, the disclosures of which are incorporated herein in their entirety by reference.

One or more embodiments relate to prevention or treatment of cardiovascular diseases, and more particularly, to a pharmaceutical composition for the prevention or treatment of a cardiovascular disease accompanied by diabetes, which includes amlodipine, losartan, and rosuvastatin, and a composite preparation including the pharmaceutical composition.

Cardiovascular diseases are one of the major causes of death and are multifactorial diseases caused by complicated interactions of chronic conditions such as hypertension, dyslipidemia, diabetes, and the like and various risk factors such as smoking, obesity, and the like, and there are many cases in which two or more cardiovascular diseases occur simultaneously. According to a joint report on disease prevalence and treatment status by the Korean Society of Hypertension, the Korean Diabetes Association, and the Korean Society of Lipid Atherosclerosis, the number of patients with all of hypertension, diabetes, and dyslipidemia has sharply increased from 340 thousand to 1.41 million over a recent ten-year period (between 2006 and 2016).

In particular, the prevalence of diabetes and other cardiovascular diseases such as hypertension, dyslipidemia, and the like has continued to increase, and for example, it is known that patients with diabetes have a risk of hypertension that is about two times that of non-diabetics, hypertension is easily triggered or aggravated by microvascular (nephropathy and retinopathy) and macrovascular complications due to diabetes, and 60% to 70% of patients with diabetes have hypertension. In addition, it is also known that, in an opposite case, patients with hypertension have a high risk of diabetes. It is also known that diabetics are classified as a very high-risk group for dyslipidemia, about 30% of diabetes show an increased concentration of plasma triglycerides (TGs), and mortality due to cardiovascular diseases in diabetics is about two to four times that of non-diabetics. Further, abnormal glucose tolerance, a gradual increase in triglycerides and a gradual decrease in HDL cholesterol are found in diabetics. The most common types of lipid disorders occurring as complications of type 2 diabetes are hypertriglyceridemia and low-HDL cholesterolemia, and according to the Third National Health and Nutrition Examination Survey (NHANES III), about 85% of patients with type 2 diabetes have 100 mg/dl or more of LDL cholesterol, 42% have 200 mg/dl or more of triglycerides, and 62% have less than 45 mg/dl of HDL cholesterol. Such an increase in cardiovascular diseases occurs in both type 1 diabetes and type 2 diabetes.

As such, there are many cases in which diabetics have accompanying cardiovascular diseases, and, as a result of comorbidity with diabetes, even when patients have the same or similar diseases, their pathophysiologic or drug treatment responses are likely to be different from those of non-diabetics, and there are many cases in which blood pressure or lipid concentration fails to be controlled or is poorly controlled by the use of existing drug therapies. In addition, patients with a cardiovascular disease accompanied by diabetes have to take large doses of various drugs, thus causing inconvenience and discomfort, and often neglect to take their medicines. As a result, a targeted therapeutic effect is unable to be achieved, and accordingly, the social burden and medical expenditure are tremendous. Therefore, in order to treat cardiovascular diseases accompanied by diabetes, there is a need to develop a cardiovascular disease therapeutic agent and composite preparation customized in consideration of characteristics of the accompanying diseases and a patient group.

Korean Patent Publication No. 10-2007-0068658 discloses a preparation including amlodipine and simvastatin, but does not disclose a preparation capable of effectively controlling blood pressure and lipid concentration in a diabetic patient group. Thus, as a result of repeatedly conducting research and clinical trials, the inventors of the present disclosure developed a pharmaceutical composition exhibiting an excellent therapeutic and preventive effect on cardiovascular diseases accompanied by diabetes, and a composite preparation including the pharmaceutical composition.

One or more embodiments include a pharmaceutical composition for the prevention or treatment of a cardiovascular disease accompanied by diabetes.

One or more embodiments include a composite preparation for the prevention or treatment of a cardiovascular disease accompanied by diabetes.

One or more embodiments include a method of preventing or treating a cardiovascular disease accompanied by diabetes.

Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description, or may be learned by practice of the presented embodiments.

According to one or more embodiments, a pharmaceutical composition for preventing or treating a cardiovascular disease accompanied by diabetes includes amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

According to one or more embodiments, a composite preparation for preventing or treating a cardiovascular disease accompanied by diabetes includes amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

According to one or more embodiments, there is provided a method of treating a cardiovascular disease accompanied by diabetes, by using a composition including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

As is apparent from the foregoing description, a pharmaceutical composition including amlodipine, losartan, and rosuvastatin, according to an embodiment, has an excellent effect of controlling blood pressure and improving lipid levels in a cardiovascular disease accompanied by diabetes, and especially in patients with both hypertension and dyslipidemia accompanied by diabetes, has an excellent effect of improving blood pressure and lipid levels. The pharmaceutical composition has excellent effects in terms of treatment or prevention of hypertension and dyslipidemia accompanied by diabetes when amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof are co-administered simultaneously, as compared to when only each single ingredient is administrated individually, or when any one of them or only a combination of two thereof is administered. In addition, the pharmaceutical composition effectively reduces a mean sitting systolic blood pressure and a mean diastolic blood pressure in a DM patient group, effectively reduces an increased TG level, and exhibits excellent blood pressure normalization and LDL-C treatment goal achievement rates.

A composite preparation according to an embodiment may enhance medication convenience and medication compliance of patients and may reduce medicine costs. In addition, the composite preparation is effective in preventing or treating a cardiovascular disease of a diabetic patient who should take both a hypertension therapeutic agent and a dyslipidemia therapeutic agent.

These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

FIG. 1 illustrates measurement results of mean sitting systolic blood pressure (sitSBP) variations (mmHg) according to drugs administered to a diabetes mellitus (DM) patient group and a non-DM patient group; and

FIG. 2 illustrates measurement results of mean sitting diastolic blood pressure (sitDBP) variations (mmHg) according to drugs administered to a DM patient group and a non-DM patient group.

Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to like elements throughout. In this regard, the present embodiments may have different forms and should not be construed as being limited to the descriptions set forth herein. Accordingly, the embodiments are merely described below, by referring to the figures, to explain aspects of the present description. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

Hereinafter, the present disclosure 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. In addition, suitable methods or samples are described herein, but similar or equivalent ones are also within the scope of the present specification. Also, the numerical values set forth herein are considered to include the meaning "about" unless otherwise specified herein. The contents of all publications referred to herein are incorporated herein by reference in their entirety. As used herein, the term "about" means that the mentioned value may vary to some extent. For example, the value may vary by 10 %, 5 %, 2 %, or 1 %. For example, the expression "about 5" is construed as including a certain value between 4.5 and 5.5, between 4.75 and 5.25, between 4.9 and 5.1, or between 4.95 and 5.05. As used herein, the expressions "has" or "may have" and "includes" or "may include," and the like indicate the presence of the corresponding characteristic (e.g., a value, or a component such as an ingredient or the like), and is not intended to exclude the presence of additional characteristics.

An embodiment of the present disclosure provides a pharmaceutical composition for the prevention or treatment of a cardiovascular disease accompanied by diabetes, which includes amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

The term "cardiovascular disease" as used herein is intended to not only include diseases directly occurring due to various causes such as abnormality and dysfunction of the circulatory system in the body, damage thereto, and the like, but also include secondary diseases induced by these direct diseases. For example, the cardiovascular disease may include hypertension, dyslipidemia, angina pectoris, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarct, congestive heart failure, arteriosclerosis, coronary heart disease, or myocardial infarction.

The term "blood pressure" as used herein refers to the pressure of blood flowing along blood vessels on the walls of the blood vessels. Blood pressure is summarized as two measures of systolic (maximum)　blood pressure and diastolic (minimum) blood pressure, and generally, normal blood pressure during rest is 100 mmHg to 140 mmHg when the heart contracts and 60 mmHg to 90 mmHg when the heart expands, and a case in which blood pressure is consistently 140/90 mmHg or higher is referred to as hypertension.

The term "hypertension" as used herein refers to a chronic disease in which the blood pressure is higher than the normal range. Hypertension may be divided into essential hypertension (primary hypertension) and secondary hypertension. According to the Korean Standard Classification of Diseases (KCD), essential hypertension and secondary hypertension are distinguished by different disease classification codes. It is known that approximately 90 % to 95 % of cases are classified as essential hypertension without distinct fundamental medical causes, and the remaining 5 % to 10% (secondary hypertension) are due to other health conditions affecting the kidneys, arteries, heart, or endocrine system. For example, the clustering of obesity, hyperlipidemia, diabetes, and hypertension may be termed "metabolic syndrome" or "insulin resistance syndrome". Hypertension may be accompanied by symptoms such as dizziness, headaches, heart palpitations, dyspnea, and the like, and if the human body is in a long-term hypertensive state, it may lead to many complications such as stroke, coronary heart disease, renal failure, and the like. The term "complication" as used herein refers to the presence of other symptoms in a certain disease.

The term "essential (primary) hypertension (KCD classification code: I10)" as used herein refers to the most common type of hypertension that occurs due to complicated interactions of genetic factors and environmental factors. In addition, essential hypertension is a common symptom of diabetes, and insulin resistance, which is an element of steroid metabolic deficiency (or metabolic syndrome) may also cause hypertension. The term "secondary hypertension (KCD classification code: I15)" as used herein originates from a recognizable cause, and kidney disease is one of the common secondary causes, and examples of the causes may include Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn syndrome, hyperaldosteronism, hyperparathyroidism, pheochromocytoma, diabetes, sleep apnea, pregnancy, coarctation of the aorta, licorice or steroid drugs, and illegal drugs. Secondary hypertension may be classified again into, according to a cause thereof and a KCD classification code, renal vascular hypertension (I15.0), secondary hypertension due to other kidney disorders (I15.1), secondary hypertension due to endocrine disorders (I15.2), other secondary hypertensions (I15.8), unspecified secondary hypertension (I15.9), and the like.

The diagnostic criteria for hypertension may be sitting systolic blood pressure (sitSBP) higher than 140 mmHg or sitting diastolic blood pressure (sitDBP) higher than 90 mmHg. According to the revised JNC VIII guidelines (2014), blood pressure normalization criteria for general patients (patients not having diabetes or chronic kidney disease) are less than 150/90 mmHg for those aged 60 years or older and less than 140/90 mmHg for those aged below 60 years, and blood pressure normalization criteria for diabetic patients or patients with chronic kidney disease are below 140/90 mmHg at all ages.

The term "hyperlipidemia" as used herein refers to a condition in which an unnecessarily large amount of a lipid substance is present in blood and accumulates in blood vessel walls, thus causing inflammation, resulting in the occurrence of cardiovascular disease, and is also referred to as dyslipidemia, which indicates an abnormal blood lipid state. To treat hyperlipidemia, drug treatment is mainly used together with lifestyle improvement through dietary control and exercise and maintenance of appropriate body weight, and for the drug treatment, statin-based drugs are widely used, and these drugs act as HMG-CoA reductase inhibitors, and thus have an effect of inhibiting the synthesis of cholesterol. In addition, these drugs intensively reduce the level of LDL-cholesterol and partially reduce the level of triglycerides.

For the diagnostic criteria of dyslipidemia, a case corresponding to any one of the following items may be diagnosed as dyslipidemia (blood LDL-cholesterol (LDL-C) concentration ≥ 130 mg/dL, blood HDL-cholesterol (HDL-C) concentration < 60 mg/dL, blood triglyceride concentration ≥ 150 mg/dL, and total cholesterol concentration > 200 mg/dL). For the diagnostic criteria of dyslipidemia, according to the inclusion of risk factors, e.g., diabetes, smoking, hypertension, age, family history such as early coronary artery disease, and the like, the risk of dyslipidemia to be treated may be classified into an ultra-high-risk group, a high-risk group, a moderate-risk group, and a low-risk group, and according to the groups, treatment goals may be set.

Cardiovascular disease may be accompanied by diabetes. Cardiovascular disease accompanied by diabetes refers to one of the symptoms of diabetes which occurs concurrently with diabetes or occurs as a primary disease, or a cardiovascular disease accompanied by diabetes as a sequela or a complication occurring thereafter. For example, the disease may include a cardiovascular disease occurring due to diabetes or a drug for the treatment of diabetes, and may be a sequela or complication due to diabetes. In addition, for example, the disease is one of the sequelae or complications occurring after a cardiovascular disease, and includes a case in which diabetes additionally occurs.

The term "diabetes mellitus (DM) or diabetes" as used herein refers to a group of metabolic diseases with high blood glucose levels lasting for a long time. Diabetes may occur because the pancreas is unable to sufficiently produce insulin or cells of the body are unable to appropriately respond to the produced insulin. Acute complications due to diabetes include diabetic ketoacidosis, hyperglycemic hyperosmolar non-ketotic coma, and the like. In addition, serious long-term complications due to diabetes include cardiovascular diseases, stroke, chronic renal failure, diabetic ulcers, diabetic retinopathy, and the like.

The term "glucose toxicity or glucotoxicity" as used herein refers to damage to body cells producing and using insulin due to high blood glucose levels. Glucose toxicity resulting from prolonged hyperglycemia may induce tissue-dependent insulin resistance and thus aggravate nephropathy, retinopathy, dyslipidemia, hypertension, hypertriglyceridemia, obesity, and cardiovascular diseases referred to as metabolic syndromes, or may cause secondary complications with these diseases. Diabetes-induced heart diseases may occur due to glucose toxicity.

The term "insulin resistance (IR)" as used herein refers to the inability of cells to effectively combust glucose due to a reduced ability of insulin to reduce blood glucose. When insulin resistance is high, the human body produces an excess amount of insulin, and as a result, hypertension, hyperlipidemia, or diabetes may be caused. For example, in type 2 diabetes, an increase in insulin in muscle and adipose tissues is unable to be recognized, and thus insulin action does not occur. Such insulin resistance is a pathophysiologic phenomenon commonly present in type 2 diabetes and unidentified essential hypertension, and in the case of patients with high plasma insulin concentrations, the probability of developing hypertension is significantly increased as compared with people with low insulin concentrations, and long-term insulin treatment causes an increase in body weight, or the like, and thus may act as a risk factor for hypertension. Diabetes-induced heart diseases may occur due to insulin resistance.

Various mechanisms for how insulin resistance occurring in diabetic patients increases blood pressure have been proposed. For example, insulin produces nitric oxide (NO), which is a blood vessel relaxant, through the nitric oxide pathway to relax blood vessels, and blood vessel relaxation does not properly occur due to resistance in such an insulin response, resulting in an increase in blood pressure. In addition, blood pressure is increased by excitement of the sympathetic nervous system, vascular smooth muscle hypertrophy, and sodium and body fluid retention, due to a high blood insulin concentration. High blood glucose levels of diabetic patients stimulate the renin-angiotensin system (RAS), thus contributing to an increase in blood pressure. In addition, it is known that insulin directly or indirectly affects blood pressure through an increase in the secretion of endothelin-1 and plasminogen activator inhibitor-1 (PAI-1), an increase in the generation of reactive oxygen species, the inhibition of nuclear factor kappa B (NF-κB), the inhibition of platelet aggregation, and the like. In addition, insulin resistance and hyperinsulinemia promote arteriosclerosis, and thus also participate in a secondary blood pressure increase.

Cardiovascular disease accompanied by diabetes includes a case of developing diabetes as a sequela or a complication of cardiovascular disease due to direct or indirect causes by abnormality and dysfunction of the body's circulatory system, damage thereto, and the like.

In addition, the cardiovascular disease accompanied by diabetes may include a cardiovascular disease due to diabetes, glucose toxicity, or insulin resistance, or a case of developing diabetes together due to endocrine disorders caused by a cardiovascular disease. The cardiovascular disease accompanied by diabetes may be, for example, hypertension, dyslipidemia (hyperlipidemia), angina pectoris, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarct, congestive heart failure, or myocardial infarction. The cardiovascular disease accompanied by diabetes may be pathophysiologically and clinically distinguished from diseases occurring alone without being accompanied by diabetes. In one embodiment, the cardiovascular disease accompanied by diabetes may exhibit a different drug response when the same drug as that for a cardiovascular disease not accompanied by diabetes is administered in the same dosage, and for example, while a non-diabetic patient group shows appropriate treatment results, a diabetic patient group may show a failure to reach normal blood pressure or normolipidemia(normal lipid levels).

In one embodiment, the cardiovascular disease accompanied by diabetes may indicate a case in which at least one cardiovascular disease selected from hypertension, dyslipidemia, angina pectoris, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarct, congestive heart failure, and myocardial infarction occurs concurrently with diabetes. According to one embodiment, the cardiovascular disease accompanied by diabetes may indicate a case in which hypertension and dyslipidemia occur concurrently with diabetes.

In one embodiment, the cardiovascular disease accompanied by diabetes may be a disease satisfying at least one of the following conditions:

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

(2) arbitrary plasma glucose level ≥ 200 mg/dL, plus at least one symptom selected from polyuria, polydipsia, polyphagia, the feeling of hunger, and unidentified body weight loss,

(3) plasma glucose ≥ 200 mg/dL at 2 hours after a 75 g oral glucose tolerance test, and

(4) glycosylated hemoglobin level (HbA1c) ≥ 6.5%,

while simultaneously satisfying at least one of the following conditions:

(a) sitting systolic blood pressure (sitSBP) ≥ 140 mmH,

(b) sitting diastolic blood pressure (sitDBP) ≥ 90 mmHg,

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

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

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

(f) total cholesterol concentration > 200 mg/dL.

Conditions (a) to (f) may be changed in accordance with a revision of the guidelines regarding the diagnosis of hypertension or dyslipidemia.

The plasma glucose after 8 hours or more of fasting (FPG) of condition (1) refers to a blood glucose level measured in a fasting state at least 8 hours after a meal.

In condition (2), polyuria, polydipsia, polyphagia, the feeling of hunger, and unidentified (causes are unknown) body weight loss refer to typical symptoms of diabetes. In addition, these symptoms may also include fatigue, blurred vision, and slow wound recovery. The arbitrary plasma glucose level refers to a blood glucose level measured regardless of the last meal time.

The oral glucose tolerance test (OGTT) of condition (3) is performed by fasting for at least 8 hours before the test and measuring a blood glucose level 2 hours after ingesting 75 g of a glucose solution in the fasting state.

The glycosylated hemoglobin level (HbA1c) of condition (4) refers to a value indicating the concentration of glycated hemoglobin obtained such that glucose is bound to blood hemoglobin of a patient by reacting therewith and is a measure of the average of three-month blood glucose levels. In 2010, the American Diabetes Association (ADA) adopted 6.5 % or more of glycated hemoglobin as a diagnostic criterion for diabetes. A method of marking glycated hemoglobin may be broadly classified into standardization through the American NGSP comparison method and standardization through the European IFCC reference method. According to the NGSP method, Hb is separated into subtypes (HbA1a, HbA1b, and HbA1c) by chromatography and HbA1c is expressed as a percentage (%). According to the IFCC method, HbA1c, in which glucose binds to valine of the N-terminal of Hb, is measured and expressed in mmol/mol. For example, 6.5 % of glycated hemoglobin measured by the NGSP method corresponds to 48 mmol/mol of glycated hemoglobin measured by the IFCC method. Conditions (1) to (4) may be changed in accordance with a revision of the guidelines regarding the diagnosis of diabetes.

For example, since diabetic patients belong to risk category C, the pharmaceutical composition according to an embodiment may be administered to diabetic patients having a blood low-density lipoprotein cholesterol (LDL-C) concentration of between 100 mg/dL or more and 250 mg/dL or less and a blood triglyceride concentration of less than 400 mg/dL.

Diabetes may be divided into diabetes mellitus type 1 or type 1 diabetes (T1DM); diabetes mellitus type 2 or type 2 diabetes (T2DM); and gestational diabetes. The diabetes mellitus type 1 or type 1 diabetes (T1DM) is caused by the inability to produce a sufficient amount of insulin, and is also referred to as "insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes", and a specific cause thereof has not yet been found. The diabetes mellitus type 2 or type 2 diabetes (T2DM) starts with insulin resistance in which cells are unable to respond properly to insulin and may also experience insulin deficiency as the disease progresses, and may also be referred to as "non-insulin dependent diabetes mellitus (NIDDM)" or "adult diabetes". This disease is known to occur mainly due to excessive weight and insufficient exercise. Gestational diabetes is the third type of diabetes which occurs in pregnant women without a history of diabetes, and develops into hyperglycemia. In diabetic patients, hypertension may act as a risk factor for nephropathy, and as the prevalence period of diabetes increases, the risk of developing hypertension may increase. According to one embodiment, in the cardiovascular disease accompanied by diabetes, the diabetes may be type 2 diabetes.

In a diabetic patient group, the risk accompanying cardiovascular diseases such as hypertension, dyslipidemia, angina pectoris, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarct, congestive heart failure, myocardial infarction, and the like, or other metabolic diseases may be increased. In addition, in a group of patients with cardiovascular disease, the risk of being accompanied by diabetes or other metabolic diseases may be increased.

The cardiovascular disease accompanied by diabetes may be a disease in which diabetes and at least one cardiovascular disease selected from hypertension and dyslipidemia occur concurrently. In one embodiment, the cardiovascular disease accompanied by diabetes may be hypertension or dyslipidemia accompanied by diabetes. In one embodiment, the cardiovascular disease accompanied by diabetes may be diabetic hypertension or diabetic dyslipidemia.

Independently of normal hypertension, diabetes may alter cardiovascular or myocardiac function, structure, and the like. The term "diabetic hypertension" as used herein refers to hypertension occurring accompanied by diabetes, and is intended to include a case of concurrently developing hypertension and diabetes, a case of developing diabetes before hypertension, or a case of developing diabetes after hypertension, at the time of drug treatment. In diabetic hypertension, a mechanism for the occurrence or alteration of hypertension due to diabetes may be, for example, due to insulin resistance. Insulin resistance may cause the loss of insulin-induced vasodilatation, and may induce increased sodium and moisture in the body due to hyperinsulinemia, activation of the sympathetic nervous system, and the like. In addition, renal function deteriorates due to diabetes, thus causing an increase in body fluid, which may be a cause of increased blood pressure. Diabetes increases atherosclerosis in large blood vessels or coronary arteries, and thus may lead to abnormal physiological conditions, resulting in reduced sensitivity. Accordingly, it may cause new occurrence of hypertension, aggravation of the symptoms of hypertension, or a reduced drug therapeutic effect of existing hypertension drugs.

According to the clinical outcomes of previous studies on diabetic hypertension, perindopril, which is an ACE inhibitor, and indapamide, which is a thiazide-based diuretic, reduced mortality and the occurrence of macrovascular and microvascular diseases. However, ACE inhibitors are contraindicated in patients with angioedema and bilateral renal artery stenosis, should be reduced or stopped when the glomerular filtration rate (GFR) is reduced by 30% or more, creatinine is increased, and hyperkalemia is developed, and requires close attention since electrolyte and renal function should be monitored periodically. In addition, when a thiazide-based diuretic is used at a high dose, blood glucose may increase, insulin secretion may be suppressed, insulin resistance may increase, and blood glucose control may be aggravated.

The pharmaceutical composition including amlodipine or a pharmaceutically acceptable salt thereof, according to an embodiment, inhibits hypertension progression, inhibits microvascular/macrovascular complications in diabetic patients, protects the cardiovascular system, inhibits the aggravation of renal function in patients with diabetic nephropathy, extends peripheral blood vessels, and increases blood flow to enhance insulin sensitivity. In addition, the pharmaceutical composition including losartan or a pharmaceutically acceptable salt thereof, according to an embodiment, extends peripheral blood vessels, and increases blood flow to enhance insulin sensitivity.

The term "diabetic dyslipidemia" refers to dyslipidemia occurring as a complication of diabetes. Diabetic dyslipidemia may be due to insulin resistance according to diabetes. Insulin resistance is commonly accompanied by dyslipidemia and its mechanism is unclear, but is well known to be associated with lipoprotein metabolism disorders. For example, hypertriglyceridemia observed in relatively well-controlled type 2 diabetes may be attributed to an increase in the concentration of free fatty acids in the hepatic portal vein as a result of intraperitoneal fat accumulation, which is considered to be one of the causes of diabetes. Free fatty acids introduced into the liver are esterified in the liver to become triglycerides and increase the production of very-low-density lipoproteins. In patients with poorly controlled diabetes, type 2b hypercholesterolemia, in which LDL-cholesterol increases along with very-low-density lipoproteins, is frequently observed, and in this case, when blood glucose is controlled using insulin or the like, LDL-cholesterol also decreases together with a decrease in the concentration of very-low-density lipoproteins.

Properties of diabetic dyslipidemia may be summarized as 1) an increase in blood triglycerides, 2) a decrease in HDL cholesterol, and 3) chemical denaturation of LDLs. In particular, with regard to 1), hypertriglyceridemia is commonly seen in diabetes and may be mainly due to over-production of VLDL-triglycerides (VLDL-TGs) in the liver and decreased removal thereof in peripheral tissues. In diabetes, insulin deficiency or insulin resistance increases the release of free fatty acids in adipose tissues, leading to an increase in uptake of free fatty acids, and accordingly, the synthesis of VLDL in the liver increases. Meanwhile, in adipose tissues and muscles, the activity of lipoprotein lipase participating in the decomposition of VLDL-TG is decreased due to insulin deficiency and insulin resistance, and thus the removal of VLDL-TG is reduced, thus increasing blood triglycerides. With regard to 2), the concentration of HDL is commonly decreased in diabetes, and particularly, a decrease in HDL2 is characteristic of diabetes, but an accurate mechanism therefor has not yet been discovered. Currently presumed mechanisms include the possibility of VLDL and chylomicron metabolic disorders occurring due to a decrease in the activity of lipoprotein lipase, and thus the conversion of HDL3 to HDL2 does not properly occur, an increase in HDL metabolism due to an increase in the activity of hepatic lipase participating in the metabolism of HDL in the liver, and the like. With regard to 3), while researchers have reported different results on whether LDL concentration increases in diabetes, and thus have been unable to draw a distinct conclusion, it has been reported that there is a structural change in LDL, associated with the occurrence of arteriosclerosis, and examples of well-known findings may include the glycosylation of LDL due to hyperglycemia and the oxidation of LDL due to a reduction in antioxidant capacity in the blood.

As an existing drug therapy for dyslipidemia, there is a method of administering niacin, a nicotinic acid preparation, a fibrate derivative, or estrogen. Niacin is a drug that inhibits lipolysis in adipose tissues, but the duration of action thereof is short, thus causing a rebound increase in free fatty acids and hyperglycemia, such that the use of niacin for the treatment of diabetic dyslipidemia is limited. Nicotinic acid preparations have long action durations, exhibit strong inhibitory effects on lipolysis, and have fewer side effects, such as rebound increases in free fatty acids and hyperglycemia, and thus are frequently selected especially when there is a large increase in TG levels, but may have side effects such as severe flushing, and the like. For a case in which triglycerides are increased alone or along with cholesterol, fibrate derivatives may be first selected, but in 2005, the department of pharmacovigilance of the Committee for Medicinal Products for Human Use (CHMP) insisted that the drug lacked evidence of long-term cardiovascular disease risk and reassessed this drug, and as a result, announced its conclusion that fibrate derivatives could not be the first choice for the treatment of dyslipidemia. The pharmaceutical composition including rosuvastatin or a pharmaceutically acceptable salt thereof, according to an embodiment, includes a high-intensity statin drug, and has an excellent effect of controlling blood pressure and lipid concentration in arteriosclerotic cardiovascular diseases, and cardiovascular diseases accompanied by diabetes.

According to one embodiment, a pharmaceutical composition including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof is provided as a customized therapeutic agent for diabetic patients in these cardiovascular diseases accompanied by diabetes.

The term "amlodipine" is the generic drug name for [3-ethyl 5-methyl 2-[(2-aminoethoxy)methyI]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate], and amlodipine is a calcium channel blocker that blocks calcium ion channels on the myocardial and vascular smooth muscle surfaces to relax vascular smooth muscle, and increases a glomerular filtration rate by relaxing the afferent arterioles of the kidneys, thus causing diuretic action, and thereby exhibiting a blood-pressure-lowering effect. In particular, amlodipine, which is a third-generation calcium channel blocker (CCB), exhibits a long-term, slow blood pressure-lowering effect due to slow absorption when orally administered and a long half-life of about 35 hours to about 40 hours, alleviates side effects such as orthostatic hypotension and the like, is effective in preventing systolic hypertension and stroke, and is useful in treatment of angina pectoris since it causes dilatation of the coronary arteries.

The term "losartan" is the generic drug name for 2-butyl-4-chloro-1-[{2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol, and losartan was the first developed angiotensin receptor antagonist-based ingredient. Losartan has a blood-pressure-lowering effect by acting as a selective and competitive antagonist against the receptor of angiotensin II, which is a potent vasoconstrictor, and is effective in treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), or the like, or preventing the progression of heart failure after myocardial infarction.

The term "rosuvastatin" is the generic drug name for [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid], and is a statin drug that inhibits the synthesis of cholesterol in the liver by acting as an HMG-CoA reductase inhibitor, increases the number of low-density lipoprotein (LDL) receptors on hepatic cell surfaces, and reduces the levels of plasma cholesterol and lipoproteins by promoting the uptake and decomposition of LDL. In addition, rosuvastatin beneficially changes the quality of circulatory LDL particles as well as reducing the production of LDL and the number of LDL particles, and is used not only for the treatment of hypercholesterolemia, hyperlipoproteinemia, or atherosclerosis, but also for the prevention of cardiovascular diseases such as stroke, myocardial infarction, and the like.

The pharmaceutical composition according to an embodiment has an excellent effect of controlling blood pressure and improving lipids especially in diabetic patients, and particularly has an excellent sitting systolic blood pressure-lowering effect and an excellent lipid improvement effect in a diabetic patient group. The excellent blood pressure-lowering effect and the excellent lipid improvement effect obtained by using the pharmaceutical composition including amlodipine, losartan, and rosuvastatin particularly in a diabetic patient group, when compared to a non-diabetic patient group, are unpredictably novel effects in the art relating to hypertension or dyslipidemia therapeutic agents.

In one embodiment, when a diabetic patient group was observed 8 weeks after being administered the composition including amlodipine, losartan, and rosuvastatin, the diabetic patient group exhibited an about 1.4-fold (about 1.36-fold) greater decrease in a mean sitting systolic blood pressure (mean sitSBP) relative to a non-diabetic patient group (see Experimental Example 1). From this result, it was confirmed that the composition including amlodipine, losartan, and rosuvastatin effectively decreased a mean sitSBP in a diabetic patient group.

In one embodiment, when a diabetic patient group was observed 8 weeks after being administered the composition including amlodipine, losartan, and rosuvastatin, the diabetic patient group exhibited an about 1.2-fold (about 1.18-fold) greater decrease in a mean sitting diastolic blood pressure (mean sitDBP) relative to a non-diabetic patient group (see Experimental Example 2). From this result, it was confirmed that the composition including amlodipine, losartan, and rosuvastatin effectively reduced a mean sitDBP in a diabetic patient group.

In one embodiment, it was confirmed that the composition including amlodipine, losartan, and rosuvastatin effectively reduced triglycerides (TGs) at 8 weeks after administration, compared to a case of being administered a composition including only amlodipine and losartan, or only losartan and rosuvastatin (see Experimental Examples 3(1) and 3(2)).

In one embodiment, the composition including amlodipine, losartan, and rosuvastatin exhibited increased triglyceride (TG) regulation effect especially at 8 weeks after administration to a diabetic patient group. In particular, when a comparison between a case in which only losartan and rosuvastatin were administered and a case in which amlodipine, losartan, and rosuvastatin were administered was performed by varying the composition of administered drugs and the groups to which the drugs were administered, a greater triglyceride (TG) decrease was not exhibited in a non-diabetic patient group in spite of further addition of amlodipine, and TGs were rather unsatisfactorily regulated due to the addition of amlodipine, compared to the case in which only losartan and rosuvastatin were administered. In contrast, a diabetic patient group showed an about 1.9-fold (about 1.93-fold) greater triglyceride (TG) decrease due to the administration of the composition including amlodipine, losartan, and rosuvastatin, compared to the composition including only losartan and rosuvastatin. From these results, it was confirmed that the diabetic patient group exhibited an enhanced TG regulation effect due to a greater TG decrease in accordance with the administration of the composition including amlodipine, losartan, and rosuvastatin (see Experimental Example 3(3)).

In one embodiment, 4 weeks or 8 weeks after the composition including amlodipine, losartan, and rosuvastatin was administered, a high blood pressure normalization rate was observed, compared to a case in which only amlodipine and losartan were administered, or a case in which only losartan and rosuvastatin were administered (see Experimental Example 4(1)). In addition, the composition including amlodipine, losartan, and rosuvastatin also exhibited a high blood pressure normalization rate for the case of cardiovascular risk classification group C, and exhibited an excellent blood pressure normalization rate in all of cardiovascular risk classification groups A, B, and C (see Experimental Example 4(2)). In addition, the composition including amlodipine, losartan, and rosuvastatin exhibited a higher blood pressure normalization rate in a patient group with accompanying diabetes than that of a case in which only amlodipine and losartan were administered, or a case in which only losartan and rosuvastatin were administered (see Experimental Example 4(3)). From these results, it was confirmed that the composition including amlodipine, losartan, and rosuvastatin exhibited an excellent blood pressure normalization rate, and also exhibited a high blood pressure normalization rate in a patient group with accompanying diabetes.

In one embodiment, 4 weeks or 8 weeks after the composition including amlodipine, losartan, and rosuvastatin was administered, a low-density lipoprotein-cholesterol (LDL-C) treatment goal achievement rate and a blood pressure normalization rate observed were higher than in a case in which only amlodipine and losartan were administered, or a case in which only losartan and rosuvastatin were administered (see Experimental Example 5(1)). In addition, the composition including amlodipine, losartan, and rosuvastatin exhibited a higher LDL-C treatment goal achievement rate and higher blood pressure normalization rate, compared to the case in which only amlodipine and losartan were administered, or the case in which only losartan and rosuvastatin were administered (see Experimental Example 5(2)). From these results, it was confirmed that the composition including amlodipine, losartan, and rosuvastatin exhibited an excellent LDL-C treatment goal achievement rate and an excellent blood pressure normalization rate, and also exhibited a high LDL-C treatment goal achievement rate and a high blood pressure normalization rate in a patient group with accompanying diabetes.

In one embodiment, the pharmaceutical composition may be used for the prevention or treatment of patients who have both hypertension and dyslipidemia simultaneously with diabetes. The pharmaceutical composition may be a composition for the prevention or treatment of diabetic hypertension or diabetic dyslipidemia. In one embodiment, the pharmaceutical composition may be a composition for the prevention or treatment of diabetic hypertension.

According to the guideline for clinical trials of hypertension therapeutic agents, in the evaluation of blood pressure-lowering effects, the effectiveness of hypertension therapeutic agents is generally evaluated first using a change in sitting systolic blood pressure before and after treatment, as a primary evaluation item, and using a change in sitting diastolic blood pressure before and after treatment as a secondary evaluation item. In addition, the degree of hypertension treatment response refers to a blood pressure normalization rate (the percentage of patients satisfying the following conditions: systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg) after treatment is completed) and a blood pressure response rate (the percentage of patients satisfying the following conditions: 20 mmHg or greater decrease in systolic blood pressure and 10 mmHg or greater decrease in diastolic blood pressure with respect to baseline values after treatment is completed) (the Korea Food and Drug Administration, the National Institute of Food and Drug Safety Evaluation, 2015. 12).

In one embodiment, the pharmaceutical composition may decrease a sitting systolic blood pressure by about 1.3-fold or greater, for example, about 1.36-fold or greater or about 1.4-fold or greater, compared to the case of cardiovascular diseases not accompanied by diabetes. In a diabetic patient group, the pharmaceutical composition may significantly further decrease a sitting systolic blood pressure by about 1.3-fold or greater, for example, about 1.36-fold or greater or about 1.4-fold or greater, for example, about 1.3-fold, about 1.36-fold, about 1.4-fold, about 1.45-fold, or about 1.5-fold, relative to a non-diabetic patient group. In one embodiment, the change in sitting systolic blood pressure of the pharmaceutical composition in the diabetic patient group compared to the non-diabetic patient group may be about 1.3-fold or greater, or range from about 1.2-fold to about 2.5-fold, about 1.3-fold to about 2.5-fold, about 1.3-fold to about 2.0-fold, about 1.35-fold to about 1.5-fold, or about 1.3-fold to about 1.5-fold.

In one embodiment, the pharmaceutical composition may be a pharmaceutical composition for lowering a sitting systolic blood pressure of a diabetic patient.

In one embodiment, the pharmaceutical composition may exhibit decreases (Mean±SD) in sitting systolic blood pressure of 20.48±17.95 mmHg and 15.04±10.86 mmHg with respect to a baseline value 8 weeks after being administered to a diabetic patient group and a non-diabetic patient group, respectively. In one embodiment, the pharmaceutical composition may exhibit maximum values of the decreases in sitting systolic blood pressure of 52.00 mmHg and 38.30 mmHg with respect to a baseline value 8 weeks after being administered to the diabetic patient group and the non-diabetic patient group, respectively.

In one embodiment, the pharmaceutical composition may decrease a sitting diastolic blood pressure by about 1.2-fold or greater, for example, about 1.10-fold or greater or about 1.18-fold or greater, when compared to the case of cardiovascular diseases not accompanied by diabetes. In a diabetic patient group, the pharmaceutical composition may further significantly decrease a sitting diastolic blood pressure by about 1.2-fold or greater, for example, about 1.10-fold or greater or about 1.18-fold or greater, for example, about 1.10-fold, about 1.15-fold, or about 1.20-fold, relative to a non-diabetic patient group.

In one embodiment, the pharmaceutical composition may be a composition for the prevention or treatment of diabetic hypertension or diabetic dyslipidemia. In another embodiment, the pharmaceutical composition may be a composition for the prevention or treatment of diabetic hypertension.

Cardiovascular diseases that are preventable or treatable by the pharmaceutical composition may satisfy at least one among the following criteria. The following criteria may be modified in accordance with a revision of the guidelines for the diagnosis of hypertension or dyslipidemia (Treatment Guidelines of the Korean Society of Hypertension and JNC 8 report, and J Lipid Atheroscler 2015;4(1):61-92).

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

(b) sitting diastolic blood pressure (sitDBP) ≥ 90 mmHg

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

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

(e) blood triglyceride concentration ≥ 150 mg/dL

(f) total cholesterol concentration > 200 mg/dL

According to the clinical practice guidelines, normal blood glucose levels are as follows: a fasting plasma glucose level of less than 100 mg/dL and a plasma glucose level of less than 140 mg/dL 2 hours after a 75 g oral glucose tolerance test, and a fasting blood glucose disorder indicates a case in which a fasting plasma glucose level is between 100 mg/dL and 125 mg/dL, and impaired glucose tolerance indicates a case in which a plasma glucose level is between 140 mg/dL and 199 mg/dL 2 hours after a 75 g oral glucose tolerance test.

A subject to which the pharmaceutical composition exhibiting blood pressure control and lipid improvement effects is applicable may be a diabetic patient group, for example, a subject having at least one among the following conditions. In addition, the following criteria may be in accordance with the diagnostic criteria for diabetes known in the art to which the present disclosure pertains, for example, the 2016 guidelines of the American Diabetes Association (ADA), and may be changed in accordance with a revision of the guidelines in this regard.

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

(4) glycosylated hemoglobin level (HbA1c) ≥ 6.5%

In one embodiment, with respect to a total amount of the pharmaceutical composition, the amount of amlodipine or a pharmaceutically acceptable salt thereof may range from about 5 mg to about 10 mg when converted into an amlodipine free base form, the amount of losartan or a pharmaceutically acceptable salt thereof may range from about 45 mg to about 100 mg when converted into a losartan free acid form, and the amount of rosuvastatin or a pharmaceutically acceptable salt thereof may range from about 5 mg to about 20 mg when converted into a rosuvastatin free acid form. In one embodiment, the pharmaceutical composition may be administered once a day.

In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amlodipine form in the pharmaceutical composition in an amount of about 5 mg to about 10 mg, e.g., 5 mg. Losartan or a pharmaceutically acceptable salt thereof may be included in a losartan form in the pharmaceutical composition in an amount of about 45 mg to about 100 mg, e.g., 50 mg or 100 mg. Rosuvastatin or a pharmaceutically acceptable salt thereof may be included in a rosuvastatin form in the pharmaceutical composition in an amount of about 5 mg to about 20 mg, e.g., 5 mg, 10 mg, or 20 mg. The doses may be appropriately adjusted in consideration of symptoms, age, race, and gender.

In another embodiment, the pharmaceutical composition may include 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.

In one embodiment, the pharmaceutical composition may be formulated into a fixed-dose combination formulation including, at the aforementioned doses, amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutical composition may be administered once to several times a day, for example, once or three times a day, according to the administered amount. For example, the pharmaceutical composition including 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin may be administered once a day.

By administering the pharmaceutical composition including 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin once a day, patient convenience and medication compliance may be enhanced, and an optimal pharmacological clinical effect may also be obtained in terms of a blood-pressure-lowering effect.

In one embodiment, the pharmaceutical composition may be administered for 4 weeks or more or less or 8 weeks or more or less in consideration of pathological conditions, the severity thereof, and the like of a subject to which the pharmaceutical composition is administered. When the pharmaceutical composition is administered in the same composition and amount, for example, when the pharmaceutical composition includes amlodipine or a pharmaceutically acceptable salt thereof in an amount of 5 mg when converted into an amlodipine free base form, losartan or a pharmaceutically acceptable salt thereof in an amount of 100 mg when converted into a losartan free acid form, and rosuvastatin or a pharmaceutically acceptable salt thereof in an amount of 20 mg when converted into a rosuvastatin free acid form, and is administered on a daily dose basis, the sitting systolic blood pressure may be more significantly reduced in a diabetic patient group than in a non-diabetic patient group.

In the pharmaceutical composition, the pharmaceutically acceptable salt of amlodipine, losartan, or rosuvastatin means a salt prepared according to a method commonly known in the art, and the preparation method is known to those of ordinary skill in the art. In particular, examples of the pharmaceutically acceptable salt include, but are not limited to, the following inorganic acids, organic acids, and base-derived salts that are pharmacologically or physiologically acceptable. Non-limiting examples of suitable acids may include 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-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methane sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, besylic acid, and camsylic acid. Examples of suitable base-derived salts may include, but are not limited to, salts of an alkali metal such as sodium or potassium and salts of an alkali earth metal such as calcium or magnesium.

The pharmaceutically acceptable salt of amlodipine is formed from an acid forming a non-toxic acid addition salt containing a pharmaceutically acceptable anion, and examples thereof may include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate, and camsylate. For example, amlodipine besylate or amlodipine camsylate may be used. In addition, the amlodipine includes amlodipine racemate and (S)-amlodipine. The pharmaceutically acceptable salt of losartan may be, for example, losartan potassium, but the present disclosure is not limited thereto. In addition, the pharmaceutically acceptable salt of rosuvastatin may be, for example, rosuvastatin calcium or rosuvastatin magnesium, but the present disclosure 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 pharmaceutically acceptable salt thereof, the losartan or pharmaceutically acceptable salt thereof, and the rosuvastatin or pharmaceutically acceptable salt thereof may be co-administered simultaneously or sequentially.

In one embodiment, the amlodipine or pharmaceutically acceptable salt thereof, the losartan or pharmaceutically acceptable salt thereof, and the rosuvastatin or pharmaceutically acceptable salt thereof may be administered in a single dosage form including all of the above ingredients or administered in multiple dosage forms separately including the respective ingredients. The amlodipine or pharmaceutically acceptable salt thereof, the losartan or pharmaceutically acceptable salt thereof, and the rosuvastatin or pharmaceutically acceptable salt thereof may be co-administered in a single dosage form or in separate dosage forms. The single dosage form or the separate dosage forms may be in a tablet or capsule form. For example, when the above ingredients are present in separate dosage forms, the ingredients may be administered via different routes. When the active ingredients are administered sequentially or independently, delay in administration of the second ingredient should not hinder, for example, the beneficial effects of co-administration therapy. In this context, sequential administration may also include, but is not limited to, for example, alternate administration of the active ingredients.

A dose of the pharmaceutical composition according to an embodiment may vary depending on the age, gender, body weight, pathologic conditions and severity of subjects to which the pharmaceutical composition is to be administered, administration routes, or determination of prescribers. A suitable dose based on these factors is determined by one of ordinary skill in the art.

The pharmaceutical composition may exist in the form of, for example, tablets, capsules, an aqueous or oily suspension, an emulsion, or dispersible powder or granules suitable for oral administration; in the form of an aqueous or oily sterilized solution or suspension suitable for parenteral administration, e.g., intravenous administration, subcutaneous administration, intramuscular administration, or intravascular administration; in the form of, for example, a cream, a gel, or an ointment suitable for local administration; or in the form of suppositories suitable for rectal administration. In one embodiment, the composition exists in the form of, for example, tablets or capsules suitable for oral administration.

In one embodiment, the pharmaceutical composition may further include one or more other drugs for preventing or treating a cardiovascular disease selected from a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and a HMG-CoA reductase inhibitor. The one or more other drugs for preventing or treating a cardiovascular disease may be administered in combination with the pharmaceutical composition.

Non-limiting examples of the CCB may include nifedipine, felodipine, and verapamil, in addition to amlodipine. Non-limiting examples of the ARB may include telmisartan, valsartan, candesartan, irbesartan, and olmesartan, in addition to losartan. Non-limiting examples of the HMG-CoA reductase inhibitor may include pravastatin, simvastatin, fluvastatin, atorvastatin, and pitavastatin, in addition to rosuvastatin. The pharmaceutical composition may further include a diuretic, for example, a thiazide-based diuretic such as hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, metolazone, polythiazide, xipamide, or the like. For example, co-administration therapy using two or more drugs for the treatment of hypertension may be adopted to enhance a blood-pressure-lowering effect and also complementarily reduce side effects of each drug. For example, when co-administration therapy using a CCB and an ARB is used, both blood vessel extension and body fluid regulation may be expected, and thus advantageous effects of co-administration may be obtained.

According to another embodiment of the present disclosure, there is provided a composite preparation for the prevention or treatment of a cardiovascular disease accompanied by diabetes, including: amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

The composite preparation according to an embodiment may be effective in treating a patient with hypertension and dyslipidemia. Each of hypertension and dyslipidemia is a single risk factor of cardiovascular diseases, and when the two diseases are simultaneously treated, a significant clinical effect is obtained. In addition, the composite preparation may enhance medication convenience and medication compliance of patients to which the amlodipine or a pharmaceutically acceptable salt thereof, the losartan or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof of are to be administered simultaneously, and may reduce medicine costs. In particular, the corresponding patient disease group mostly consists of elderly patients after middle age due to the characteristics of the disease, and when considering that there are many cases in which multiple drugs need to be simultaneously administered, the effect of an increase in medication compliance is more significantly obtained when the composite preparation is administered.

Suitable doses of the amlodipine or a pharmaceutically acceptable salt thereof, the losartan or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof included in the composite preparation are the same as those described above with regard to the pharmaceutical composition.

In one embodiment, the composite preparation may include amlodipine or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 10 mg, losartan or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to about 100 mg, and rosuvastatin or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 20 mg. For example, the composite preparation may include the three active ingredients in respective amounts of: 5 mg, 50 mg, and 5 mg; 5 mg, 50 mg, and 10 mg; 5 mg, 50 mg, and 20 mg; 5 mg, 100 mg, and 5 mg; 5 mg, 100 mg, and 10 mg; or 5 mg, 100 mg, and 20 mg. In one embodiment, the composite preparation may be in the form of tablets, capsules, or caplets. The composite preparation may be in a bi-layer tablet form or in a three-layer tablet form.

The composite preparation may include, for example, in a first mixed part, amlodipine or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof, and in a second mixed part, losartan or a pharmaceutically acceptable salt thereof, wherein the first mixed part and the second mixed part are present in a state physically separated from each other. For example, each of the first mixed part and the second mixed part may further include a pharmaceutically acceptable additive.

In addition, the composite preparation may be, for example, in the form of a bi-layer tablet including, in a first layer, amlodipine or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof, and in a second layer, losartan or a pharmaceutically acceptable salt thereof. For example, each of the first layer and the second layer may further include a pharmaceutically acceptable additive.

According to one embodiment, the pharmaceutical composition including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, or the composite preparation including the same exhibited excellent effects in terms of treatment of hypertension and dyslipidemia.

In addition, as a result of conducting clinical trials, it was confirmed that, 8 weeks after co-administration (A5+L100+R20) of 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin, an effect of treating dyslipidemia (changes in LDL-C, total cholesterol, HDL-C, and triglyceride, and NCEP ATP III LDL-C treatment goal achievement rate) and hypertension (mean sitDBP, change in sitSBP, and JNC VII blood pressure normalization rate) was superior to that of a control. Especially in diabetic patients, effective blood pressure control and lipid improvement effects were observed and a sitting systolic blood-pressure-lowering effect was excellent.

According to another embodiment of the present disclosure, there is provided a method of treating a cardiovascular disease accompanied by diabetes, by using a composition including amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

In one embodiment, the amlodipine or a pharmaceutically acceptable salt thereof, the losartan or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof included in the composition may be administered using various administration methods such as orally or parenterally according to the purpose of use in an amount effective for the treatment or prevention of a disease of an individual or a patient. In the administration methods, a suitable dose for particular individuals or patients may be determined depending on various associated factors such as the body weight, age, race, gender, health conditions, and diet of patients, administration period, administration methods, the severity of diseases, and the like, and it is to be understand that the suitable dose may be appropriately increased or decreased by experts, and the dose is not intended to limit the scope of the present disclosure in any way. If needed, a dose of compound used may be easily determined and prescribed by doctors of ordinary skill in the related art. For example, a dose of a compound used in the pharmaceutical composition of the present disclosure may be adjusted by a doctor such that the dose is first adjusted to be of a lower level than required to achieve a desired therapeutic effect and then is gradually increased until a desired effect is achieved.

The term "treatment" as used herein is intended to include all of treatment, improvement, amelioration, and management of diseases. The term "treating" or "treatment" as used herein refers to inhibiting a disease, for example, inhibiting a disease or pathologic condition or disorder in an individual experiencing or exhibiting a pathologic condition or symptom of the disease or pathologic condition or disorder, preventing further development of pathologic conditions and/or symptoms, ameliorating a disease, or reversing pathologic conditions and/or symptoms, e.g., reducing the severity of diseases.

The term "preventing" or "prevention" as used herein refers to preventing a disease, for example, preventing a disease, condition, or disorder in an individual who may have a risk of the disease, condition or disorder, but has not yet experienced or exhibited the condition or symptom of a disease.

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

The term "has", "may have", "includes", or "may include" as used herein is intended to include the presence of the corresponding property (e.g., a value, or a component such as an ingredient or the like), but do not preclude the presence of additional properties.

Hereinafter, the present disclosure will be described in further detail with reference to the following examples. However, these examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[Examples]

Example 1: Selection of Trial Subject and Administration of Clinical Trial Drug

1. Selection of Trial Subject

Trial subjects were selected based on the following selection criteria:

1) adults aged 19 years old to 75 years old

2) patients satisfying the following conditions at the time of screening at the first visit

① Blood pressure standard: sitDBP ≥ 90 mmHg

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

3) Patients satisfying the following conditions at the second visit after 4 weeks of therapeutic lifestyle change (TLC)

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

② Lipid standard: Patients satisfying the following conditions when classified into groups A, B, and C according to the risk of cardiovascular disease

Coronary Heart Disease (CHD) Risk Factor

1) Current smoker

2) Taking blood pressure medicine

3) low HDL-C (< 40 mg/dL)^†

4) Early CHD family history: case of males under the age of 55 or females under the age of 65 with CHD among a parent, brothers, sisters, and brother and sister

5) age (45 years old or older for males; 55 years old or older for females)

^†However, in the case of HDL-C ≥ 60 mg/dL, the case is regarded as a protective factor, and thus one should be subtracted from the total number of risk factors.

^* CHD Risk Equivalents

Coronary artery disease, diabetes (HbA1c ≥ 6.5 %, but in the case of being diagnosed with diabetes or taking a diabetes medication, the case is regarded as diabetes regardless of the HbA1C standard), or other clinical forms of atherosclerosis (e.g., peripheral artery disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and the like)

In particular, a case in which the number of CHD risk factors was 0 or 1 was classified into Group A. In addition, a case in which the number of CHD risk factors was 2 or more was classified into Group B. In addition, a case, in which CHD/CHD risk equivalents or the risk of developing cardiovascular disease within 10 years was greater than 20%, was classified into Group C. Detailed classification according to the LDL-C or TG condition is the same as shown in the above table.

In addition, the cases not appropriate for clinical trials were excluded from subjects according to the predetermined criteria.

2. Formulation and Preparation of Clinical Trial Drug

(1) Formulation of Drug for Trial

Tablets including 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin were prepared as a trial drug to be administered to a selected subject group and used as a drug for trial.

In particular, amlodipine camsylate, rosuvastatin calcium, lactose hydrate, microcrystalline cellulose, and crospovidone were mixed and formulated, and then magnesium stearate was added thereto, and the resulting mixture was finally mixed in a mixer to prepare a blend of amlodipine and rosuvastatin. In addition, losartan potassium, microcrystalline cellulose, and crospovidone were mixed and formulated, and pressurized to be formed into granules, magnesium stearate was added thereto, and then the resulting mixture was finally mixed to prepare losartan granules. Finally, composite bi-layer tablets consisting of the prepared blend of amlodipine and rosuvastatin and the prepared losartan granules were prepared.

(2) Preparation of Drug for Control

As a control, 5 mg of Amodipin^TMtablets (5 mg as amlodipine), 100 mg of Cozzar^TM tablets (100.0 mg as losartan), and 20 mg of Crestor^TM tablets (20 mg as rosuvastatin) were prepared.

3. Assignment of Trial Subjects

Phase III clinical 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 the TLC period, existing hypertension and dyslipidemia therapeutic agents were washed out, followed by monotherapy using 100 mg of losartan. After 4 weeks of the TLC, blood pressure and fasting serum lipids were checked again at the second visit, and subjects satisfying the selection criteria were randomly assigned to three groups.

Experimental group: group administered a tablet (A5+L100+R20) including 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin

Control 1: group administered 5 mg of amlodipine and 100 mg of losartan (5 mg of an Amodipin^TMtablet and 100 mg of a Cozzar^TM tablet) (A5+L100)

Control 2: group administered 100 mg of losartan and 20 mg of rosuvastatin (100 mg of a Cozzar^TM tablet and 20 mg of a Crestor^TM tablet) (L100+R20)

A full analysis set (FAS) was aimed at trial subjects on whom a primary efficacy evaluation was performed at least once after administration of the clinical trial drug until the clinical trial was completed, among trial subjects administered the clinical trial drug once or more after random assignment of the trial subjects.

A per protocol set (PPS) was aimed at trial subjects on whom the clinical trial was completed according to the clinical trial protocol, among the FAS subjects, and subjects who deviated from the protocol were excluded from the PPS.

The main analytical group FAS of the clinical trial included 143 trial subjects except for 2 subjects having not undergone the primary efficacy evaluation even once after the random assignment, and according to the drug-administered group, the A5+L100+R2-administered group included 54 subjects, the A5+L100-administered group included 46 subjects, and the L100+R20-administered group included 43 subjects. 131 subjects who completed the clinical trial according to the clinical trial protocol in the FAS were included in the PPS, and according to the drug-administered group, the A5+L100+R20-administered group included 50 subjects, the A5+L100-administered group included 41 subjects, and the L100+R20-administered group included 40 subjects. 12 subjects were excluded from the PPS due to dropout, taking drugs banned for co-administration, clinical trial drug dispensing errors, and the like.

Comparative evaluation for homogeneity between the drug-administered groups was performed on the FAS based on basic demographic data such as gender, age, height, body weight, smoking history, and drinking history, and there was no significant difference between the groups except in body weight. In addition, all the drug-administered groups exhibited a medication compliance of 95% or more.

4. Administration of Clinical Trial Drug

A phase III clinical trial was conducted on the selected trial subjects by administering the prepared trial drug and the control according to the protocol. In particular, the A5+L100+R20-administered group (experimental group) was administered 1 tablet of the prepared trial drug (tablets including 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin) once a day. The A5+L100-administered group (Control 1) was administered 1 tablet of each of amlodipine and Cozzar^TM once a day, and the L100+R20-administered group (Control 2) was administered 1 tablet of each of Cozzar^TM and Crestor^TM as trial drugs once a day. The clinical trial drugs were administered to the experimental group and controls 1 and 2 for 8 weeks. During 8 weeks of administration of the clinical trial drug, the trial subjects visited the trial institute at intervals of 4 weeks and underwent effectiveness and safety evaluations. In addition, the clinical trial results were analyzed according to the following evaluation standards.

5. Evaluation Standards

(1) Efficacy Evaluation

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

1) Primary Efficacy Endpoints

① LDL-C change rates of the group administered amlodipine/losartan/rosuvastatin (A5+L100+R20) (experimental group) and the group administered amlodipine/losartan (A5+L100) (control 1), with respect to a baseline after 8 weeks

② Mean sitDBP variations of the group administered amlodipine/losartan/rosuvastatin and the group administered losartan/rosuvastatin, with respect to a baseline after 8 weeks

2) Secondary Efficacy Endpoints

① Rates of change in LDL-C of the group administered amlodipine/losartan/rosuvastatin and the group administered amlodipine/losartan, with respect to a baseline after 4 weeks

② Rates of change in LDL-C of the group administered amlodipine/losartan/rosuvastatin and the group administered losartan/rosuvastatin, with respect to a baseline after 4 weeks and 8 weeks

③ Rates of change in TC, HDL-C, and TG of the group administered amlodipine/losartan/rosuvastatin, the group administered losartan/rosuvastatin, and the group administered amlodipine/losartan, with respect to a baseline after 4 weeks and 8 weeks

④ Mean sitDBP (mmHg) variations of the group administered amlodipine/losartan/rosuvastatin and the group administered losartan/rosuvastatin, with respect to a baseline after 4 weeks

⑤ Mean sitDBP (mmHg) variations of the group administered amlodipine/losartan/rosuv and the group administered amlodipine/losartan, with respect to a baseline after 4 weeks and 8 weeks

⑥ Mean sitSBP (mmHg) variations of the group administered amlodipine/losartan/rosuvastatin, the group administered losartan/rosuvastatin, and the group administered amlodipine/losartan, with respect to a baseline after 4 weeks and 8 weeks

⑦ LDL-C treatment goal achievement rates according to the NCEP ATP III guidelines of the group administered amlodipine/losartan/rosuvastatin, the group administered losartan/rosuvastatin, and the group administered amlodipine/losartan after 4 weeks and 8 weeks

⑧ Blood pressure normalization rates according to the JNC VII guidelines of the group administered amlodipine/losartan/rosuvastatin, the group administered losartan/rosuvastatin, and the group administered amlodipine/losartan after 4 weeks and 8 weeks

⑨ The percentage of trial subjects achieving the LDL-C treatment goal according to the NCEP ATP III guidelines and blood pressure normalization according to the JNC VII guidelines of the group administered amlodipine/losartan/rosuvastatin, the group administered losartan/rosuvastatin, and the group administered amlodipine/losartan after 4 weeks and 8 weeks

(2) Safety Evaluation

1) Adverse event

2) Vital signs

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

4) Physical examination

5) Electrocardiogram (ECG)

6) Hormone test, etc.

6. Statistical Analysis Method and Standard

The results obtained based on the clinical trial evaluation criteria were statistically analyzed using the following method. Statistical analysis was carried out according to the 'Intend to Treat Principle' when assessing the efficacy of clinical trials, and statistical analysis was performed for the safety evaluation as it was actually taken. The demographic information and baseline characteristics of the FAS were analyzed, and statistical analysis was performed for the efficacy evaluation on the FAS as a main analytical group and the PPS as an auxiliary analytical group. In addition, for the safety evaluation, statistical analysis was performed on a safety analysis set.

For all statistical tests, two-sided tests were performed at a significance level of 5%. When missing values were found for the primary and secondary efficacy variables, statistical analysis was performed by applying the Last Observation Carried Forward (LOCF) method, and for the safety evaluation variables, the LOCF method was not applied and statistical analysis was performed according to the original data.

(1) Efficacy Evaluation Analysis

1) Primary Efficacy Evaluation

For comparison of the difference in the rate of change in LDL-C with respect to a baseline after 8 weeks between the group administered amlodipine/losartan/rosuvastatin and the group administered amlodipine/losartan, covariance analysis (ANCOVA) in which LDL-C at the baseline was corrected with a covariate was performed, and the number of trial subjects, an arithmetic mean, a standard deviation, a median, and minimum and maximum values were presented for LDL-C according to the time point in each drug-administered group.

In addition, for comparison of the difference in sitDBP variation with respect to the baseline after 8 weeks between the group administered amlodipine/losartan/rosuvastatin and the group administered losartan/rosuvastatin, covariance analysis (ANCOVA) in which sitDBP at the baseline was corrected with a covariate was performed, and the number of trial subjects, an arithmetic mean, a standard deviation, a median, and minimum and maximum values were presented for sitDBP according to the time point in each drug-administered group.

2) Secondary Efficacy Evaluation

For comparison of the difference in the rates of change in LDL-C, TC, HDL-C, and TG and sitDBP and sitSBP variations with respect to the baseline except for the primary efficacy evaluation variables after 4 weeks and 8 weeks between the group administered amlodipine/losartan/rosuvastatin as an experimental group and the controls, i.e., the group administered losartan/rosuvastatin and the group administered amlodipine/losartan, covariance analysis (ANCOVA) in which each efficacy evaluation variable at the baseline was corrected with a covariate was performed, and the number of trial subjects, an arithmetic mean, a standard deviation, a median, and minimum and maximum values were presented for each evaluation variable according to the time point in each group.

In addition, for comparison between the experimental group and the controls in the percentage of trial subjects having achieved the LDL-C treatment goal achievement rate according to the NCEP ATP III guidelines, the blood pressure normalization rate according to the JNC VII guidelines, and the LDL-C treatment goal achievement rate according to the NCEP ATP III guidelines, and having reached blood pressure normalization according to the JNC VII guidelines 4 weeks and 8 weeks after administration of the clinical trial drugs, the Cochran-Mantel-Haenszel (CMH) test using cardiovascular risk categories as strata was performed. Additionally, Pearson's chi-square test or Fisher's exact test was performed on each cardiovascular risk classification group for comparison between the drug-administered groups.

(2) Safety Evaluation Analysis

1) Adverse Event

All the investigated adverse events (AEs) were classified and listed into pre-existing AEs and treatment emergent AEs (TEAEs). The number and percentage (%) of subjects with TEAEs were presented for serious AEs, the severity of AEs, and a causal relationship with the clinical trial drug according to the drug-administered group.

2) Other Safety Evaluation Variables

For each drug-administered group, a shift table was presented for normality, not clinically significant (NCS) abnormality, and clinically significant (CS) abnormality according to the time point, and the McNemar's　test was performed to conduct statistical significance testing for changes in each drug-administered group before/after administration of the clinical trial drug. Additionally, in the case of continuous variables, the number of trial subjects, an arithmetic mean, a standard deviation, a median, and minimum and maximum values were presented for each time point.

Experimental Example 1: Measurement of Decrease (mmHg) in Mean Sitting Systolic Blood Pressure (sitSBP) in Diabetic mellitus (DM) Patient Group Compared to Non-DM Patient Group

Variations (mmHG) in mean sitSBP of the group administered 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin (A5+L100+R20) (experimental group) and the group administered 5 mg of amlodipine and 100 mg of losartan (A5+L100) (control 1), with respect to a baseline after 8 weeks were measured. Each of the experimental group and the control includes a DM patient group and a non-DM patient group. The results thereof are shown in Table 1 below and FIG. 1.

[Table 1]

As shown in Table 1 and FIG. 1, the (A5+L100+R20)-administered group exhibited a greater variation (mmHg) in mean sitSBP after 8 weeks than that of the (A5+L100)-administered group. From this result, it can be seen that when 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin are all administered, a mean sitSBP-lowering effect is significantly increased, compared to when only 5 mg of amlodipine and 100 mg of losartan are administered.

In addition, this effect was shown in both the DM patient group and the non-DM patient group, and it was shown that when the (A5+L100+R20)-administered group was compared with the (A5+L100)-administered group, the width of variation in mean sitSBP (mmHg) was more significantly increased in the DM patient group. From this result, it can be seen that when 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin are all administered, the effect of significantly lowering mean sitSBP is further increased and thus more significant especially in the DM patient group, as compared to when only 5 mg of amlodipine and 100 mg of losartan are administered. In addition, the results of the PPS were similar to those of the FAS.

In both the DM patient group and the non-DM patient group, an additional blood-pressure-lowering effect was more significant in the (A5+L100+R20)-administered group than in the (A5+L100)-administered group. In addition, while the non-DM patient group showed no significant difference between sitSBP variations (mean±SD) when A5+L100+R20 were administered and when A5+L100 were administered, i.e., -15.04±10.86 mmHg and -13.42±14.42 mmHg, respectively, the DM patient group showed a significant difference between sitSBP variations (mean±SD) when administered A5+L100+R20 and when administered A5+L1, i.e., -20.48±17.95 mmHg and -13.30±15.03 mmHg, respectively in terms of lowering blood pressure. In particular, in the case of the group administered A5+L100, the sitSBP variation, i.e., an effect of lowering a systolic blood pressure was similarly exhibited in the DM patient group and the non-DM patient group, whereas, when administered A5+L100+R20, the DM patient group exhibited a greater sitSBP variation (mean±SD) than that of the non-DM patient group, from which it was confirmed that the DM patient group exhibited an about 1.4-fold (about 1.36-fold) decrease in systolic blood pressure, relative to the non-DM patient group.

Experimental Example 2: Measurement of Decrease (mmHg) in Mean Sitting Diastolic Blood Pressure (sitDBP) of DM Patient Group Compared to Non-DM Patient Group

Mean sitDBP variations (mmHg) of the group administered 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin (A5+L100+R20) (experimental group) with respect to a baseline after 8 weeks were measured. Each of the experimental group and the control includes a DM patient group and a non-DM patient group. The results thereof are shown in Table 2 below and FIG. 2.

[Table 2]

As shown in Table 2 and FIG. 2, when compared to the (A5+L100)-administered group, the (A5+L100+R20)-administered group exhibited an increased sitDBP variation (mmHg) after 8 weeks. From this result, it can be seen that when 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin are administered, a mean diastolic blood-pressure-lowering effect is more significantly increased, as compared to when only 5 mg of amlodipine and 100 mg of losartan are administered.

In addition, this effect was shown in both of the DM patient group and the non-DM patient group, and it was shown that when the (A5+L100+R20)-administered group was compared with the (A5+L100)-administered group, the width of the mean sitDBP variation (mmHg) was increased more in the DM patient group. In particular, it was confirmed that the DM patient group exhibited an about 1.2-fold (about 1.18-fold) decrease in diastolic blood pressure, relative to the non-DM patient group.

From this result, it can be seen that, when 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin are administered, the mean diastolic blood-pressure-lowering effect is more significant in the DM patient group, compared to when only 5 mg of amlodipine and 100 mg of losartan are administered. In addition, the results of the PPS were also similar to those of the FAS.

From the results shown in Tables 1 and 2 above and FIGS. 1 and 2, it can be seen that an effect of lowering both diastolic and systolic blood pressures is more significantly increased according to co-administration of amlodipine, losartan, and rosuvastatin. In addition, the blood-pressure-lowering effect was more significantly exhibited in the DM patient group. In addition, the blood-pressure-lowering effect was increased more in mean sitSBP, and in particular, the mean sitSBP of the DM patient group was effectively reduced.

Experimental Example 3: Measurement of Rate of Change in Triglyceride with respect to Baseline after 4 Weeks and 8 Weeks

For comparison of the difference in the rate of change in triglyceride (TG) with respect to a baseline after 4 weeks and 8 weeks between the group administered A5+L100+R20 as an experimental group and the controls, i.e., the group administered L100+R20 and the group administered A5+L100, covariance analysis (ANCOVA) in which each efficacy evaluation variable at the baseline was corrected with a covariate was performed. The rates of change in TG of the group administered A5+L100+R20, the group administered L100+R20, and the group administered A5+L100 with respect to the baseline after 4 weeks and 8 weeks, estimated as a result of the covariance analysis, were measured. In addition, the rate of change in TG of the DM patient group compared to the non-DM patient group was measured.

(1) FAS Analysis

The rates (%) of change in TG with respect to a baseline at 4 weeks and 8 weeks after drug administration of the FAS were measured.

First, least square (LS) means of the rates of change in TG with respect to the baseline after 4 weeks of the group administered A5+L100+R20 and the group administered A5+L100, estimated as a result of the covariance analysis, were -31.33 ± 4.60 % and 4.78 ± 4.98 %, respectively, the group administered A5+L100+R20 exhibited a greater rate of change in TG than that in the group administered A5+L100, and this difference was statistically significant (p<0.0001). In addition, LS means of the rates of change in TG with respect to the baseline after 4 weeks of the group administered A5+L100+R20 and the group administered L100+R20 were -28.92 ± 4.04 % and -17.43 ± 4.53 %, respectively (p=0.0622).

In addition, the LS means of the rates of change in TG with respect to the baseline after 8 weeks of the group administered A5+L100+R20 and the group administered A5+L100, estimated as a result of the covariance analysis, were -21.77 ± 5.03 % and 2.21 ± 5.45 %, respectively. The group administered A5+L100+R20 exhibited a greater rate of change in TG than that in the group administered A5+L100, and this difference was statistically significant (p=0.0018).

(2) PPS Analysis

The rates (%) of change in TG with respect to the baseline, estimated as a result of the covariance analysis, 4 weeks and 8 weeks after drug administration of the PBS were measured, and the results thereof are shown in Tables 3 and 4 below.

Table 3 shows the rates (%) of change in TG with respect to the baseline 4 weeks after drug administration in the PPS.

[Table 3]

As shown in Table 3 above, LS means of the rates of change in TG with respect to the baseline after 4 weeks of the group administered A5+L100+R20 and the group administered A5+L100, estimated as a result of the covariance analysis, were -30.64 ± 4.46 % and 0.80± 4.93 %, respectively, the group administered A5+L100+R20 exhibited a greater rate of change in TG than that of the group administered A5+L100, and this difference was statistically significant (p<0.0001). In addition, the LS means of the rates of change in TG with respect to the baseline after 4 weeks of the group administered A5+L100+R20 and the group administered L100+R20 were -28.62 ± 4.23 % and -15.64 ± 4.74 %, respectively, and this difference was statistically significant (p=0.0444).

Table 4 shows the rates (%) of change in TG with respect to the baseline 8 weeks after drug administration in the PPS.

[Table 4]

As shown in Table 4, LS means of the rates of change in TG with respect to the baseline after 8 weeks of the group administered A5+L100+R20 and the group administered A5+L100, estimated as a result of the covariance analysis, were -23.06 ± 4.82 % and -3.11± 5.33 %, respectively, and the group administered A5+L100+R20 exhibited a greater rate of change in TG than that in the group administered A5+L100, and this value was statistically significant (p= 0.007).

As shown in Tables 3 and 4 above, as compared to the group administered L100+R20 and the group administered A5+L100, the group administered A5+L100+R20 exhibited a significant difference in the rate of change in TG. From this result, it was confirmed that, when 5 mg of amlodipine, 100 mg of losartan, and 20 mg of rosuvastatin were administered, the rate of change in TG was more significantly decreased and a statistically significant difference was exhibited, compared to when only 100 mg of losartan and 20 mg of rosuvastatin were administered or when only 5 mg of amlodipine and 100 mg of losartan were administered.

(3) Analysis of Rate of Change in TG in DM Patient Group Compared to Non-DB Patient Group

The rates (%) of change in TG with respect to the baseline 8 weeks after administration of A5+L100+R20 or L100+R20 in patient groups with or without diabetes were measured, and the results thereof are shown in Table 5 below.

[Table 5]

As shown in Table 5, when the DM patient group was compared with the non-DM patient group, the DM patient group exhibited a more significant decrease in the rate (%) of change in TG when administered A5+L100+R20, compared to when administered L100+R20.

In particular, the non-DB patient group exhibited the rates (%) of change in TG (mean ± SD) of -23.60 ± 40.89 % and -16.98 ± 39.39 % when administered L100+R20 and when administered A5+L100+R20, respectively, which is a rather slight decrease, and did not show a greater TG decrease according to additional administration of amlodipine, whereas the DB patient group exhibited the rates (%) of change in TG (mean ± SD) of -14.41±34.98 % and -27.75±21.03 % when administered L100+R20 and administered A5+L100+R20, respectively, which is a significantly greater TG decrease according to additional administration of amlodipine. From these results, it was confirmed that, when administered A5+L100+R20, the DM patient group exhibited a greater TG decrease than that when administered L100+R20, which indicates an increase in a TG regulation effect, as compared to the non-DB patient group.

Experimental Example 4: Measurement of Blood Pressure Normalization Rate according to JNC VII Guidelines

The Cochran-Mantel-Haenszel (CMH) test using baseline cardiovascular risk categories as strata was performed on blood pressure normalization rates according to the JNC VII guidelines 4 weeks and 8 weeks after administration of the clinical trial drug, and Pearson's chi-square test or Fisher's exact test was further performed on each cardiovascular risk category for comparison between the drug-administered groups. The cardiovascular risk categories were classified in the same manner as described above in the present specification. That is, a case in which the number of CHD risk factors was 0 or 1 was classified into Group A, a case in which the number of CHD risk factors was 2 or more and the risk of developing cardiovascular disease within 10 years was 10 % to 20 % was classified into Group B, and a case in which CHD/CHD risk equivalents or the risk of developing cardiovascular disease within 10 years was greater than 20 % was classified into Group C.

(1) Analysis of Blood Pressure Normalization Rate in FAS

The standard for blood pressure normalization according to the JNC VII guidelines is based on 'sitSBP/sitDBP < 140/90 mmHg' for cardiovascular risk category groups A and B and is based on 'sitSBP/sitDBP < 130/80 mmHg' for group C. The results thereof are shown in Tables 6 and 7 below. In Tables 6 and 7 below, the percentage (%) is based on subjects in each drug-administered group. With regard to p-value, a) denotes Pearson's chi-square test; b) denotes Fisher's exact test; and c) denotes the Cochran-Mantel-Haenzel test.

[Table 6]

Table 6 above shows blood pressure normalization achievement rates in the FAS at week 4 according to the cardiovascular risk category.

As shown in Table 6, in the case of the number of risk factors of 0 to 1 (risk factor 0-1), the blood pressure normalization rates for each cardiovascular risk category group 4 weeks after drug administration were 60.00 % (3/5 persons) in the group administered A5+L100+R20, 66.67 % (2/3 persons) in the group administered A5+L100, and 33.33 % (1/3 persons) in the group administered L100+R20. In addition, in cases in which the number of risk factors was 2 or more (risk factor ≥ 2) and there was a risk of developing cardiovascular disease within 10 years, the blood pressure normalization rates were 61.11 % (11/18 persons) for the group administered A5+L100+R20, 52.94 % (9/17 persons) for the group administered A5+L100, and 23.08 % (3/13 persons) for the group administered L100+R20, and in cases in which the CHD/CHD risk equivalents or the risk of developing cardiovascular disease within 10 years was greater than 20 % (CHD/CHD risk equivalents or 10 year risk > 20 %), the blood pressure normalization rates were 19.35 % (6/31 persons) for the group administered A5+L100+R20, 7.69 % (2/26 persons) for the group administered A5+L100, and 0.00 % (0/27 persons) for the group administered L100+R20.

4 weeks after administration of the clinical trial drug, the blood pressure normalization rates according to the JNC VII guidelines were 37.04 % (20/54 persons) for the group administered A5+L100+R20, 28.26 % (13/46 persons) for the group administered A5+L100, and 9.30 % (4/43 persons) for the group administered L100+R20. A statistically significant difference in blood pressure normalization rate according to the baseline cardiovascular risk category between the group administered A5+L100+R20 and the group administered L100+R20 was confirmed (p=0.0017).

[Table 7]

Table 7 shows blood pressure normalization achievement rates in the FAS at week 8 according to the cardiovascular risk category.

As shown in Table 7 above, in cases where the number of risk factors was 0 to 1, the blood pressure normalization rates for each cardiovascular risk category 8 weeks after drug administration were shown to be 80.00 % (4/5 persons) for the group administered A5+L100+R20, 66.67 % (2/3 persons) for the group administered A5+L100, and 66.67 % (2/3 persons) of the group administered L100+R20. In addition, in cases in which the number of risk factors was 2 or more (risk factor ≥ 2) and the risk of developing cardiovascular disease within 10 years was 20% or less, the blood pressure normalization rates were shown to be 77.78 % (14/18 persons) for the group administered A5+L100+R20, 64.71 % (11/17 persons) for the group administered A5+L100, and 30.77 % (4/13 persons) for the group administered L100+R20, and in the case in which CHD/CHD risk equivalents or the risk of developing cardiovascular disease within 10 years was greater than 20 %, the blood pressure normalization rates were shown to be 29.03 % (9/31 persons) for the group administered A5+L100+R20, 19.23 % (5/26 persons) for the group administered A5+L100, and 3.70 % (1/27 persons) for the group administered L100+R20.

(2) Analysis of Blood Pressure Normalization Rate according to Cardiovascular Risk Category

The cardiovascular risk category groups of the present clinical trial subjects consisted of Group A: 11 persons (7.69 %), Group B: 48 persons (33.57 %), and Group C: 84 persons (58.74 %), from which it was confirmed that 50 % or more of the subjects belonged to Group C. By considering the fact that while the standard for blood pressure normalization of Groups A and B was sitSBP/sitDBP < 140/90 mmHg, the standard for blood pressure normalization of Group C was sitSBP/sitDBP < 130/80 mmHg, the blood pressure normalization rates of Groups A and B (risk factor 0 to 1 or risk factor ≥ 2 and 10 year risk ≤ 20 %) and Group C (CHD/CHD risk equivalents or 10 year risk > 20 %) were separately analyzed.

As a result of examining the blood pressure normalization rates of Groups A and B and Group C according to the cardiovascular risk category 4 weeks after administration of the clinical trial drug, Groups A and B exhibited blood pressure normalization rates of 60.87 % (14/23 persons) for the group administered A5+L100+R20, 55.00 % (11/20 persons) for the group administered A5+L100, and 25.00 % (4/16 persons) for the group administered L100+R20, and Group C exhibited blood pressure normalization rates of 19.35 % (6/31 persons) for the group administered A5+L100+R20, 7.69 % (2/26 persons) for the group administered A5+L100, and 0.00 % (0/27 persons) for the group administered L100+R20, from which it was confirmed that the blood pressure normalization rate of Group C was relatively lower than that of Groups A and B.

When the blood pressure normalization rates 8 weeks after administration of the clinical trial drug of Groups A and B and Group C according to the cardiovascular risk category were compared with each other, Groups A and B exhibited blood pressure normalization rates of 78.26 % (18/23 persons) for the group administered A5+L100+R20, 65.00 % (13/20 persons) for the group administered A5+L100, and 37.50 % (6/16 persons) for the group administered L100+R20, and Group C exhibited blood pressure normalization rates of 29.03 % (9/31 persons) for the group administered A5+L100+R20, 19.23 % (5/26 persons) for the group administered A5+L100, and 3.70 % (1/27 persons) for the group administered L100+R20.

Consequently, the blood pressure normalization rate was relatively lower in Group C than in Groups A and B, which is assumed to be because Group C exhibits a high mean blood pressure baseline, and thus blood pressure control is difficult. Overall, in all of Groups A and B and Group C according to the cardiovascular risk category, the group administered A5+L100+R20 exhibited a superior blood pressure normalization rate to that of the group administered A5+L100 or the group administered L100+R20.

(3) Analysis of Blood Pressure Normalization Rate in DM

Rates at which blood pressure normalization was achieved 8 weeks after administration of A5+L100+R20, A5+L100, or L100+R20 in the DM patient group were analyzed, and results thereof are shown in Table 8 below.

[Table 8]

As shown in Table 8, the DB patient group exhibited blood pressure normalization rates of 21.43 % (3/14 persons) when administered A5+L100+R20, 18.75 % (3/16 persons) when administered A5+L100, and 0.00 % (0/12 persons) when administered L100+R20. From this result, it was confirmed that the DM patient group exhibited a higher blood pressure normalization rate when administered A5+L100+R20 than when administered A5+L100 or L100+R20.

Experimental Example 5: Measurement of Percentage of Trial Subjects Having Achieved LDL-C Treatment Goal according to NCEP ATP III Guidelines and Reached Blood Pressure Normalization according to JNC VII Guidelines

The Cochran-Mantel-Haenszel (CMH) test was performed on the percentage of trial subjects that achieved LDL-C treatment goals according to the NCEP ATP III guidelines and reached blood pressure normalization according to the JNC VII guidelines 4 weeks or 8 weeks after administration of the clinical trial drug, for comparison between the drug-administered groups. Additionally, Pearson's chi-square test or Fisher's exact test was performed for comparison of LDL-C treatment goal and blood pressure normalization rates between the drug-administered groups.

(1) Analysis of LDL-C and Blood Pressure Normalization Rate in FAS

4 weeks after administration of the clinical trial drug, the percentage of trial subjects having achieved LDL-C treatment goals according to the NCEP ATP III guidelines and reached blood pressure normalization according to the JNC VII guidelines was shown to be 35.19 % (19/54 persons) when administered A5+L100+R20, 0.00 % (0/46 persons) when administered A5+L100, and 9.30 % (4/43 persons) when administered L100+R20, from which it was confirmed that the blood pressure normalization rate was much higher in the group administered A5+L100+R20 than in the other two drug-administered groups, and this difference was statistically significant (A5+L100+R20 vs. A5+L100: p<0.0001, A5+L100+R20 vs. L100+R20: p=0.0028).

In addition, 8 weeks after administration of the clinical trial drug, the percentage of trial subjects having achieved LDL-C treatment goals and reached blood pressure normalization was also shown to be 48.15 % (26/54 persons) for the group administered A5+L100+R20, 8.70 % (4/46 persons) for the group administered A5+L100, and 16.28 % (7/43 persons) for the group administered L100+R20, from which it was confirmed that the group administered A5+L100+R20 exhibited a higher treatment goal achievement rate than that in the other two drug-administered groups, and this difference was statistically significant (A5+L100+R20 vs. A5+L100: p<0.0001, A5+L100+R20 vs. L100+R20: p=0.0007). It was confirmed that the percentage of trial subjects having achieved LDL-C treatment goals and reached blood pressure normalization 8 weeks after administration of the clinical trial drug was higher than that 4 weeks after administration of the clinical trial drug.

From these results, it was confirmed that the group administered A5+L100+R20 exhibited a more excellent effect of treating dyslipidemia and hypertension than that of the group administered A5+L100 or L100+R20.

(2) Analysis of LDL-C Treatment Goal Achievement and Blood Pressure Normalization Rates in DM Patient Group

The percentage of trial subjects having achieved LDL-C treatment goals and reached blood pressure normalization 8 weeks after administration of A5+L100+R20, A5+L100, or L100+R20 in the DM patient group was analyzed, and results thereof are shown in Table 9 below.

[Table 9]

As shown in Table 9, the DM patient group exhibited blood pressure normalization rates of 21.43 % (3/14 persons) when administered A5+L100+R20, 18.75 % (3/16 persons) when administered A5+L100, and 0.00 % (0/12 persons) when administered L100+R20. From these results, it was confirmed that the DM patient group exhibited higher LDL-C treatment goal achievement and blood pressure normalization rates when administered A5+L100+R20 than when administered A5+L100 or L100+R20.

[Description of Abbreviations]

A5: amlodipine (A) 5 mg

L100: losartan (L) 100 mg

R20: rosuvastatin (R) 20 mg

sitDBP: sitting diastolic blood pressure

sitSBP: sitting systolic blood pressure

DM: diabetes mellitus patient group

non-DM: non-DM patient group

LDL-C: low-density lipoprotein cholesterol

TG: triglyceride

Hb1Ac: glycated hemoglobin (Hb) A1c

While one or more embodiments have been described with reference to the figures, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the following claims.

It should be understood that embodiments described herein should be considered in a descriptive sense only and not for purposes of limitation. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments.

Claims

A pharmaceutical composition for preventing or treating a cardiovascular disease accompanied by diabetes, the 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.
The pharmaceutical composition of claim 1, wherein the cardiovascular disease accompanied by diabetes comprises a case with both diabetes and at least one cardiovascular disease selected from hypertension, dyslipidemia, angina pectoris, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarct, congestive heart failure, and myocardial infarction.
The pharmaceutical composition of claim 1, wherein the cardiovascular disease accompanied by diabetes comprises a disease satisfying at least one selected from the following conditions:

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

(2) arbitrary plasma glucose level ≥ 200 mg/dL, plus at least one symptom selected from polyuria, polydipsia, polyphagia, a feeling of hunger, and unidentified body weight loss,

(3) plasma glucose ≥ 200 mg/dL at 2 hours after a 75 g oral glucose tolerance test, and

(4) glycated hemoglobin level (HbA1c) ≥ 6.5%,

while simultaneously satisfying at least one of the following conditions:

(a) sitting systolic blood pressure (sitSBP) ≥ 140 mmH,

(b) sitting diastolic blood pressure (sitDBP) ≥ 90 mmHg,

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

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

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

(f) total cholesterol concentration > 200 mg/dL.
The pharmaceutical composition of claim 1, wherein the cardiovascular disease accompanied by diabetes comprises a case with both diabetes and at least one cardiovascular disease selected from hypertension and dyslipidemia.
The pharmaceutical composition of claim 1, wherein the cardiovascular disease accompanied by diabetes is diabetic hypertension.
The pharmaceutical composition of claim 1 or 5, wherein the pharmaceutical composition exhibits a further 1.3-fold or greater decrease in sitting systolic blood pressure in a cardiovascular disease accompanied by diabetes than in a cardiovascular disease not accompanied by diabetes.
The pharmaceutical composition of claim 1, wherein, with respect to a total amount of the pharmaceutical composition, an amount of the amlodipine or a pharmaceutically acceptable salt thereof is in a range of about 5 mg to about 10 mg when converted into an amlodipine free base form, an amount of the losartan or a pharmaceutically acceptable salt thereof is in a range of about 45 mg to about 100 mg when converted into a losartan free acid form, and an amount of the rosuvastatin or a pharmaceutically acceptable salt thereof is in a range of about 5 mg to about 20 mg when converted into a rosuvastatin free acid form.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once a day.
The pharmaceutical composition of claim 1, wherein, as a daily dose of the pharmaceutical composition, an amount of the amlodipine or a pharmaceutically acceptable salt thereof is 5 mg when converted into an amlodipine free base form, an amount of the losartan or a pharmaceutically acceptable salt thereof is 100 mg when converted into a losartan free acid form, and an amount of the rosuvastatin or a pharmaceutically acceptable salt thereof is 20 mg when converted into a rosuvastatin free acid form, the amounts being based on a total amount of the pharmaceutical composition.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises amlodipine camsylate, losartan potassium, and rosuvastatin calcium.
The pharmaceutical composition of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof, the losartan or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof are co-administered simultaneously or sequentially.
The pharmaceutical composition of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof, the losartan or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof are administered in a single dosage form including all of the above ingredients, or are administered in multiple dosage forms separately including the respective ingredients.
The pharmaceutical composition of claim 1, further comprising one or more other drugs for preventing or treating a cardiovascular disease, selected from a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), and a HMG-CoA reductase inhibitor.
A composite preparation for preventing or treating a cardiovascular disease accompanied by diabetes, the composite preparation comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.
The composite preparation of claim 14, wherein the composite preparation is formulated into tablets, capsules, or caplets.