阅读说明：本技术 预防以及治疗糖尿病伴发的心血管疾病的药物组成物、其包含氨氯地平、络舒坦以及瑞舒伐他汀、以及包含所述组成物的复合物制备 (Pharmaceutical composition for preventing and treating cardiovascular diseases accompanied by diabetes, preparation method of pharmaceutical composition containing amlodipine, rosuvastatin and rosuvas) 是由 丁真儿 裵惠宁 于 2018-10-17 设计创作，主要内容包括：本发明提供一种预防或治疗伴有糖尿病的心血管疾病的药物组成物以及一种包含所述药物组成物的复合制剂。所述药物组成物包含氨氯地平或其药学上可接受的盐、络舒坦或其药学上可接受的盐以及瑞舒伐他汀或其药学上可接受的盐。(The present invention provides a pharmaceutical composition for preventing or treating cardiovascular diseases accompanied with diabetes and a complex formulation comprising the same. The pharmaceutical composition comprises amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.)

1. A pharmaceutical composition for preventing or treating cardiovascular diseases accompanied by diabetes, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the cardiovascular disease accompanied by diabetes includes a case where diabetes coexists with at least one cardiovascular disease selected from the group consisting of: hypertension, dyslipidemia, angina pectoris, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.

3. The pharmaceutical composition of claim 1, wherein the cardiovascular disease with diabetes comprises a disease that meets at least one condition selected from the group consisting of:

(1) after 8 hours or more than 8 hours of fasting, the blood plasma glucose is more than or equal to 126 mg/dl,

(2) optionally a plasma glucose value of 200 mg/dl or more, plus at least one symptom selected from the group consisting of polyuria, polydipsia, polyphagia, hunger sensation and indeterminate weight loss,

(3) plasma glucose of not less than 200 mg/dl 2 hours after 75 g oral glucose tolerance test, an

(4) The value of the glycosylated hemoglobin (HbA1c) is more than or equal to 6.5 percent,

while satisfying at least one of the following conditions:

(a) the sitting contraction blood pressure (sitSBP) is more than or equal to 140 mm Hg,

(b) the sitting diastolic blood pressure (sitDBP) is more than or equal to 90 mm Hg,

(c) the concentration of blood L D L-cholesterol (L D L-C) is not less than 130 mg/dl,

(d) the concentration of blood HD L-cholesterol (HD L-C) is less than 60 mg/dl,

(e) blood triglyceride concentration of 150 mg/dl or more, an

(f) The total cholesterol concentration is > 200 mg/dl.

4. The pharmaceutical composition according to claim 1, wherein the cardiovascular disease accompanied by diabetes includes a case where diabetes and at least one cardiovascular disease selected from hypertension and dyslipidemia coexist.

5. The pharmaceutical composition of claim 1, wherein the cardiovascular disease with diabetes is diabetic hypertension.

6. The pharmaceutical composition of claim 1 or 5, wherein the pharmaceutical composition exhibits a further 1.3-fold or greater than 1.3-fold reduction in sitting systolic blood pressure in the cardiovascular disease with diabetes compared to cardiovascular disease without diabetes.

7. The pharmaceutical composition of claim 1, wherein the amount of amlodipine or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 10 mg when converted to amlodipine free base form, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof ranges from about 45 mg to about 100 mg when converted to rosuvastatin free acid form, and the amount of rosuvastatin or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 20 mg when converted to rosuvastatin free acid form, relative to the total amount of the pharmaceutical composition.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once daily.

9. The pharmaceutical composition according to claim 1, wherein as a daily dose of the pharmaceutical composition, the amount of amlodipine or a pharmaceutically acceptable salt thereof is 5 mg when converted into amlodipine free base form, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof is 100 mg when converted into rosuvastatin free acid form, and the amount of rosuvastatin or a pharmaceutically acceptable salt thereof is 20 mg when converted into rosuvastatin free acid form, and the amount of amlodipine or a pharmaceutically acceptable salt thereof, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof, and the amount of rosuvastatin or a pharmaceutically acceptable salt thereof are based on the total amount of the pharmaceutical composition.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises amlodipine camsylate, potassium rosuvastatin, and calcium rosuvastatin.

11. The pharmaceutical composition of claim 1, wherein said amlodipine or a pharmaceutically acceptable salt thereof, said rosuvastatin or a pharmaceutically acceptable salt thereof, and said rosuvastatin or a pharmaceutically acceptable salt thereof are co-administered simultaneously or sequentially.

12. The pharmaceutical composition of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the rosuvastatin or a pharmaceutically acceptable salt thereof are administered in a single dosage form comprising all of the above components or in multiple dosage forms comprising each of the components.

13. The pharmaceutical composition of claim 1, further comprising one or more additional agents for preventing or treating cardiovascular diseases selected from the group consisting of Calcium Channel Blockers (CCBs), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors.

14. A complex formulation for preventing or treating cardiovascular diseases accompanied by diabetes mellitus, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

15. The composite formulation of claim 14, wherein the composite formulation is formulated as a lozenge, a capsule, or a capsule-type lozenge.

Technical Field

The application claims the right of korean patent application nos. 10-2017-0134809 and 10-2018-0112376, which were filed by the korean intellectual property office at 17.2017 and 19.2018, respectively, the disclosures of which are incorporated herein by reference in their entireties.

One or more embodiments relate to the prevention or treatment of cardiovascular diseases, and more particularly, to a pharmaceutical composition for the prevention or treatment of cardiovascular diseases accompanied by diabetes, which comprises amlodipine, rosuvastatin, and a complex formulation comprising the same.

Background

According to the Korean Hypertension Society (the Korean Society of Diabetes) and the Korean Society of lipid Atherosclerosis (the Korean Society of Atherosclerosis of L ipid Atherosclerosis) in Association with the joint report on prevalence and treatment status of diseases, the number of patients suffering from all of Hypertension, Diabetes and dyslipidemia has increased sharply from 34 million to 141 in nearly one decade (between 2006 and 2016), which is one of the leading causes of death.

In particular, the prevalence of diabetes and other cardiovascular diseases (e.g. hypertension, dyslipidemia, etc.) continues to increase, and for example, it is known that diabetic patients are at about twice the risk of non-diabetic patients to suffer from hypertension, which is easily induced or exacerbated by diabetes-induced microvascular (nephropathy and retinopathy) and macrovascular complications, and 60% to 70% of diabetic patients suffer from hypertension, furthermore, it is also known that in the opposite case, hypertensive patients are at high risk of suffering from diabetes mellitus, it is also known that diabetic patients are classified in the very high risk group of dyslipidemia, about 30% of diabetic patients show an increase in plasma Triglyceride (TG) concentration, and the mortality rate due to cardiovascular disease in diabetic patients is about 2 to 4 times the mortality rate of non-diabetic patients, furthermore, it is found that glucose is abnormally, triglycerides are gradually increased and HD L is gradually decreased in diabetic patients, the most common types of lipid disorders occurring as complications of type 2 diabetes mellitus are hypertriglyceridemia and HD 6754% of cholesterol are examined as high cholesterol/3645 mg, and about 100 mg cholesterol/20% of patients are examined as high cholesterol/3645 mg cholesterol/20 mg/11 mg cholesterol in nature diabetes mellitus, and 3645 mg cholesterol/20 mg cholesterol in diabetic patients.

Therefore, there are many cases where diabetic patients are accompanied by cardiovascular diseases, and, due to co-morbidities with diabetes, their pathophysiological or pharmacotherapeutic responses may differ from those of non-diabetic patients even when the patients have the same or similar diseases, and there are many cases where blood pressure or lipid concentration cannot be controlled or is difficult to control by using existing medications. In addition, patients with cardiovascular diseases accompanied with diabetes must take large doses of various medicines, causing inconvenience and discomfort, and often neglecting to take medicines. As a result, the target therapeutic effect cannot be achieved, and thus the social burden and medical expenses are enormous. Therefore, in order to treat cardiovascular diseases accompanied by diabetes, it is necessary to develop a cardiovascular disease therapeutic agent and a complex formulation which are customized in consideration of the accompanied diseases and the characteristics of a patient group.

Korean patent laid-open publication No. 10-2007-0068658 discloses a formulation comprising amlodipine and simvastatin, but does not disclose a formulation capable of effectively controlling blood pressure and lipid concentration in a group of diabetic patients. Accordingly, as a result of repeated research and clinical trials, the inventors of the present disclosure developed a pharmaceutical composition exhibiting excellent therapeutic and prophylactic effects on cardiovascular diseases accompanied by diabetes, and a composite preparation comprising the same.

Disclosure of Invention

Technical problem

One or more embodiments include a pharmaceutical composition for preventing or treating cardiovascular diseases associated with diabetes.

One or more embodiments include a complex formulation for preventing or treating cardiovascular diseases accompanied by diabetes.

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

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

Solution scheme

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

According to one or more embodiments, a complex formulation for preventing or treating cardiovascular diseases accompanied by diabetes comprises amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin 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 for treating cardiovascular disease accompanied by diabetes by using a composition comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

Advantageous effects of the invention

As apparent from the foregoing description, according to one embodiment, a pharmaceutical composition comprising amlodipine, rosuvastatin and rosuvastatin has excellent effects of controlling blood pressure and improving lipid levels in cardiovascular diseases complicated with diabetes, particularly in patients having diabetes and cardiovascular diseases, has excellent effects of improving blood pressure and blood lipid levels when amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof are simultaneously used in combination, has excellent effects of treating or preventing hypertension and blood lipid levels accompanied with diabetes, as compared with administration of only each single ingredient alone, or combination of any one or only two thereof, in addition, effectively lowers mean systolic blood pressure and mean diastolic blood pressure in DM patients groups, effectively lowers elevated levels, and exhibits excellent normalization of blood pressure and L D L-C therapeutic target rates.

The complex formulation according to one embodiment can enhance the convenience and compliance of patients and can reduce the cost of administration. In addition, the composite preparation is effective in preventing or treating cardiovascular diseases of diabetic patients who should take a hypertension therapeutic agent and a dyslipidemia therapeutic agent at the same time.

Drawings

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

fig. 1 shows the results of measurements of mean sitting systolic blood pressure (sitSBP) change (mmhg) based on drug administration to a Diabetic (DM) patient group and a non-diabetic patient group.

Figure 2 shows the results of measurements of mean sitting diastolic blood pressure (sitDBP) change (mmhg) from drugs administered to a diabetic group and a non-diabetic group.

Detailed Description

Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the like elements throughout. In this regard, the embodiments of the invention may have different forms and should not be construed as limited to the description set forth herein. Therefore, the embodiments are set forth below by referring to the drawings only for the purpose of explaining the embodiments 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. For example, the expression at least one of (at least one of) when preceding a list of elements modifies the entire list of elements rather than modifying individual elements of the list.

Hereinafter, the present disclosure will be explained in more detail.

Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in the related art. In addition, suitable methods or samples are described herein, but similar or equivalent methods or samples are also within the scope of this specification. Further, unless otherwise indicated herein, the numerical values set forth herein are deemed to include the meaning "about (about)". The contents of all publications mentioned herein are incorporated by reference in their entirety. The term "about" as used herein means that the 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 to be interpreted as including a 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. The expressions "having (has)" or "may have (may have)" and "include(s)" or "may include (may include)" and the like used herein mean that corresponding features (e.g., values or components such as components and the like) exist, and are not intended to exclude the presence of other features.

One embodiment of the present disclosure provides a pharmaceutical composition for preventing or treating cardiovascular diseases accompanied by diabetes, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

The term "cardiovascular disease" as used herein is intended to include not only diseases that directly occur due to various causes such as abnormalities and dysfunctions of the circulatory system in the body, damage thereof, and the like, but also secondary diseases induced by such direct diseases. For example, cardiovascular disease may include hypertension, dyslipidemia, angina, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, 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 a blood vessel on a blood vessel wall. The blood pressure is summarized as two metrics of systolic (maximum) blood pressure and diastolic (minimum) blood pressure, and in a general case, when the heart contracts, the normal blood pressure during rest is 100 to 140 mmHg, and when the heart expands, the normal blood pressure is 60 to 90 mmHg, and a case where the blood pressure continues to be 140/90 or more than 140/90 mmHg is called hypertension.

The term "hypertension" as used herein refers to a chronic disease in which the blood pressure is above the normal range. Hypertension can be classified into essential hypertension (essential hypertension) and secondary hypertension. The present hypertension and the secondary hypertension are distinguished by different disease Classification codes according to the Korean disease Classification Standard (KCD). It is known that about 90% to 95% of cases are classified as intrinsic hypertension without obvious fundamental medical causes, and the remaining 5% to 10% (secondary hypertension) are caused by other health conditions affecting the kidneys, arteries, heart or endocrine system. For example, the accumulation of obesity, hyperlipidemia, diabetes, and hypertension may be referred to as "metabolic syndrome" or "insulin resistance syndrome". Hypertension may be accompanied by symptoms such as dizziness, headache, palpitation, dyspnea, etc., and if a human body is in a long-term hypertensive state, many complications such as stroke, coronary heart disease, renal failure, etc. may be caused. The term "complication" as used herein refers to the presence of other symptoms in a disease.

The term "intrinsic (essential) hypertension (KCD classification code: I10)" as used herein refers to the most common type of hypertension that occurs due to a complex interaction of genetic and environmental factors. In addition, hypertension in this state is a common symptom of diabetes, and insulin resistance, which is a factor of steroid metabolism deficiency (or metabolic syndrome), may also cause hypertension. The term "secondary hypertension (KCD classification code: I15)" used herein is caused by identifiable causes, and kidney disease is one of the common secondary causes, and examples of the causes may include Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, conus disease (Conn syndrome), hyperaldosteronism, hyperparathyroidism, pheochromocytoma, diabetes, sleep apnea, pregnancy, aortic constriction, licorice or steroid drugs, and illegal drugs. Secondary hypertension can be classified again into renovascular hypertension (I15.0), secondary hypertension due to other kidney diseases (I15.1), secondary hypertension due to endocrine disorders (I15.2), other secondary hypertension (I15.8), ambiguous secondary hypertension (I15.9), etc. according to the cause and KCD classification code.

The diagnostic criteria for hypertension may be a systolic sitting blood pressure (sitSBP) above 140 mm hg or a diastolic sitting blood pressure (sitDBP) above 90 mm hg. According to the revised JNCVIII guidelines (2014), the blood pressure normalization criteria for patients in general (non-diabetic or chronic kidney disease patients) are below 150/90 mmhg for people aged 60 years or older and below 140/90 mmhg for people aged below 60 years, and the blood pressure normalization criteria for diabetic patients or chronic kidney disease patients are below 140/90 mmhg at all ages.

As used herein, the term "hyperlipidemia (hyperlipidemia)" refers to a condition in which an unnecessarily large amount of lipid substances exists in blood and accumulates in the vascular wall, thereby causing inflammation, resulting in the occurrence of cardiovascular diseases, and is also called dyslipidemia, which means dyslipidemia, for the treatment of hyperlipidemia, drug therapy is mainly used together with improvement of lifestyle through diet control and exercise and maintenance of appropriate body weight, and for drug therapy, statins are widely used, and these drugs act as HMG-CoA reductase inhibitors, thus having the effect of inhibiting cholesterol synthesis, furthermore, these drugs can strongly reduce L D L-cholesterol value, and partially reduce triglyceride value.

For the diagnostic criteria for dyslipidemia, a case corresponding to any one of the following can be diagnosed as dyslipidemia (blood L D L-cholesterol (L D L-C) concentration ≧ 130 mg/dl, blood HD L-cholesterol (HD L-C) concentration < 60 mg/dl, blood triglyceride concentration ≧ 150 mg/dl, and total cholesterol concentration > 200 mg/dl.) for the diagnostic criteria for dyslipidemia, the risk of dyslipidemia to be treated can be classified into an ultra-high risk group, a medium risk group, and a low risk group according to the inclusion of risk factors such as diabetes, smoking, hypertension, age, family history (e.g., early coronary artery disease, etc.), and the treatment target can be set according to these groups.

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

The term "Diabetes Mellitus (DM) or diabetes" as used herein refers to a group of metabolic diseases having a prolonged high blood glucose value. Diabetes may occur due to insufficient insulin production by the pancreas or an inability of the body's cells to respond appropriately to the insulin produced. Acute complications caused by diabetes include diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic coma, and the like. In addition, serious long-term complications caused by diabetes include cardiovascular disease, stroke, chronic renal failure, diabetic ulcer, diabetic retinopathy, and the like.

The term "glucotoxicity or glucotoxicity" as used herein refers to damage to body cells that produce and use insulin due to high blood glucose levels. Glucotoxicity caused by long-term hyperglycemia may induce tissue-dependent insulin resistance and thus exacerbate nephropathy, retinopathy, dyslipidemia, hypertension, hypertriglyceridemia, obesity, and cardiovascular diseases, which are called metabolic syndrome, or may cause secondary complications of these diseases. Glucotoxicity may lead to diabetes-induced heart disease.

The term "Insulin Resistance (IR)" as used herein means that a cell cannot burn glucose efficiently due to a reduced ability of insulin to reduce blood glucose. When insulin resistance is high, the human body produces excessive amounts 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 tissue cannot be recognized, and thus insulin action does not occur. Such insulin resistance is a pathophysiological phenomenon common to type 2 diabetes and intrinsic hypertension of undetermined nature, and in the case of a patient with high plasma insulin concentration, the possibility of suffering from hypertension is significantly increased as compared with a person with low insulin concentration, and long-term insulin treatment causes weight gain and the like, and thus may become a risk factor of hypertension. Due to insulin resistance, diabetes-induced heart disease may occur.

Various mechanisms have been proposed for how insulin resistance, which occurs in diabetic patients, leads to elevated blood pressure. For example, insulin produces nitric oxide as a vascular relaxant via the Nitric Oxide (NO) pathway to relax blood vessels, and the vascular relaxation cannot properly occur due to resistance in such insulin response, resulting in an increase in blood pressure. In addition, due to high blood insulin concentrations, blood pressure increases due to sympathetic nervous system excitation, vascular smooth muscle hypertrophy, and sodium and fluid retention. The hyperglycemic values of diabetic patients stimulate the renin-angiotensin system (RAS), resulting in an increase in blood pressure. Furthermore, insulin is known to affect blood pressure directly or indirectly via: increase the secretion of endothelin-1 and plasmalogen activator inhibitor-1 (PAI-1), increase the generation of active oxygen substances, inhibit nuclear factor kappa B (NF-kappa B), and inhibit platelet aggregation. In addition, insulin resistance and hyperinsulinemia contribute to arteriosclerosis and thus to secondary blood pressure increases.

Cardiovascular diseases accompanied with diabetes include the development of diabetes as a sequela or complication due to cardiovascular diseases caused directly or indirectly by abnormalities and dysfunction of the body's circulatory system, damage thereof, and the like.

In addition, cardiovascular diseases accompanied with diabetes may include a case where diabetes develops together with cardiovascular diseases due to diabetes, glucotoxicity or insulin resistance, or endocrine disorders due to cardiovascular diseases. The cardiovascular disease accompanied by diabetes may be, for example, hypertension, dyslipidemia (hyperlipidemia), angina pectoris, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure or myocardial infarction. Cardiovascular diseases with diabetes can be distinguished pathophysiologically and clinically from those that occur alone without diabetes. In one embodiment, when the same drug as that for treating cardiovascular disease not accompanied by diabetes is administered at the same dose, the cardiovascular disease accompanied by diabetes may show different drug response, and for example, although the non-diabetic group shows appropriate treatment results, the diabetic group may fail to reach normal blood pressure or normal blood lipid (normal blood lipid value).

In one embodiment, the cardiovascular disease accompanied by diabetes may indicate a situation in which at least one cardiovascular disease selected from hypertension, dyslipidemia, angina, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction occurs simultaneously with diabetes. According to one embodiment, cardiovascular disease with diabetes may indicate a situation in which hypertension and dyslipidemia occur concurrently with diabetes.

In one embodiment, the cardiovascular disease with diabetes may be a disease that meets at least one of the following conditions:

(1) after 8 hours or more than 8 hours of fasting, the blood plasma glucose is more than or equal to 126 mg/dl,

(2) optionally a plasma glucose value of 200 mg/dl or more, plus at least one symptom selected from the group consisting of polyuria, polydipsia, polyphagia, hunger sensation and indeterminate weight loss,

(3) plasma glucose of not less than 200 mg/dl 2 hours after 75 g oral glucose tolerance test, an

(4) The value of the glycosylated hemoglobin (HbA1c) is more than or equal to 6.5 percent,

while satisfying at least one of the following conditions:

(a) the sitting contraction blood pressure (sitSBP) is more than or equal to 140 mm Hg,

(b) the sitting diastolic blood pressure (sitDBP) is more than or equal to 90 mm Hg,

(c) the concentration of blood L D L-cholesterol (L D L-C) is not less than 130 mg/dl,

(d) the concentration of blood HD L-cholesterol (HD L-C) is less than 60 mg/dl,

(e) blood triglyceride concentration of 150 mg/dl or more, an

(f) The total cholesterol concentration is > 200 mg/dl.

The conditions (a) to (f) may be changed according to the revision of guidelines for diagnosis of hypertension or dyslipidemia.

Plasma Glucose (FPG) after a fasting state for 8 hours or more in condition (1) means a blood glucose level measured in a state of fasting for at least 8 hours after a meal.

In condition (2), polyuria, polydipsia, polyphagia, hunger sensation and undetermined (unknown-cause) weight loss refer to typical symptoms of diabetes. In addition, these symptoms may also include fatigue, blurred vision, and slow wound recovery. Any plasma glucose value refers to a blood glucose value measured regardless of the last meal time.

The Oral Glucose Tolerance Test (OGTT) of condition (3) is performed by measuring the blood glucose value at least 8 hours before the test in the fasting state and 2 hours after the intake of 75 g of a glucose solution in the fasting state.

The glycated hemoglobin (HbAlc) value of condition (4) refers to a value indicating the concentration of glycated hemoglobin obtained by allowing glucose to bind thereto by reacting with hemoglobin of a patient, and is a measure of the average value of blood glucose values for three months. In 2010, the American Diabetes Association (ADA) adopted 6.5% or more than 6.5% glycated hemoglobin as a diagnostic standard for Diabetes. The method of labeling glycated hemoglobin can be roughly classified into standardization by the National Glycohemoglobin Standardization Program (NGSP) comparison method and standardization by the european International Federaiton of Clinical Chemistry (IFCC) reference method. According to the NGSP method, Hb is separated into subtypes (HbA1a, HbA1b, and HbA1c) by chromatography, and HbA1c is expressed in percentage (%). HbA1c was measured and expressed in millimoles per mole (mmol/mol) according to the IFCC method, where glucose binds to valine at the N-terminus of Hb. 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. The conditions (1) to (4) may be changed according to revision of guidelines for diabetes diagnosis.

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

Diabetes can be classified as diabetes type 1 or type 1 (T1 DM); diabetes type 2 or type 2 diabetes (T2 DM); and gestational diabetes. Diabetes type 1 or type 1 diabetes (T1DM) is caused by the inability to produce sufficient amounts of insulin, and is also known as "insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes", and the specific cause thereof has not been discovered. Diabetes type 2 or type 2 diabetes (T2DM) begins with insulin resistance, in which cells fail to respond appropriately 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 overweight and hypokinesia. Gestational diabetes is a third type of diabetes that occurs in pregnant women with no history of diabetes and develops into hyperglycemia. In diabetics, hypertension may be a risk factor for kidney disease, and as the diabetic cycle increases, the risk of hypertension may increase. According to one embodiment, in cardiovascular disease with diabetes, the diabetes may be type 2 diabetes.

In the diabetic group, the risk associated with cardiovascular diseases (e.g., hypertension, dyslipidemia, angina pectoris, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure, myocardial infarction, etc., or other metabolic diseases) may be increased. Furthermore, in a group of patients suffering from cardiovascular diseases, the risk of accompanying diabetes or other metabolic diseases may be increased.

The cardiovascular disease accompanied with diabetes may be a disease in which diabetes and at least one cardiovascular disease selected from hypertension and dyslipidemia are simultaneously developed. In one embodiment, the cardiovascular disease with diabetes may be hypertension or dyslipidemia with diabetes. In one embodiment, the cardiovascular disease associated with diabetes may be diabetic hypertension or diabetic dyslipidemia.

Diabetes, independently of normal hypertension, can alter cardiovascular or myocardial function, structure, etc. The term "diabetic hypertension" as used herein refers to hypertension occurring with diabetes, and is intended to include a case where hypertension and diabetes occur simultaneously when medication is performed, a case where diabetes occurs before hypertension, or a case where diabetes occurs after hypertension. In diabetic hypertension, the mechanism by which hypertension caused by diabetes mellitus occurs or is altered may be due to insulin resistance, for example. Insulin resistance may lead to insulin-induced loss of vasodilation, and may induce an increase in sodium and water in the body due to hyperinsulinemia, sympathetic nervous system activation, and the like. In addition, renal function deteriorates due to diabetes, resulting in an increase in body fluid, which may be a cause of the increase in blood pressure. Diabetes increases atherosclerosis in large blood vessels or coronary arteries and thus may lead to abnormal physiological conditions leading to reduced sensitivity. Therefore, it may cause the occurrence of new hypertension, the aggravation of hypertension symptoms, or the decrease in the pharmacological effect of existing hypertension drugs.

According to the clinical results of the existing studies on diabetic hypertension, perindopril (perindopril) as an ACE inhibitor and indapamide (indapamide) as a thiazide diuretic reduce the mortality and incidence of macrovascular and microvascular diseases. However, ACE inhibitors are contraindicated in patients with angioedema and bilateral renal artery stenosis, and should be reduced or discontinued when the Glomerular Filtration Rate (GFR) decreases by 30% or more, creatinine increases and hyperkalemia develops, and close attention is required because electrolyte and renal function should be monitored periodically. In addition, when thiazide diuretics are used at high doses, blood glucose may increase, insulin secretion may be inhibited, insulin resistance may increase, and glycemic control may be exacerbated.

The pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof according to the examples inhibits the progression of hypertension, inhibits microvascular/macrovascular complications in diabetic patients, protects the cardiovascular system, inhibits renal function deterioration in diabetic nephropathy patients, extends peripheral blood vessels, and increases blood flow, thereby enhancing insulin sensitivity. In addition, the pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof according to the 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 mellitus, diabetic dyslipidemia may be caused by insulin resistance depending on diabetes mellitus, insulin resistance is usually accompanied by dyslipidemia, and the mechanism thereof is not yet known, but is known to be associated with disorders of lipoprotein metabolism, for example, hypertriglyceridemia observed in relatively well-controlled type 2 diabetes may be due to accumulation of abdominal fat leading to an increase in the concentration of free fatty acids in the hepatic portal vein, which is considered to be one of the causes of diabetes mellitus.

The nature of diabetic dyslipidemia can be summarized as 1) increased blood triglycerides, 2) decreased HD L cholesterol, and 3) chemical degeneration of L D L0. in particular, with respect to 1), hypertriglyceridemia is common in diabetes and may be mainly due to the reduced removal of V L D L-triglyceride (very-low-intensity lipoprotein-triglyceridemia, V L D L4-TG) in the liver. in diabetes, insulin deficiency or insulin resistance increases the release of free fatty acids in adipose tissue, leading to an increased uptake of free fatty acids, and thus increased synthesis of V L D L in the liver, while in adipose tissue and muscle, due to insulin deficiency and insulin resistance, the decreased activity of lipolase involved in the breakdown of V867D 8748-D L is due to the decreased metabolic mechanisms of V L D L, and thus increased metabolic mechanisms of HD L, and thus decreased metabolic mechanisms of hc L, and thus decreased activities of hc L in the liver L, and no significant changes in the hc-72, TG L, no significant changes in the metabolic mechanisms of the HD L, no detectable metabolic processes of the hc-72, no change in the hc-L, no detectable metabolic mechanisms of the hc-72, no change in the hc-L, no such as observed by the insulin metabolism of the insulin-8 and no detectable changes in the metabolic mechanisms of the insulin-L, no detectable markers of the lipid metabolism of the insulin-L, no detectable markers of the hypo L, no detectable changes in the hypo L, no detectable and no detectable markers of the hypo L, no detectable changes in the hypoactivity of the hypo L, no evidence of the.

As the existing drug therapy for dyslipidemia, there is a method of administering nicotine (niacin), nicotinic acid (nicotinic) preparations, fibrate derivatives or estrogen. Nicotine is a drug that inhibits lipolysis in adipose tissue, but its duration of action is short, thus leading to increased rebound of free fatty acids and hyperglycemia, limiting the use of nicotine for the treatment of diabetic dyslipidemia. Nicotinic acid preparations have a long duration of action, show a strong inhibitory effect on lipolysis, and have fewer side effects such as increased rebound of free fatty acids and hyperglycemia, and are therefore frequently selected, particularly when the TG value is greatly increased, but may have serious flushing side effects. In the case of elevated triglycerides alone or with cholesterol, the fibrate derivative was first selected, but in 2005, the pharmaco-alert sector of the Committee for Human medicine (Committee for medical Products for Human Use, CHMP) insisted on the lack of evidence of long-term cardiovascular disease risk and re-evaluated this drug, with the result that it announced the conclusion that the fibrate derivative could not be the first choice for the treatment of dyslipidemia. The pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof according to the embodiment includes a high-strength statin drug and has an excellent effect of controlling blood pressure and lipid concentration in arteriosclerotic cardiovascular diseases as well as cardiovascular diseases accompanied with diabetes.

According to one embodiment, a pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin 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 cardiovascular diseases accompanied with diabetes.

The term "amlodipine" is a generic drug name of [ 3-ethyl 5-methyl 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylate ] (3-ethyl 5-methyl 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylate), and amlodipine is a calcium channel blocker, it can block calcium ion channel on the surface of cardiac muscle and vascular smooth muscle to relax vascular smooth muscle, and increasing glomerular filtration rate by relaxing afferent arterioles of the kidney to produce a diuretic effect, and thus exhibit a hypotensive effect. Particularly, amlodipine, which is a third-generation Calcium Channel Blocker (CCB), exhibits a long-term slow hypotensive effect, alleviates side effects such as orthostatic hypotension, effectively prevents systolic hypertension and stroke, and is suitable for treating angina pectoris, which causes coronary artery dilatation, because it is slowly absorbed and has a long half-life of about 35 hours to about 40 hours when orally administered.

The term "rosuvastatin" is the generic drug name for 2-butyl-4-chloro-1- [ {2 '- (1H-tetrazol-5-yl) [1, 1' -biphenyl ] -4-yl ] methyl ] -1H-imidazole-5-methanol (2-butyl-4-chloro-1- [ {2 '- (1H-tetrazol-5-yl) [1, 1' -biphenyl ] -4-y1] methyl ] -1H-imidozole-5-methanol), and rosuvastatin is the first angiotensin receptor antagonist based component developed. Rosuvastatin has a blood pressure lowering effect by acting as a selective and competitive antagonist against angiotensin II receptor, which is an effective vasoconstrictor and is effective in treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), etc., or preventing the progression of heart failure after myocardial infarction.

The term "rosuvastatin" is the generic drug name of [ (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] - (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid ] ((E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidane-5-y 1] - (3R, 5S) -3, 5-dihydroohept-6-enoic acid), and is a statin drug that inhibits cholesterol synthesis in the liver by acting as an HMG-CoA reductase inhibitor, increases the number of low-density lipoprotein (low-densitypoprotein, L D L) receptors on the surface of hepatocytes, and reduces the plasma cholesterol uptake and lipoprotein values and decreases the number of circulating lipoproteins in addition to the quality of atherosclerotic plaques, such as atherogenic myocardial infarction, pulmonary infarction.

The pharmaceutical composition according to the embodiment has excellent effects of controlling blood pressure and improving lipids, particularly in diabetic patients, and particularly in the group of diabetic patients, excellent sitting contraction blood pressure lowering effects and excellent lipid improving effects. The excellent blood pressure lowering effect and the excellent lipid improving effect obtained by using the pharmaceutical composition comprising amlodipine, rosuvastatin and rosuvastatin particularly in the diabetic patient group, compared with the non-diabetic patient group, are novel effects unpredictable in the therapeutic agent technology regarding hypertension or dyslipidemia.

In one embodiment, the diabetic group showed a greater decrease of about 1.4 times (about 1.36 times) the mean sitting systolic blood pressure (mean sitSBP) relative to the non-diabetic group when observed 8 weeks after administration of the composition comprising amlodipine, rosuvastatin and rosuvastatin (see experimental example 1). From the results, it was confirmed that the composition comprising amlodipine, rosuvastatin and rosuvastatin effectively reduced the average sitSBP in the diabetic patient group.

In one example, when the diabetic patient group was observed 8 weeks after administration of the composition comprising amlodipine, rosuvastatin and rosuvastatin, the diabetic patient group exhibited a greater decrease of about 1.2 times (about 1.18 times) the mean sitting diastolic blood pressure (mean sitDBP) relative to the non-diabetic patient group (see experimental example 2). From the results, it was confirmed that the composition comprising amlodipine, rosuvastatin and rosuvastatin effectively reduced the average sitDBP in the diabetic patient group.

In one example, it was confirmed that the composition comprising amlodipine, rosuvastatin and rosuvastatin effectively reduced Triglyceride (TG) at 8 weeks after the administration, compared to the case where the composition comprising only amlodipine and rosuvastatin or only rosuvastatin and rosuvastatin was administered (see experimental examples 3(1) and 3 (2)).

In one embodiment, the composition comprising amlodipine, rosuvastatin and rosuvastatin exhibits an increased Triglyceride (TG) modulating effect, particularly at 8 weeks after administration to a group of diabetic patients. In particular, when the case of administering only rosuvastatin and rosuvastatin is compared with the case of administering amlodipine, rosuvastatin and rosuvastatin by changing the composition of the administered drugs and the group of administered drugs, no higher reduction of Triglyceride (TG) is exhibited in the non-diabetic patient group despite further addition of amlodipine and the adjustment of TG is rather unsatisfactory due to the addition of amlodipine, compared with the case of administering only rosuvastatin and rosuvastatin. In contrast, the diabetic patient group showed about 1.9-fold (about 1.93-fold) greater reduction in Triglyceride (TG) compared to the composition containing only rosuvastatin and rosuvastatin due to the administration of the composition containing amlodipine, rosuvastatin and rosuvastatin. From these results, it was confirmed that the diabetic group exhibited an enhanced TG-regulating effect by having a greater TG reduction due to the administration of the composition comprising amlodipine, rosuvastatin and rosuvastatin (see experimental example 3 (3)).

In one example, a high normalization rate of blood pressure was observed 4 weeks or 8 weeks after the administration of the composition comprising amlodipine, rosuvastatin and rosuvastatin, compared to the case of administration of only amlodipine and rosuvastatin or only rosuvastatin (see experimental example 4 (1)). In addition, the composition comprising amlodipine, rosuvastatin and rosuvastatin also showed a high blood pressure normalization rate in the case of the cardiovascular risk classification group C, and an excellent blood pressure normalization rate in all cardiovascular risk classification groups A, B and C (see experimental example 4 (2)). In addition, the composition comprising amlodipine, rosuvastatin and rosuvastatin showed a higher blood pressure normalization rate in the group of patients with diabetes than the case of administration of only amlodipine and rosuvastatin or the case of administration of only rosuvastatin and rosuvastatin (see experimental example 4 (3)). From these results, it was confirmed that the composition comprising amlodipine, rosuvastatin and rosuvastatin exhibited an excellent blood pressure normalization rate, and also exhibited a high blood pressure normalization rate in the group of patients accompanied with diabetes.

In one example, the low-density lipoprotein-cholesterol (L D L-C) treatment target achievement rate and blood pressure normalization rate were observed to be higher 4 weeks or 8 weeks after the administration of the composition comprising amlodipine, rosuvastatin and rosuvastatin than in the case of the administration of only amlodipine and rosuvastatin or the case of the administration of only rosuvastatin and rosuvastatin (see experimental example 5(1)), in addition, the composition comprising amlodipine, rosuvastatin and rosuvastatin exhibited higher L D L-C treatment target achievement rate and higher blood pressure normalization rate than in the case of the administration of only amlodipine and rosuvastatin or the case of the administration of only rosuvastatin (see experimental example 5(2)), from which it was confirmed that the composition comprising amlodipine, rosuvastatin and rosuvastatin exhibited excellent treatment target normalization rate and blood pressure normalization rate of L D L-C, and also exhibited high blood pressure normalization rate in the group of patients with diabetes mellitus L-L.

In one embodiment, the pharmaceutical composition can be used for preventing or treating a patient suffering from hypertension and dyslipidemia of diabetes mellitus. The pharmaceutical composition may be a composition for preventing or treating diabetic hypertension or diabetic dyslipidemia. In one embodiment, the pharmaceutical composition may be a composition for preventing or treating diabetic hypertension.

According to the clinical trial guidelines for therapeutic agents for hypertension, in evaluating the antihypertensive effect, the effectiveness of the therapeutic agent for hypertension is generally evaluated by the following steps: firstly, the change of the systolic blood pressure of the sitting position before and after treatment is used as a main evaluation item, and the change of the diastolic blood pressure of the sitting position before and after treatment is used as a secondary evaluation item. In addition, the degree of hypertension treatment response refers to a blood pressure normalization rate (percentage of patients satisfying the condition that systolic blood pressure is < 140 mm Hg and diastolic blood pressure is < 90 mm Hg after completion of treatment) and a blood pressure response rate (percentage of patients satisfying the condition that systolic blood pressure is lowered by 20 mm Hg or more and diastolic blood pressure is lowered by 10 mm Hg or more relative to a base line value after completion of treatment) (Korea Food and Drug Administration, National Institute of Food and Drug Safety Evaluation (National Institute of Food and Drug Evaluation), and 2015 12 months).

In one embodiment, the pharmaceutical composition may lower the sitting systolic blood pressure by about 1.3-fold or more than 1.3-fold, such as about 1.36-fold or more than 1.36-fold or about 1.4-fold or more than 1.4-fold, compared to the situation in cardiovascular disease not accompanied by diabetes. The pharmaceutical composition may significantly further reduce the sitting systolic blood pressure by about 1.3 times or more than 1.3 times, such as about 1.36 times or more than 1.36 times or about 1.4 times or more than 1.4 times, such as about 1.3 times, about 1.36 times, about 1.4 times, about 1.45 times or about 1.5 times in the diabetic group relative to the non-diabetic group. In one embodiment, the change in sitting systolic blood pressure of the pharmaceutical composition in the diabetic patient group may be about 1.3 fold or greater than 1.3 fold, or in a range from about 1.2 fold to about 2.5 fold, from about 1.3 fold to about 2.0 fold, from about 1.35 fold to about 1.5 fold, or from about 1.3 fold to about 1.5 fold compared to the non-diabetic patient group.

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

In one embodiment, the pharmaceutical composition may exhibit a decrease in sitting systolic blood pressure (mean ± SD) of 20.48 ± 17.95 mm hg and 15.04 ± 10.86 mm hg, respectively, from baseline values 8 weeks after administration to the diabetic patient group and the non-diabetic patient group. In one embodiment, the pharmaceutical composition may exhibit maximum reductions in sitting systolic blood pressure relative to baseline values of 52.00 mmhg and 38.30 mmhg 8 weeks after administration to the diabetic and non-diabetic patient groups, respectively.

In one embodiment, the pharmaceutical composition may reduce the sitting diastolic blood pressure by about 1.2-fold or more than 1.2-fold, such as about 1.10-fold or more than 1.10-fold, or about 1.18-fold or more than 1.18-fold, compared to the situation in cardiovascular disease not accompanied by diabetes. The pharmaceutical composition may further significantly reduce the sitting diastolic blood pressure by about 1.2 times or more than 1.2 times, such as about 1.10 times or more than 1.10 times, or about 1.18 times or more than 1.18 times, such as about 1.10 times, about 1.15 times or about 1.20 times in the diabetic group relative to the non-diabetic group.

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

The following criteria can be modified according to the revision of Guidelines for diagnosis of Hypertension or dyslipidemia (Korean institute of Hypertension Treatment Guidelines and JNC8 reports), and the journal of lipid atherosclerosis (J L ipid Atherosealer) 2015; 4 (1): 61-92).

(a) The sitting position systolic blood pressure (sitSBP) is more than or equal to 140 mm Hg

(b) Sitting diastolic blood pressure (sitDBP) not less than 90 mm Hg

(c) Blood L D L-cholesterol (L D L-C) concentration is not less than 130 mg/dl

(d) Blood HD L-cholesterol (HD L-C) concentration < 60 mg/dl

(e) Blood triglyceride concentration is not less than 150 mg/dl

(f) Total cholesterol concentration > 200 mg/dl

According to clinical practice guidelines, normal blood glucose values are as follows: fasting plasma glucose values at 2 hours after the 75 g oral glucose tolerance test are below 100 mg/dl and plasma glucose values are below 140 mg/dl, and a fasting glucose disturbance is indicative of a fasting plasma glucose value between 100 mg/dl and 125 mg/dl, and impaired glucose tolerance is indicative of a plasma glucose value between 140 mg/dl and 199 mg/dl at 2 hours after the 75 g oral glucose tolerance test.

The subject to which the pharmaceutical composition exhibiting blood pressure control and lipid improvement effects can be applied may be a diabetic patient group, for example, a subject having at least one of the following conditions. In addition, the following criteria may be in accordance with diabetes diagnostic criteria known in the art to which the present disclosure pertains (e.g., the 2016 guide for the American Diabetes Association (ADA)), and may be changed according to revisions in the guide regarding this.

(1) After 8 hours or more than 8 hours of fasting, the blood plasma glucose is more than or equal to 126 mg/dl,

(2) (ii) any plasma glucose value of 200 mg/dl, plus at least one symptom selected from the group consisting of polyuria, polydipsia, polyphagia, hunger sensation, and indeterminate weight loss,

(3) plasma glucose of not less than 200 mg/dl 2 hours after 75 g oral glucose tolerance test, an

(4) The value of glycosylated hemoglobin (HbA1c) is more than or equal to 6.5%

In one embodiment, the amount of amlodipine or a pharmaceutically acceptable salt thereof may range from about 5 mg to about 10 mg when converted to amlodipine free base form, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof may range from about 45 mg to about 100 mg when converted to rosuvastatin 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 to rosuvastatin free acid form, relative to the total amount of the pharmaceutical composition. In one embodiment, the pharmaceutical composition may be administered once daily.

In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in the form of amlodipine in an amount of about 5 mg to about 10 mg, for example, 5 mg. The rosuvastatin or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in the form of rosuvastatin in an amount of about 45 mg to about 100 mg, for example 50 mg or 100 mg. Rosuvastatin or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in the form of rosuvastatin in an amount of about 5 mg to about 20 mg, e.g., 5 mg, 10 mg or 20 mg. The dose can be adjusted appropriately according to the symptoms, age, race and sex.

In another embodiment, the pharmaceutical composition may comprise amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin 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 as a fixed-dose combination formulation comprising the above-mentioned doses of amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin 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, depending on the amount administered. For example, a pharmaceutical composition comprising 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin may be administered once daily.

By administering once a day a pharmaceutical composition comprising 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin, patient convenience and medication compliance can be enhanced and also the best pharmacological clinical effect in terms of blood pressure lowering effect can be obtained.

In one embodiment, the pharmaceutical composition may be administered for a period of 4 weeks or more than 4 weeks or less than 4 weeks or for a period of 8 weeks or more than 8 weeks or less than 8 weeks, taking into account the pathological condition, severity thereof, etc. of the subject to whom the pharmaceutical composition is administered. When the pharmaceutical composition is administered in the same composition and amount, for example, when the pharmaceutical composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount of 5 mg when converted to amlodipine free base form, rosuvastatin or a pharmaceutically acceptable salt thereof in an amount of 100 mg when converted to rosuvastatin free acid form, and rosuvastatin or a pharmaceutically acceptable salt thereof in an amount of 20 mg when converted to rosuvastatin free acid form, and the reduction of the sitting systolic blood pressure may be more significant in a diabetic patient group than in a non-diabetic patient group based on daily dose administration.

In the pharmaceutical composition, the pharmaceutically acceptable salt of amlodipine, rosuvastatin or rosuvastatin means a salt prepared according to a method well known in the art, and the preparation method is known to those skilled in the art. Specifically, examples of the pharmaceutically acceptable salts include, but are not limited to, the following pharmacologically or physiologically acceptable salts derived from inorganic acids, organic acids and bases. Non-limiting examples of suitable acids can 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, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid (besylic acid), and camphorsulfonic acid (camsylic acid). Examples of suitable base-derived salts may include, but are not limited to, salts of alkali metals such as sodium or potassium or salts of alkaline earth metals such as calcium or magnesium.

The pharmaceutically acceptable salt of amlodipine is formed from an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, and examples thereof may include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulfonate and camphorsulfonate. For example, amlodipine besylate or amlodipine camsylate may be used. Further, amlodipine includes amlodipine racemate and (S) -amlodipine. A pharmaceutically acceptable salt of rosuvastatin may be, for example, potassium rosuvastatin, although the disclosure is not limited thereto. Further, 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 comprise amlodipine camsylate, potassium rosuvastatin, and calcium rosuvastatin.

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

In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof may be administered in a single dosage form including all the above components or in multiple dosage forms including the respective components, respectively. Amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof may be administered in combination in a single dosage form or in separate dosage forms. The single dosage form or the divided dosage form may be in the form of a lozenge or capsule. 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, delaying the administration of the second ingredient should not interfere with the beneficial effects of, for example, the co-administration therapy. In this context, sequential administration may also include, but is not limited to, for example, alternating administration of the active ingredients.

The dosage of the pharmaceutical composition according to the embodiment may vary according to the age, sex, body weight, pathological conditions and severity of the subject to which the pharmaceutical composition is to be administered, the administration route, or the decision of the prescriber. Suitable dosages based on such factors are determined by those skilled in the art.

The pharmaceutical composition may be present in the form of, for example, lozenges, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules suitable for oral administration; in the form of an aqueous or oily sterile solution or suspension suitable for parenteral administration, for example, intravenous, subcutaneous, intramuscular or intravascular administration; in a form suitable for topical administration, e.g. a cream, gel or ointment; or in the form of suppositories suitable for rectal administration. In one embodiment, the composition is in the form of, for example, a lozenge or capsule suitable for oral administration.

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

Non-limiting examples of CCBs may include nifedipine (nifedipine), felodipine (felodipine), and verapamil (verapamil) in addition to amlodipine. Non-limiting examples of ARBs, in addition to luosutan, may include temisatan (telmisartan), valsultan (valsartan), candesultan (candisartan), irbesartan (irbesartan), and olmesatan (olmesartan). Non-limiting examples of HMG-CoA reductase inhibitors other than rosuvastatin may include pravastatin (pravastatin), simvastatin (simvastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), and pitavastatin (pitavastatin). The pharmaceutical composition may further comprise a diuretic, such as a thiazide-based diuretic, for example hydrochlorothiazide (hydrochlorothiazide), chlorothiazide (chlorothiazide), chlorthalidone (chlorothalidone), indapamide (indapamide), metolazone (metazone), polythiazide (polythiazide), cimetide (xipamide), and the like. For example, co-drug therapy using two or more drugs to treat hypertension may be employed to enhance the hypotensive effect and also to complementarily reduce the side effects of each drug. For example, when a combination therapy using CCB and ARB is employed, vascular extension and fluid regulation can be achieved at the same time, and thus the advantageous effects of the combination administration can be obtained.

According to another embodiment of the present disclosure, there is provided a complex formulation for preventing or treating cardiovascular diseases accompanied by diabetes, the complex formulation including: amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

The complex formulation according to the embodiment is effective for treating patients with hypertension and dyslipidemia. Each of hypertension and dyslipidemia is a single risk factor for cardiovascular disease and significant clinical effects are obtained when both diseases are treated simultaneously. In addition, the complex formulation can enhance the convenience of administration and the compliance of patients who will be administered amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof at the same time, and possibly reduce the drug cost. In particular, the corresponding disease group of patients is mainly composed of elderly patients after middle-aged due to the characteristics of the disease, and when considering that there are many cases where a plurality of drugs need to be administered simultaneously, the effect of increased drug compliance when a complex formulation is administered is more remarkable.

Suitable dosages of amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof contained in the composite preparation are the same as those described above with respect to the pharmaceutical composition.

In one embodiment, the complex formulation may include amlodipine or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 10 mg, rosuvastatin 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 complex formulation may comprise the following respective amounts of the three active ingredients: 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 formulation may be in the form of a lozenge, capsule, or capsule-type lozenge. The composite formulation may be in the form of a bi-layer lozenge or a tri-layer lozenge.

The complex formulation may, for example, comprise amlodipine or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof in a first mixing part and rosuvastatin or a pharmaceutically acceptable salt thereof in a second mixing part, wherein the first mixing part and the second mixing part are present in a state physically separated from each other. For example, each of the first mixing portion and the second mixing portion can further comprise a pharmaceutically acceptable additive.

Further, the complex formulation may be in the form of, for example, a bi-layer lozenge comprising amlodipine or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof in a first layer and rosuvastatin or a pharmaceutically acceptable salt thereof in a second layer. For example, each of the first and second layers may further comprise a pharmaceutically acceptable additive.

According to one embodiment, the pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof or a complex formulation comprising the same shows excellent effects in the treatment of hypertension and dyslipidemia.

In addition, as a result of clinical trials, it was confirmed that the effect of treating dyslipidemia (change in L D L-C, total cholesterol, HD L-C and triglycerides and achievement rate of NCEP ATP III L D L-C therapeutic target) and hypertension (change in mean sitDBP, sitSBP and normalization rate of JNC VII blood pressure) was superior to that of the control group 8 weeks after combined administration of 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin (A5+ L100 + R20).

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

In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof contained in the composition may be administered using various administration methods, for example, oral or parenteral administration, in an amount effective for treating or preventing diseases of an individual or a patient according to the use purpose. In the administration method, an appropriate dose for a specific individual or patient may be determined according to various associated factors, such as the weight, age, race, sex, health condition and diet of the patient, administration period, administration method, severity of disease, and the like, and it should be understood that an expert may suitably increase or decrease the appropriate dose, and the dose is not intended to limit the scope of the present disclosure in any way. Dosages for the compounds used can be readily determined and prescribed, if desired, by a physician having ordinary skill in the relevant art. For example, the dosage of the compounds used in the pharmaceutical compositions of the present disclosure may be adjusted by the physician such that the dosage is first adjusted to a level below that required to achieve the desired therapeutic effect, and then gradually increased until the desired effect is achieved.

The term "treatment" as used herein is intended to include all treatment, amelioration, palliation and control of the disease. The term "treating" or "treatment" as used herein refers to inhibiting a disease, e.g., inhibiting a disease or pathological condition or disorder in an individual experiencing or exhibiting a pathological condition or symptom of the disease or pathological condition or disorder, preventing further development of the pathological condition and/or symptom, alleviating the disease, or reversing the pathological condition and/or symptom, e.g., reducing the severity of the disease.

The term "preventing" or "prevention" as used herein refers to preventing a disease, e.g., preventing a disease, disorder or condition in an individual who may be at risk for the disease, disorder or condition but who has not experienced or exhibited the condition or symptoms of the disease.

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

The terms "having", "may have", "includes" or "may include" as used herein are intended to include the presence of the corresponding property (e.g., a value or a component such as an ingredient), but not to exclude the presence of other properties.

Hereinafter, the present disclosure will be further explained in 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 test subjects and administration of clinical trial drugs

1. Selection of test subjects

Test subjects were selected based on the following selection criteria:

1) adults aged between 19 and 75 years

2) Patients who meet the following conditions in the first visit screening

① blood pressure standard, sitDBP is not less than 90 mm Hg

② lipid standard, L D L-C is less than or equal to 250 mg/dl, TG is less than 400 mg/dl

3) Patients who met the following conditions at the second visit after 4 weeks of therapeutic lifestyle change (T L C)

① standard blood pressure, sitDBP is not more than 80 mm Hg and less than 110 mm Hg

② lipid criteria patients who meet the following criteria when classified into groups A, B and C according to cardiovascular disease risk

Coronary Heart Disease (CHD) risk factor

1) Current smokers

2) Taking hypotensor

3) Low HD L-C (< 40 mg/dl)

4) Family history of early CHD: in cases where parents, brothers, sisters and brothers and sisters have CHD in men under 55 years old or women under 65 years old

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

However, in the case of HD L-C ≧ 60 mg/dl, the condition is considered a protective factor and therefore should be subtracted by one from the total number of risk factors.

Risk equivalent of CHD

Coronary artery disease, diabetes (HbAlc ≧ 6.5%, but in cases diagnosed with diabetes or taking diabetic medications, the condition is considered diabetes regardless of HbA1c criteria), or other clinical forms of atherosclerosis (e.g., peripheral artery disease, abdominal aortic aneurysm, symptomatic carotid artery disease, etc.).

In particular, cases where the number of CHD risk factors is 0 or 1 are classified as group A. furthermore, cases where the number of CHD risk factors is 2 or greater than 2 are classified as group B. furthermore, cases where the CHD/CHD risk equivalent or the risk of faithful cardiovascular disease within 10 years is greater than 20% are classified as group C. the detailed classification according to L D L-C or TG conditions is the same as shown in the above table.

In addition, situations unsuitable for clinical trials are excluded from the subject according to predetermined criteria.

2. Preparation and preparation of clinical trial medicine

(1) Preparation of test drugs

Lozenges comprising 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin were prepared as test drugs to be administered to selected groups of subjects and used as test drugs.

Specifically, amlodipine camsylate, rosuvastatin calcium, lactose hydrate, microcrystalline cellulose, and crospovidone are mixed and formulated, then magnesium stearate is added thereto, and finally the resultant mixture is mixed in a mixer to prepare a blend of amlodipine and rosuvastatin. In addition, rosuvastatin potassium, microcrystalline cellulose, and crospovidone are mixed and formulated, and pressurized to form granules, magnesium stearate is added thereto, and then the resulting mixture is finally mixed to prepare rosuvastatin granules. Finally, a composite bi-layer lozenge consisting of the prepared blend of amlodipine and rosuvastatin and the prepared rosuvastatin granules was prepared.

(2) Preparation of control drug

As a control drug, 5 mg of amlodipine (Amodipin) was prepared^TMLozenges (5 mg as amlodipine), 100 mg couze (Cozzar)^TMLozenge (100.0 mg as luosutan) and 20 mg Kurui scott (Crestor)^TMLozenges (20 mg as rosuvastatin).

3. Assignment of test Subjects

First, subjects were subjected to therapeutic lifestyle changes at the first visit (T L C) for 4 weeks, during T L C, existing hypertension and dyslipidemia therapeutics were washed away, then treated with 100 mg of rosuvastatin monotherapy, after 4 weeks at T L C, blood pressure and fasting serum lipids were again examined at the second visit, and subjects meeting the selection criteria were randomly assigned to three groups.

Experimental group A group administered with troches containing 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin (A5+ L100 + R20)

Control group 1: administration of 5 mg amlodipine and 100 mg rosuvastatin (5 mg Amodipin)^TMTablets and 100 mg of Cozzar^TMLozenges) group (A5+ L100)

Control group 2: 100 mg of rosuvastatin and 20 mg of rosuvastatin (100 mg of Cozzar) are administered^TMTablets and 20 mg of Crestor^TMLozenges) group (L100 + R20)

The Full Analysis Set (FAS) is directed to trial subjects who were subjected to at least one primary efficacy evaluation after administration of a clinical trial drug in trial subjects administered one or more times after random assignment of trial subjects until completion of the clinical trial.

Protocol Set (PPS) is a trial subject for which a clinical trial is completed according to a clinical trial protocol in FAS subjects, and subjects deviating from the protocol are excluded from PPS.

FAS, the main analysis group of clinical trials, included 143 trial subjects, 2 subjects without any primary efficacy evaluation after random assignment, and according to the administration group, the a5+ L100 + R2 administration group included 54 subjects, the a5+ L100 administration group included 46 subjects, and the L100 + R20 administration group included 43 subjects, 131 subjects in FAS who completed clinical trials according to the clinical trial protocol were included in PPS, and according to the administration group, the a5+ L100 + R20 administration group included 50 subjects, the a5+ L100 administration group included 41 subjects, and the L100 + R20 administration group included 40 subjects.

FAS was evaluated for comparative homogeneity between drug administration groups based on baseline demographic data such as gender, age, height, weight, smoking history, and history of alcohol consumption, and there were no significant differences between groups except weight. In addition, all drug combinations showed 95% or greater than 95% drug compliance.

4. Administration of clinical trial drugs

Specifically, the A5+ L100 + R20 administration group (experimental group) administered 1 tablet of the prepared test drug (tablet comprising 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin) once a day, the A5+ L100 administration group (control group 1) administered 1 tablet of amlodipine and Cozzar once a day^TMAnd L100 + R20 administration group (control group 2) administered 1 tablet of Cozzar as a test drug once a day^TMAnd Crestor^TMEach of the above. The clinical trial drug was administered to the experimental group, control group 1 and control group 2 for 8 weeks. Test subjects visit the test study facility and evaluate efficacy and safety every 4 weeks during the 8 week period of clinical trial drug administration. In addition, the clinical trial results were analyzed according to the following evaluation criteria.

5. Evaluation criteria

(1) Evaluation of efficacy

In the case of a continuous variable between the primary or secondary efficacy evaluation variables, the rate or change is calculated as follows.

Change-4 or 8 week measurement baseline

1) End of primary efficacy

① change rate of L D L-C from baseline after 8 weeks in the group to which amlodipine/rosuvastatin was administered (A5+ L100 + R20) (experimental group) and the group to which amlodipine/rosuvastatin was administered (A5+ L100) (control group 1)

② mean sitDBP change from baseline after 8 weeks for the group administered amlodipine/rosuvastatin and the group administered rosuvastatin/rosuvastatin

2) Secondary efficacy endpoints

① change rate of L D L-C after 4 weeks from baseline in the amlodipine/rosuvastatin administration group and the amlodipine/rosuvastatin administration group

② change rate of L D L-C from baseline after 4 and 8 weeks in the group administered amlodipine/rosuvastatin and the group administered rosuvastatin

③ change rates of TC, HD L-C, and TG from baseline after 4 weeks and 8 weeks for the amlodipine/rosuvastatin administration group, the rosuvastatin/rosuvastatin administration group, and the amlodipine/rosuvastatin administration group

④ mean sitDBP (millimeter Hg) change from baseline after 4 weeks for the group administered amlodipine/rosuvastatin and the group administered rosuvastatin

⑤ mean sitDBP (millimeter Hg) change from baseline after 4 and 8 weeks for the group administered amlodipine/rosuvastatin and the group administered amlodipine/rosuvastatin

⑥ mean sitSBP (mmhg) change from baseline after 4 and 8 weeks for the amlodipine/rosuvastatin administered group, the rosuvastatin/rosuvastatin administered group, and the amlodipine/rosuvastatin administered group

⑦ group administered amlodipine/rosuvastatin, group administered rosuvastatin and group administered amlodipine/rosuvastatin after 4 weeks and 8 weeks achieved rate of L D L-C therapeutic objectives according to National Cholesterol reduction Program (NCEP) adult treatment team (ATP) III guidelines

⑧ group administered amlodipine/rosuvastatin, group administered rosuvastatin and group administered amlodipine/rosuvastatin after 4 weeks and 8 weeks according to the blood pressure normalization rate of Joint Commission (JNC) VII guidelines

⑨ percentage of test subjects who reached L D L-C therapeutic goals according to the NCEP ATP III guidelines and blood pressure normalization according to the JNC VII guidelines after 4 and 8 weeks in the group of amlodipine/rosuvastatin, the group of rosuvastatin and the group of amlodipine/rosuvastatin

(2) Security assessment

1) Adverse events

2) Vital signs

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

4) Physical examination 5) Electrocardiogram (ECG)

6) Hormone test or the like

6. Statistical analysis methods and standards

The results obtained based on the evaluation criteria of the clinical trial were subjected to statistical analysis using the following method. In evaluating the efficacy of the clinical trial, statistical analysis was performed according to the "Intent to Treat Principle" and the safety evaluation was performed as actually performed. Demographic information and baseline characteristics of FAS were analyzed and statistical analysis was performed on FAS as the primary analysis group and PPS as the secondary analysis group for efficacy assessment. In addition, for the security evaluation, a statistical analysis was performed on the security analysis set.

When missing values for primary and secondary efficacy variables were found, statistical analysis was performed by applying the last Observation push (L ast observer Carried Forward, L OCF) method, and for safety evaluation variables, statistical analysis was performed based on raw data instead of applying the L OCF method.

(1) Efficacy evaluation analysis

1) Evaluation of major efficacy

In order to compare the difference in the rate of change of L D L-C from baseline after 8 weeks between the group administered amlodipine/rosuvastatin and the group administered amlodipine/rosuvastatin, an analysis of covariance (ANCOVA) in which L D L-C at baseline was corrected with covariates was performed, and the number of test subjects, arithmetic mean, standard deviation, median, and minimum and maximum values were presented for L D L-C according to time points in each group.

In addition, in order to compare the difference in the change of sitDBP from baseline after 8 weeks between the group administered amlodipine/rosuvastatin and the group administered rosuvastatin/rosuvastatin, covariance analysis (ANCOVA) in which sitDBP at baseline is corrected with covariates was performed, and the number of test subjects, arithmetic mean, standard deviation, median, and minimum and maximum values were presented for sitDBP according to time points in each group of administration.

2) Secondary efficacy evaluation

In order to compare the amlodipine/rosuvastatin-administered group as the experimental group with the control group, i.e., the rosuvastatin/rosuvastatin-administered group and the amlodipine/rosuvastatin-administered group, the change rates of L D L-C, TC, HD L-C, and TG from the baseline and the differences of sitDBP and sitSBP from the baseline after 4 weeks and 8 weeks, except for the main efficacy evaluation variables, covariance analysis (ANCOVA) in which each efficacy evaluation variable at the baseline was corrected with a covariate was performed, and the number of test subjects, arithmetic mean, standard deviation, median, and minimum and maximum values were presented for each evaluation variable according to the time point in each group.

In addition, the Kokran-Mantel-Henschel (CMH) test using cardiovascular risk categories as stratification has been conducted for comparing the experimental groups with the control group at a percentage of the test subjects who have reached 4 weeks and 8 weeks after administration of the clinical trial drug, has reached L D L-C treatment target achievement rate according to the NCEP ATP III guideline, has reached blood pressure normalization rate according to the JNC VII guideline, has reached L D L-C treatment target achievement rate according to the NCEP ATP III guideline, and has reached blood pressure normalization according to the JNC VII guideline.

(2) Safety evaluation analysis

1) Adverse events

All Adverse Events (AEs) studied were classified and listed into existing AEs and AEs occurring during Treatment (TEAE). The number and percentage (%) of subjects with TEAE are presented for severe AEs, severity of AEs, and causal relationship to clinical trial drug, according to the application group.

2) Other safety evaluation variables

For each group of administrations, a moving table was presented for normality, clinically insignificant (NCS) and Clinically Significant (CS) abnormalities according to time points, and a McNemar (McNemar) test was performed to statistically significant test for changes before/after administration of the clinical trial drug for each group of administrations. In addition, in the case of continuous variables, the number of test subjects, arithmetic mean, standard deviation, median, and minimum and maximum values were presented for each time point.

Experimental example 1: measuring mean sitting systolic blood pressure in a group of Diabetic (DM) patients compared to a group of non-diabetic patients (sitSBP) reduction (mm Hg)

The change of the mean sitSBP from baseline (mmhg) after 8 weeks was measured for the group administered with 5 mg amlodipine, 100 mg rosuvastatin and 20 mg rosuvastatin (a5+ L100 + R20) (experimental group) and the group administered with 5 mg amlodipine and 100 mg rosuvastatin (a5+ L100) (control group 1). the experimental group and the control group each included one diabetic patient group and one non-diabetic patient group, the results of which are shown in table 1 below and fig. 1.

[ Table 1]

a) A5+ L100 + R20(DM) vs. A5+ L100 (DM)

b) A5+ L100 + R20(DM) vs. A5+ L100 (non-DM)

c) A5+ L100 + R20 (non-DM) vs. A5+ L100 (non-DM)

As shown in Table 1 and FIG. 1, the (A5+ L100 + R20) administration group exhibited a greater change (mmHg) in the average sitSBP after 8 weeks than the (A5+ L100) administration group, it can be seen from the results that, when 5 mg of amlodipine, 100 mg of rosuvastatin, and 20 mg of rosuvastatin were administered, the effect of reducing the average sitSBP was significantly increased compared to administration of only 5 mg of amlodipine and 100 mg of rosuvastatin.

In addition, this effect was shown in both the diabetic patient group and the non-diabetic patient group, and it was shown that the width of change (mmHg) of the average sitSBP was more significantly increased in the diabetic patient group when the (A5+ L100 + R20) administration group was compared with the (A5+ L100) administration group from this result, it can be seen that the effect of significantly reducing the average sitSBP was further increased when 5 mg of amlodipine, 100 mg of rosuvastatin, and 20 mg of rosuvastatin were all administered, and thus more significantly in the diabetic patient group in particular, compared with when only 5 mg of amlodipine and 100 mg of rosuvastatin were administered.

In addition, although the non-diabetic group showed no significant difference between the changes in sitSBP (mean + -SD) when administered A5+ L100 + R20 and when administered A5+ L100, i.e., -15.04 + -10.86 mm Hg and-13.42 + -14.42 mm Hg, respectively, in the blood pressure reduction, the diabetic group showed no significant difference between the changes in sitSBP (mean + -SD) when administered A5+ L + R20 and when administered A5+ L, the changes in sitSBP (mean + -SD) when administered A6329 + L + R20 and when administered A5+ L, i.e., -20.48 + -17.95 mm Hg and-13.30 + -15.03 mm Hg, respectively, in the diabetic group and the non-diabetic group, the non-diabetic group showed a significant difference between the changes in the group when administered A5+ 826, the group administered SItSBP (mean + -SD), i.42 mm Hg and about 15.42 mm Hg, respectively, the non-diabetic group showed a similar effects when administered SB19.27. the non-diabetic group and the non-diabetic group showed similar changes in the non-diabetic group.

Experimental example 2: measuring mean sitting diastolic blood pressure in the diabetic group compared to the non-diabetic group (sitDBP) reduction (mmHg)

The change of the average sitDBP from the baseline (mmhg) was measured for the group (a5+ L100 + R20) administered with 5 mg amlodipine, 100 mg rosuvastatin and 20 mg rosuvastatin after 8 weeks (experimental group). the experimental group and the control group included diabetic patients and non-diabetic patients, respectively, the results are shown in table 2 below and fig. 2.

[ Table 2]

a) A5+ L100 + R20(DM) vs. A5+ L100 (DM)

b) A5+ L100 + R20(DM) vs. A5+ L100 + R20 (non-DM)

c) A5+ L100 + R20 (non-DM) vs. A5+ L100 (non-DM)

As shown in table 2 and fig. 2, the (a5+ L100 + R20) administration group exhibited an increase in sitDBP change (mmhg) after 8 weeks, as compared to the (a5+ L100) administration group, from this result, it can be seen that the effect of reducing mean diastolic blood pressure was more significantly increased when 5 mg of amlodipine, 100 mg of rosuvastatin, and 20 mg of rosuvastatin were administered, as compared to when only 5 mg of amlodipine and 100 mg of rosuvastatin were administered.

In addition, this effect was shown in both the diabetic patient group and the non-diabetic patient group, and it was shown that the width of change (mmhg) in the average sitDBP was increased more in the diabetic patient group when the (a5+ L100 + R20) administration group was compared with the (a5+ L100) administration group.

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

As can be seen from the results shown in table 1 and table 2 above and fig. 1 and fig. 2, the effect of reducing both diastolic and systolic blood pressures increased more significantly with the co-administration of amlodipine, rosuvastatin and rosuvastatin. In addition, the blood pressure lowering effect was more significant in the group of diabetic patients. Furthermore, the blood pressure lowering effect in terms of mean sitSBP increased even more, especially the mean sitSBP was effectively reduced in the diabetic patient group.

Experimental example 3: measurement of the rate of change of triglycerides from baseline after 4 and 8 weeks

In order to compare the difference in the rate of change of Triglyceride (TG) from baseline after 4 and 8 weeks between the group administered with a5+ L100 + R20 and the control group (i.e., the group administered with L100 + R20 and the group administered with a5+ L100) as the experimental group, covariance analysis (ANCOVA) in which each efficacy evaluation variable at baseline was corrected with covariates was performed, the rate of change of TG from baseline (estimated by covariance analysis) was measured for the group administered with a5+ L100 + R20, the group administered with L100 + R20, and the group administered with a5+ L100 after 4 and 8 weeks.

(1) FAS analysis

The change (%) of TG from baseline at 4 and 8 weeks after administration of FAS was measured.

First, the least squares (1east square, L S) mean values of the change rates of TG from baseline after 4 weeks for the group administered with a5+ L100 + R20 and the group administered with a5+ L100 were-31.33 ± 4.60% and 4.78 ± 4.98%, respectively (estimated by covariance analysis), the group administered with a5+ L100 + R20 showed a greater change rate of TG than the group administered with a5+ L100, and this difference was statistically significant (p < 0.0001) — in addition, the least squares mean values of the change rates of TG from baseline after 4 weeks for the group administered with a5+ L100 + R20 and the group administered with L100 + R20 were-28.92 ± 4.04% and-17.43 ± 4.53% (p ═ 0.0622), respectively.

In addition, the least square mean (estimated by covariance analysis) of the rate of change of TG from baseline after 8 weeks for the group administered with a5+ L100 + R20 and the group administered with a5+ L100 were-21.77 ± 5.03% and 2.21 ± 5.45%, respectively, the group administered with a5+ L100 + R20 showed a greater rate of change of TG than the group administered with a5+ L100, and this difference was statistically significant (p ═ 0.0018).

(2) PPS analysis

The rate of change (%) of TG from baseline at 4 and 8 weeks after PBS administration was measured (estimated by covariance analysis), and the results thereof are shown in tables 3 and 4 below.

[ Table 3]

ANCOVA results 1: A5+ L100 + R20 vs A5+ L100

ANCOVA results 2, A5+ L100 + R20 vs A5+ L100

As shown in table 3 above, the least squares means (estimated by covariance analysis) of the rates of change of TG from baseline after 4 weeks for the group administered with a5+ L100 + R20 and the group administered with a5+ L100 were-30.64 ± 4.46% and 0.80 ± 4.93%, respectively, and the group administered with a5+ L100 + R20 showed a TG rate of change greater than that of the group administered with a5+ L100, and this difference was statistically significant (p < 0.0001). further, the least squares means of the rates of change of TG from baseline after 4 weeks for the group administered with a5+ L100 + R20 and the group administered with 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 rate of change (%) of TG from baseline at 8 weeks after administration in PPS.

[ Table 4]

ANCOVA results 1: A5+ L100 + R20 vs A5+ L100

ANCOVA results 2, A5+ L100 + R20 vs A5+ L100

As shown in table 4, the least squares means (estimated by covariance analysis) of the rates of change of TG from baseline after 8 weeks for the group administered a5+ L100 + R20 and the group administered a5+ L100 were-23.06 ± 4.82% and-3.11 ± 5.33%, respectively, and the group administered a5+ L100 + R20 exhibited a greater rate of change of TG than the group administered a5+ L100, and the values were statistically significant (p ═ 0.007).

From the results, it was confirmed that the TG change rate was more significantly reduced and statistically significant difference was exhibited when 5 mg of amlodipine, 100 mg of rosuvastatin and 20 mg of rosuvastatin were administered, as compared to when L + R20 and a5+ L were administered.

(3) Analysis of TG Change Rate in diabetic group compared with non-diabetic group

The change rate (%) of TG from baseline 8 weeks after administration of a5+ L100 + R20 or L100 + R20 in the patient group with or without diabetes was measured, and the results thereof are shown in table 5 below.

[ Table 5]

a) A5+ L100 + R20(DM) pair L100 + R20(DM)

b) A5+ L100 + R20(DM) vs. A5+ L100 + R20 (non-DM)

c) A5+ L100 + R20 (non-DM) vs L100 + R20 (non-DM)

As shown in table 5, when the diabetic patient group was compared with the non-diabetic patient group, the TG change rate (%) exhibited by the diabetic patient group was more significantly reduced when a5+ L100 + R20 was administered than when L100 + R20 was administered.

Specifically, the non-diabetic patient group exhibited TG change rates (%) (mean ± SD) of-23.60 ± 40.89% and-16.98 ± 39.39% when L100 + R20 and a5+ L100 + R20 were administered, respectively, with a considerably slight decrease in TG, and did not exhibit a greater decrease in TG according to additional administration, whereas the diabetic patient group exhibited TG change rates (%) (mean ± SD) of-14.41 ± 34.98% and-27.75 ± 21.03% when L100 + R20 and a5+ L100 + R20 were administered, respectively, with a significantly greater decrease in TG according to additional administration, from these results, it was confirmed that, when a5+ L100 + R20 was administered, the diabetic patient group exhibited a greater decrease in TG than when L100 + R20 was administered, indicating an increase in TG adjustment effect, compared to the non-diabetic patient group.

Experimental example 4: blood pressure normalization rate measurement according to JNC VII guidelines

At 4 and 8 weeks after administration of the clinical trial drug, the normalization rate of blood pressure was tested according to the JNC VII guidelines using the baseline cardiovascular risk category as stratification for the cocken-mantel-henschel (CMH) test, and further the pilson chi-square test or the fisher exact test was performed for each cardiovascular risk category for comparison between the administration groups. Cardiovascular risk categories are classified in the same manner as described above in this specification. That is, the cases where the number of CHD risk factors is 0 or 1 are classified as group a, the cases where the number of CHD risk factors is 2 or more and the risk of cardiovascular disease within 10 years is 10% to 20% are classified as group B, and the cases where the CHD/CHD risk equivalent or the risk of cardiovascular disease within 10 years is more than 20% are classified as group C.

(1) Analysis of blood pressure normalization Rate in FAS

The blood pressure normalization criteria according to the JNC VII guidelines were based on the cardiovascular risk categories 'sitSBP/sitDBP < 140/90 mmHg' for groups A and B and on the group C 'sitSBP/sitDBP < 130/80 mmHg'. The results are shown in tables 6 and 7 below. In tables 6 and 7 below, the percentages (%) are based on the subjects in each drug group. For p-values, a) represents the pearson chi-square test; b) represents a fisher exact test; and c) represents the Kokronen-Mantel-Henschel test.

[ Table 6]

Reference: percentages are based on subjects in each treatment group.

p-value: a) pearson's chi-square test; b) performing Fisher's exact test; c) kokronen-mantel-henschel test

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

As shown in table 6, in the case where the number of risk factors was 0 to 1 (risk factors 0-1), the blood pressure normalization rate per cardiovascular risk category group at 4 weeks after administration was 60.00% (3/5 people) in the group administered a5+ L100 + R20, 66.67% (2/3 people) in the group administered a5+ L100 and 33.33% (1/3 people) in the group administered L + R20. furthermore, in the case where the number of risk factors was 2 or more (risk factors ≧ 2) and there was a risk of cardiovascular disease within 10 years, the blood pressure normalization rate was 61.11% (1/3 people) for the group administered a 1/3 + R1/3, 52.94% (1/3 people) for the group administered a 1/3 + 1/3, and 23.08% (1/3 people) for the group administered a 1/3 + 1/3, and the CHD/1/3 equivalent or more than 20% (1/3) for the group administered CHD 1/3 + 1/3, the blood pressure normalization rate was 23.08% (1/3) for the group administered CHD 1/3) (1/3) for the group administered CHD/1/3) or more than 20% (1/3) for the group administered CHD 1/3 + 1/3, and the risk factor 1/3 was 20% (1/3) for the group administered CHD 1/3 + 1/3).

At 4 weeks after administration of the clinical trial drug, the blood pressure normalization rate obtained according to the JNC VII guidelines was 37.04% for the group administered a5+ L100 + R20 (20/54 people), 28.26% for the group administered a5+ L100 (13/46 people), and 9.30% for the group administered L100 + R20 (4/43 people) — a statistically significant difference in the blood pressure normalization rate obtained 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]

Reference: percentages are based on subjects in each treatment group.

p-value: a) pearson's chi-square test; b) performing Fisher's exact test; c) kokronen-mantel-henschel test

Table 7 shows the achievement rate of blood pressure normalization in FAS at 8 weeks according to cardiovascular risk category.

As shown in table 7 above, in the case where the number of risk factors is 0 to 1, the normalized rate of blood pressure per cardiovascular risk category at 8 weeks after administration was shown to be 80.00% (4/5 people) for the group administered with a5+ L100 + R20, 66.67% (2/3 people) for the group administered with a5+ L, and 66.67% (2/3 people) for the group administered with a 2/3 + R2/3, in addition, in the case where the number of risk factors is 2 or more (risk factor ≧ 2) and the risk of cardiovascular disease is 20% or less than 20% within 10 years, the normalized rate of blood pressure shown was 77.78% (2/3 people) for the group administered with a 2/3 + R2/3, 2/3% (2/3 people) for the group administered with a 2/3 + 2/3, and 30.77% (2/3 people) for the group administered with a 2/3 + 2/3, and 30.72% (2/3 people) for the group administered with a CHD/2/3 + 2/3), and the normalized rate of blood pressure shown to the group administered with a 2/3 (2/3) (2/3 + 2/3) and the group administered with a 2/3, and the group administered with a 2/3 + 2/3, and the group administered with a 2/3 (2/3, and the risk of cardiovascular disease is 30.3% for the group administered with a 2/3 + 2/3) (2/3, and the group administered with a.

(2) Analysis of blood pressure normalization rates by cardiovascular risk categories

The cardiovascular risk category group of subjects in this clinical trial consisted of: group A: 11 persons (7.69%), group B: 48 persons (33.57%), and group C: 84 persons (58.74%), wherein 50% or more than 50% of the subjects were confirmed to belong to group C. Considering the fact that the blood pressure normalization criteria of group A and group B were sitSBP/sitDBP < 140/90 mmHg and the blood pressure normalization criteria of group C were sitSBP/sitDBP < 130/80 mmHg, the blood pressure normalization rates (risk factors 0 to 1 or risk factors ≧ 2 and 10-year risk ≦ 20%) and group C (CHD/CHD risk equivalent or 10-year risk > 20%) of group A and group B were analyzed separately.

As a result of examining the blood pressure normalization rates of the a and B groups and the C group according to cardiovascular risk categories at 4 weeks after the administration of the clinical trial drug, the blood pressure normalization rates exhibited by the a and B groups were 60.87% (14/23 people) for the group administered a5+ L100 + R20, 55.00% (11/20 people) for the group administered a5+ L100, and 25.00% (4/16 people) for the group administered L100 + R20, and the blood pressure normalization rate exhibited by the C group was 19.35% (6/31 people) for the group administered a5+ L100 + R20, 7.69% (2/26 people) for the group administered a5+ L100, and 0.00% (0/27 people) for the group administered L100 + R20, thereby confirming that the blood pressure normalization rate of the C group was relatively lower than that of the a and B groups.

When the blood pressure normalization rates of the groups a and B and the group C according to cardiovascular risk categories were compared with each other at 8 weeks after the administration of the clinical trial drug, the blood pressure normalization rates exhibited by the group a and the group B were 78.26% (18/23 humans) for the group administered a5+ L100 + R20, 65.00% (13/20 humans) for the group administered a5+ L100, and 37.50% (6/16 humans) for the group administered L100 + R20, and the blood pressure normalization rate exhibited by the group C was 29.03% (9/31 humans) for the group administered a5+ L100 + R20, 19.23% (5/26 humans) for the group administered a5+ L100, and 3.70% (1/27 humans) for the group administered L100 + R20.

In general, the group administered A5+ L100 + R20 exhibited a blood pressure normalization rate that was superior to that of the group administered A5+ L100 or that of the group administered L100 + R20, in all of the groups A and B and C according to cardiovascular risk categories.

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

The rate of normalization of blood pressure achieved 8 weeks after administration of a5+ L100 + R20, a5+ L100 or L100 + R20 was analyzed in the group of diabetic patients, and the results thereof are shown in table 8 below.

[ Table 8]

Proportion of subjects achieving blood pressure control at 8 weeks (diabetes), FAS

As shown in table 8, the group of diabetic patients exhibited a blood pressure normalization rate of 21.43% (3/14 people) when a5+ L100 + R20 was administered, 18.75% (3/16 people) when a5+ L100 was administered, and 0.00% (0/12 people) when a L100 + R20 was administered, from which it was confirmed that the group of diabetic patients exhibited a higher blood pressure normalization rate when a5+ L100 + R20 was administered than when a5+ L100 or L100 + R20 was administered.

Experimental example 5 measurements L D L-C therapeutic goals have been achieved according to the NCEP ATP III guidelines and according to JNC VII Percentage of test subjects who reached normalization of blood pressure

The percentage of test subjects who had achieved L D L-C therapeutic objectives according to the NCEP ATP III guidelines and achieved blood pressure normalization according to the JNC VII guidelines 4 or 8 weeks after administration of clinical trial drugs was subjected to a cockeron-mantel-henschel (CMH) test to compare the administration groups, hi addition, a pearson chi-square test or a fisher's exact test to compare the L D L-C therapeutic objectives and blood pressure normalization rates between the administration groups.

(1) Analysis of L D L-C and blood pressure normalization in FAS

At 4 weeks after administration of the clinical trial drug, the percentage of test subjects who had achieved L D L-C therapeutic objectives according to the NCEP ATP III guidelines and achieved blood pressure normalization according to the JNC VII guidelines was shown to be 35.19% (19/54 people) when a5+ L100 + R20 was administered, 0.00% (0/46 people) when a5+ L100 was administered, and 9.30% (4/43 people) when L100 + R20 was administered, thereby confirming that the group administered a5+ L100 + R20 had a blood pressure normalization rate that was much higher than those of the other two drug groups, and that the difference was statistically significant (a5+ L100 + R20 vs a5+ L100: p < 0.0001, a5+ L100 + R20 vs L100 + R20: p ═ 0.0028).

Furthermore, at 8 weeks after administration of the clinical trial drug, it was also shown that the percentage of the test subjects who had achieved the L D L-C therapeutic target and reached blood pressure normalization was 48.15% (26/54 people) for the group administered A5+ L0100 + R20, 8.70% (4/46 people) for the group administered A5+ L1100, and 16.28% (7/43 people) for the group administered L100 + R20, thereby confirming that the group administered A5+ L100 + R20 exhibited a higher therapeutic target achievement rate than the other two groups administered, and that the difference was statistically significant (a 20 + R20 vs a 20 + 20: p < 0.0001, a 20 + R20 vs 20 + R20 + 20: p ═ 0.0007). it was confirmed that the percentage of the test subjects who had achieved the blood pressure treatment target and reached blood pressure normalization after 8 weeks after administration of the clinical trial drug was higher than the percentage of the test subjects administered.

From these results, it was confirmed that the group to which a5+ L100 + R20 was administered exhibited more excellent therapeutic effects on dyslipidemia and hypertension than the group to which a5+ L100 or L100 + R20 was administered.

(2) Analysis of L D L-C treatment goal achievement rate and blood pressure normalization rate in diabetic patients

The percentage of test subjects who had achieved L D L-C therapeutic objectives and achieved normalization of blood pressure 8 weeks after administration of a5+ L100 + R20, a5+ L100 or L100 + R20 in the group of diabetic patients was analyzed, and the results thereof are shown in table 9 below.

[ Table 9]

Proportion of subjects who achieved L D L-C target and blood pressure control at 8 weeks (diabetes), FAS

As shown in table 9, the blood pressure normalization rate exhibited by the diabetic patient group was 21.43% (3/14 people) when a5+ L100 + R20 was administered, 18.75% (3/16 people) when a5+ L100 was administered, and 0.00% (0/12 people) when L100 + R20 was administered, it was confirmed from these results that the diabetic patient group exhibited higher achievement rate of the therapeutic target of L D L-C and blood pressure normalization rate when a5+ L100 + R20 was administered than when a5+ L100 or L100 + R20 was administered.

[ brief description ]

A5: amlodipine (A)5 mg

L100 Laosutan (L) 100 mg

R20: rosuvastatin (R)20 mg

sitDBP: diastolic blood pressure in sitting position

And (3) sitSBP: contraction blood pressure in sitting position

DM: diabetic patients group

non-DM: non-diabetic patients group

L D L-C LDL cholesterol

TG: triglycerides

Hb1 Ac: glycated hemoglobin (Hb) A1c

Industrial applicability

As is apparent from the foregoing description, the pharmaceutical composition comprising amlodipine, rosuvastatin and rosuvastatin according to the examples has excellent effects of controlling blood pressure and improving lipid levels in cardiovascular diseases accompanied by diabetes, particularly, excellent effects of improving blood pressure and lipid levels in patients simultaneously suffering from hypertension accompanied by diabetes and dyslipidemia, when amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof are simultaneously administered in combination, the pharmaceutical composition has excellent effects of treating or preventing hypertension accompanied by diabetes and dyslipidemia, compared to when each of the individual ingredients is administered alone or when any one of the ingredients is administered or only a combination of two of the ingredients is administered, and further, the pharmaceutical composition effectively reduces the mean sitting systolic blood pressure and mean diastolic blood pressure in the group of diabetic patients, effectively reduces the increase in TG values, and exhibits excellent normalization rate of blood pressure and therapeutic target rate of TG L-C L.

The composite preparation according to the embodiment can enhance the medication convenience and medication compliance of patients and can reduce the cost of the medicine. In addition, the composite preparation is effective in preventing or treating cardiovascular diseases in diabetic patients who should take a hypertension therapeutic agent together with a dyslipidemia therapeutic agent.

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

It is to be understood that the embodiments set forth herein are to be considered in all respects only as illustrative and not restrictive. It is generally contemplated that the descriptions of features or embodiments in each embodiment can be applied to other similar features or embodiments in other embodiments.