Pharmaceutical composite formulation for preventing or treating hypertension comprising candesartan, amlodipine, and indapamide

Abstract

The present invention relates to a pharmaceutical composite formulation containing candesartan, amlodipine, and indapamide as active ingredients for preventing or treating hypertension. By including candesartan, amlodipine, and indapamide at low doses, the pharmaceutical composite formulation according to the present invention can reduce side effects that may occur due to excessive blood pressure reduction, and can be utilized as a composite formulation for preventing or treating hypertension owing to sufficient tolerability and excellent blood pressure-lowering effects.

Description

A pharmaceutical combination preparation containing candesartan, amlodipine, and indapamide for the prevention or treatment of hypertension

[0001] The present invention relates to a pharmaceutical combination preparation for preventing or treating hypertension, comprising candesartan, amlodipine, and indapamide as active ingredients.

[0002] Hypertension is a condition in which blood pressure remains above the normal range. Hypertension is associated with hardening and thickening of the blood vessel and ventricular walls, and is an independent risk factor for cardiovascular and renal diseases, including coronary heart disease (CHD), stroke, arrhythmias, heart failure, and vascular dementia. It also causes various complications and remains a leading cause of death worldwide, both in developed and developing countries.

[0003] According to the Korea National Health and Nutrition Examination Survey, the prevalence of hypertension in adults aged 30 years or older decreased slightly from 29.8% in 1998 to 25.9% in 2007-09, but increased again to the previous level after 2010, and recently increased to 29.1% (35.0% for men, 22.9% for women) in the 2016 survey. The prevalence of blood pressure, which includes both alert blood pressure and prehypertension, was 25.9% (30.8% for men, 20.8% for women) as of 2016, meaning that 55% of the adult population aged 30 years or older had blood pressure higher than normal. The prevalence of hypertension in the elderly population aged 65 years or older reached 65.2% (61.7% for men, 67.7% for women), and it is higher in women than in men.

[0004] Hypertension is classified into primary and secondary hypertension based on the cause of the elevated blood pressure. Primary hypertension is essential hypertension, where the cause is unknown, while secondary hypertension is secondary hypertension, which occurs as a result of a specific disease or condition. While secondary hypertension can be treated by identifying the underlying cause, primary hypertension, which accounts for approximately 95% of all hypertension cases, has an unknown cause. Therefore, treatment for patients with primary hypertension typically involves pharmacological therapies based on several blood pressure-lowering mechanisms.

[0005] For patients with stage 1 hypertension (140 mmHg ≤ SBP < 160 mmHg, 90 ≤ DBP < 100 mmHg), lifestyle modifications are given priority, but it is recommended to begin drug treatment as soon as possible. In general, lifestyle modifications should be considered a supplementary, rather than a substitute, method for drug treatment. For patients with stage 2 hypertension (160 ≤ SBP, 100 ≤ DBP), drug treatment should be started immediately along with lifestyle modifications, as the effects of drug treatment are evident.

[0006] Drugs used to treat high blood pressure include beta-blockers, which reduce the heart rate and burden on the heart by reducing the electrical stimulation of the nerves to the heart and blood vessels; diuretics, which lower blood pressure by promoting the excretion of water, sodium, and chloride from the body and thus reducing the amount of circulating body fluids; angiotensin-converting enzyme inhibitors, which relax blood vessels by inhibiting the conversion of angiotensin I to angiotensin II in the body; alpha-blockers, which lower blood pressure by inhibiting the vasoconstrictive action of catecholamines; and calcium channel blockers, which lower blood pressure by blocking calcium channels to prevent the influx of calcium, thereby expanding blood vessels.

[0007] In general, hypertensive patients often have other cardiovascular diseases, including hyperlipidemia, and thus are often prescribed two or more medications concurrently. Furthermore, because long-term medication use is required, careful consideration must be given to the selection of treatment medications. Consequently, rather than focusing on a single drug, it is necessary to combine medications with different mechanisms of action and reduce the dosage of a single drug to minimize the potential side effects associated with long-term medication use.

[0008] In fact, one of the most commonly used triple therapy combinations for hypertension is a renin-angiotensin system inhibitor, a calcium channel blocker, and a diuretic.

[0009] Meanwhile, candesartan, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, is known as an angiotensin II receptor blocker (ARB). It is being used as an antihypertensive because it has the effect of lowering blood pressure, preserving ventricular function, and preventing and preventing fibrosis. Since candesartan has a very low absorption rate when administered orally, it is being formulated as a prodrug, candesartan cilexetil.

[0010] Amlodipine is 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate and is used to treat hypertension as a calcium channel blocker. Amlodipine is a racemic compound with a missing carbon atom, and among the enantiomers, (S)-amlodipine is known to have superior activity and is used in various salt forms, including benzenesulfonate, camphorsulfonate, nicotinate, and maleate. Amlodipine is highly hygroscopic and decomposes by absorbing water, and one of the major decomposition products is 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate, known as impurity D.

[0011] Indapamide is 4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-sulfamoylbenzamide and is a thiazide-like diuretic. It is used for cardiovascular disease because it exhibits a longer duration of action and stronger blood pressure-lowering effect at a similar dose level than hydrochlorothiazide, a thiazide-type diuretic.

[0012] In this regard, Korean Patent Publication No. 10-2019-0127691 relates to a pharmaceutical composition useful for treating hypertension, including an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, and discloses a pharmaceutical composition including candesartan, amlodipine, and indapamide, and specifically discloses a pharmaceutical composition in which the dose of telmisartan, which is an angiotensin II receptor blocker, is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0013] In addition, Korean Patent Publication No. 10-2009-0057538 relates to a pharmaceutical composition for treating hypertension containing an angiotensin II antagonist, a calcium antagonist, and a diuretic as active ingredients, and discloses a pharmaceutical composition comprising candesartan, amlodipine, and indapamide, and specifically discloses a pharmaceutical composition comprising 80 mg of valsartan, an angiotensin II receptor blocker, 6.944 mg of amlodipine besylate, and 1.5 mg of indapamide.

[0014] Additionally, American Journal of Hypertension, Volume 19, Issue 1, Pages 113-121, Gerard London et al., “Indapamide SR Versus Candesartan and Amlodipine in Hypertension: The X-CELLENT Study” discloses the blood pressure change patterns in groups administered candesartan 8 mg, amlodipine 5 mg, and indapamide 1.5 mg alone, respectively.

[0015] Research is ongoing into combinations of two or more drugs with different mechanisms of action. However, high-dose single agents or high-dose combinations pose the risk of adverse reactions (e.g., peripheral edema) due to excessive blood pressure reduction. Therefore, there is a continuing need for the development of low-dose combinations that offer superior blood pressure lowering effects, good tolerability, and a reduced risk of side effects.

[0016] Accordingly, the present inventors have confirmed that by combining candesartan cilexetil, amlodipine besylate, and indapamide at a specific low dose, the blood pressure lowering effect is excellent in proportion to the dose, the administration is convenient, and the amount of a single drug used is reduced, thereby reducing side effects that may occur due to long-term drug use, and have completed the present invention.

[0017] [Prior Art Literature]

[0018] Patent documents

[0019] (Patent Document 1) Republic of Korea Publication No. 10-2019-0127691

[0020] (Patent Document 2) Republic of Korea Publication Patent No. 10-2009-0057538

[0021] Non-patent literature

[0022] (Non-patent Document 1) American Journal of Hypertension, Volume 19, Issue 1, Pages 113-121, Gerard London et al.

[0023] The present invention has been made to solve the above problems, and provides a pharmaceutical combination preparation characterized by including as active ingredients candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; and indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0024] In one embodiment of the present invention for achieving such a task, a pharmaceutical combination preparation is provided, characterized in that it comprises as an active ingredient candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; and indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0025] The pharmaceutical composition according to the present invention can be used as a combination preparation for the prevention or treatment of hypertension by reducing side effects that may occur due to excessive blood pressure reduction by including candesartan, amlodipine, and indapamide in low doses, and by ensuring sufficient tolerability and excellent blood pressure lowering effect.

[0026] Figure 1 is a result of FAS (Full Analysis Set) analysis that measures the change in MSSBP (Mean Sitting Systolic Blood Pressure) compared to the baseline at 8 weeks according to one embodiment of the present invention.

[0027] Figure 2 is a result of FAS analysis measuring the change in MSSBP at 4 weeks compared to the baseline according to one embodiment of the present invention.

[0028] Figure 3 is a result of FAS analysis measuring the change in MSDBP (Mean Sitting Diastolic Blood Pressure) at 4 weeks compared to the baseline according to one embodiment of the present invention.

[0029] Figure 4 is a result of FAS analysis measuring the change in MSDBP at 8 weeks compared to the baseline according to one embodiment of the present invention.

[0030] Figure 5 is a result of FAS analysis measuring the blood pressure normalization rate at 4 weeks compared to the baseline according to one embodiment of the present invention.

[0031] Figure 6 is a result of FAS analysis measuring the blood pressure normalization rate at 8 weeks compared to the baseline according to one embodiment of the present invention.

[0032] Figure 7 is a result of FAS analysis measuring blood pressure response rate at 4 weeks compared to baseline according to one embodiment of the present invention.

[0033] Figure 8 is a result of FAS analysis measuring blood pressure response rate at 8 weeks compared to baseline according to one embodiment of the present invention.

[0034] Figure 9 is a result of FAS analysis measuring the change in MSSBP at 8 weeks compared to the baseline in patients with early hypertension (ad-hoc) according to one embodiment of the present invention.

[0035] Figure 10 is a result of FAS analysis measuring the blood pressure normalization rate at 8 weeks compared to the baseline in patients with early hypertension (ad-hoc) according to one embodiment of the present invention.

[0036] Figure 11 shows the results of FAS analysis measuring the blood pressure response rate at 8 weeks compared to the baseline of an early hypertensive patient (ad-hoc) according to one embodiment of the present invention.

[0037] Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used in their common sense to those of ordinary skill in the art to which the present invention pertains. Furthermore, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0038] As used herein, the singular form may include the plural form unless the context clearly indicates otherwise.

[0039] When a part in this specification is said to “include” a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0040] In addition, all numbers and expressions indicating the amounts of components, reaction conditions, etc. described in this specification should be understood to be modified by the term “about” in all cases unless otherwise specified.

[0041] When “candesartan” is referred to herein, it may refer to candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0042] When “amlodipine” is referred to herein, it may refer to amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0043] When “indapamide” is referred to herein, it may refer to indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0044] As used herein, “pharmaceutically acceptable” means that which is approved by a governmental or equivalent regulatory body for use in animals, and more particularly in humans, by avoiding significant toxic effects when used at usual pharmaceutical doses, is listed in a pharmacopoeia, or is otherwise generally recognized by the pharmacopoeia.

[0045] As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound of the present invention, but is not a biologically or otherwise undesirable salt. Examples of such salts include, but are not limited to, non-toxic inorganic and organic base or acid addition salts.

[0046] As used herein, “optical isomer” refers to any of various stereoisomeric configurations that may exist for the compound according to the present invention, and includes geometric isomers.

[0047] As used herein, the term "hydrate" refers to a compound according to the present invention and water that are bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.

[0048] As used herein, “solvate” refers to a compound according to the present invention and a solvent other than water that are bound by intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount. Specifically, the solvate may contain solvent molecules in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.

[0049] Additionally, the experimental procedures specified in this specification are identical to those commonly performed in the art unless specifically described otherwise.

[0050] Hereinafter, the present invention will be described in detail.

[0051] One aspect of the present invention provides a pharmaceutical combination preparation comprising, as active ingredients, candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; and indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

[0052] In one specific embodiment of the present invention, the candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof may be included in an amount of 0.1 to 7 mg when converted to the candesartan free base form. Specifically, the candesartan free base form may be included in an amount of 1 to 5 mg, 1.1 to 4.9 mg, 1.2 to 4.8 mg, 1.3 to 4.7 mg, 1.4 to 4.6 mg, 1.5 to 4.5 mg, 1.6 to 4.4 mg, 1.7 to 4.3 mg, 1.8 to 4.2 mg, 1.9 to 4.1 mg, 2 to 4 mg, more specifically, 2 mg, 2.67 mg, or 4 mg, but is not limited thereto.

[0053] The above candesartan or a pharmaceutically acceptable salt thereof may be, but is not limited to, candesartan cilexetil.

[0054] In another specific embodiment of the present invention, the amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof may be included in an amount of 0.1 to 4 mg when converted to the amlodipine free base form. Specifically, it may be included in an amount of 1 to 3 mg, 1.05 to 2.95 mg, 1.1 to 2.9 mg, 1.15 to 2.85 mg, 1.2 to 2.8 mg, 1.25 to 2.75 mg, 1.25 to 2.7 mg, 1.25 to 2.65 mg, 1.25 to 2.6 mg, 1.25 to 2.55 mg, 1.25 to 2.5 mg, more specifically, 1.25 mg, 1.67 mg or 2.5 mg, when converted to amlodipine free base form, but is not limited thereto.

[0055] The above amlodipine or a pharmaceutically acceptable salt thereof may be, but is not limited to, amlodipine besylate.

[0056] In another specific embodiment of the present invention, the indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, may be included in an amount of 0.1 to 1.4 mg when converted to the indapamide free base form. Specifically, when converted to the free base form of indapamide, 0.5 to 1.3 mg, 0.505 to 1.295 mg, 0.51 to 1.29 mg, 0.515 to 1.285 mg, 0.52 to 1.28 mg, 0.525 to 1.275 mg, 0.53 to 1.27 mg, 0.535 to 1.265 mg, 0.54 to 1.26 mg, 0.545 to 1.255 mg, 0.55 to 1.25 mg, 0.555 to 1.25 mg, 0.56 to 1.25 mg, 0.565 to 1.25 mg, 0.57 to 1.25 mg, 0.575 to 1.25 mg, 0.58 to It may be included in an amount of, but is not limited to, 1.25 mg, 0.585 to 1.25 mg, 0.59 to 1.25 mg, 0.595 to 1.25 mg, 0.6 to 1.25 mg, 0.605 to 1.25 mg, 0.61 to 1.25 mg, 0.615 to 1.25 mg, 0.62 to 1.25 mg, 0.625 to 1.25 mg, more specifically, 0.625 mg, 0.83 mg or 1.25 mg.

[0057] In another specific embodiment of the present invention, the pharmaceutical combination preparation may further comprise a pharmaceutical additive selected from a diluent, a disintegrant, a lubricant, and a combination thereof.

[0058] The above diluent may be any one selected from among microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate (DCP), lactose, low-substituted hydroxypropyl cellulose, and combinations thereof, but is not limited thereto.

[0059] The disintegrant may be any one selected from, but is not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.

[0060] The above lubricant may be any one selected from, but is not limited to, magnesium stearate, palmitic acid, talc, magnesium stearate, zinc stearate, calcium stearate, or a combination thereof.

[0061] In another specific embodiment of the present invention, the pharmaceutical combination preparation is for preventing or treating hypertension.

[0062] The term "prevention" as used herein refers to inhibiting the occurrence of a disease or condition in an individual who has not been diagnosed with the disease or condition but is predisposed to such a disease or condition. The term "treatment" as used herein refers to inhibiting the development of a disease or condition; alleviating the disease or condition; and / or eliminating the disease or condition.

[0063] In another specific embodiment of the present invention, the pharmaceutical combination preparation may be selected from the group consisting of tablets, orally disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, dispersible tablets, dissolving tablets, capsules, granules, effervescent granules, powders, oral liquids, elixirs, suspensions, emulsions, lemonades, aromatic waters, preparations and infusions, alcoholic beverages, tinctures, syrups, syrup preparations, oral jellies, polypharmacy products, extracts, fluid extracts, and pills, but is not limited thereto.

[0064] In another embodiment of the present invention, the pharmaceutical combination preparation may be essentially free of an angiotensin converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta blocker or a pharmaceutically acceptable salt thereof, a lipid modifier, a platelet function modulator, a serum homocysteine ​​lowering agent, or a combination thereof.

[0065] Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are intended only to illustrate the present invention, and the scope of the present invention is not limited to these examples.

[0066]

[0067] <Example> Preparation of a low-dose combination formulation of candesartan, amlodipine, and indapamide

[0068] As shown in Table 1 below, tablets, orally disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, dispersible tablets, dissolving tablets, capsules, granules, effervescent granules, powders, oral liquids, elixirs, suspensions, emulsions, lemonades, aromatic waters, infusions and infusions, alcoholic beverages, tinctures, syrups, syrup preparations, oral jellies, multi-drugs, extracts, fluid extracts, and pills were manufactured together with conventional excipients.

[0069] Dosage (mg) Candesartan Amlodipine Indapamide Example 142.5 1.25 Example 241.25 1.25 Example 32.6 7 1.67 0.83 Example 421.25 0.625

[0070]

[0071] <Comparative Example> Manufacturing of single-dose and high-dose combination preparations of candesartan, amlodipine, and indapamide

[0072] As shown in Table 2 below, a single formulation containing the ingredients of Comparative Examples 1 to 3 was prepared. Except for the active ingredient, it was prepared in the same manner as Example 1.

[0073] Distinctive dosage (mg) Candesartan Amlodipine Indapamide Comparative Example 18--Comparative Example 2-5-Comparative Example 3-10-

[0074]

[0075] Experimental example

[0076] The low-dose combination formulations prepared in Examples 1 to 4 were administered to patients with essential hypertension for 8 weeks, and the safety and efficacy were compared with those of the placebo and each of the single formulations of Comparative Examples 1 to 4. The specific clinical trial methods and evaluation factors are as follows.

[0077] Clinical trial design

[0078] This clinical trial was planned as a randomized, double-blind, parallel-design, placebo-active drug comparison, multicenter clinical trial to evaluate the safety and efficacy of the investigational drug in patients with essential hypertension after 8 weeks of administration.

[0079] Test method

[0080] Subjects eligible for this study were selected through screening, and the subjects were administered a placebo during the two-week run-in period while also undergoing a lifestyle improvement program. However, if they were already taking antihypertensive medication at the time of screening, they were required to discontinue taking the existing antihypertensive medication for at least four weeks from the run-in period to the time of randomization to prevent it from affecting the clinical trial results. At the end of the run-in period, the final selected subjects were randomly assigned 1:1:1:1:1:1:1:1 to each treatment group and were prescribed the clinical trial drug and administered it in a double-blind manner for eight weeks. The subjects were encouraged to continue the lifestyle improvement program during the eight-week period of administration of the clinical trial drug, and the efficacy and safety were evaluated at the four and eighth weeks of the eight-week trial period excluding randomization.

[0081] Drug administration method

[0082] The clinical trial drug was administered orally once daily after breakfast. However, the clinical trial drug was administered starting on the day of issuance, regardless of the time of day, and from the following day onwards, it was administered at the same time as possible. On the day of a routine examination, the clinical trial drug was not administered. The newly prescribed clinical trial drug was administered after the examination was completed. The specific administration method is shown in Table 3 below.

[0083] Classification Administration group Administration method Administration period Run-in period All subjects ◎ 2 weeks Administration period Example 1 ● △ □ ◇ 8 weeks Example 3 ▣ △ □ ◇ Example 2 ◈ △ ◇ Example 4 ◐ △ □ Placebo ○ △ ◇ Comparative example 1 (candesartan 8 mg) ○ ▲ □ ◇ Comparative example 2 (amlodipine 5 mg) ○ △ ■ ◇ Comparative example 3 (amlodipine 10 mg) ○ △ □ ◆ Placebo for run-in period: ◎ Example 1: ●, Example 3: ▣, Example 2: ◈, Example 4: ◐, Example Placebo: ○ Comparative example 1: ▲, Comparative example 1 placebo: △, Comparative example 2: ■, Comparative example 2 placebo: □, Comparative example 3: ◆, Comparative example 3 placebo: ◇

[0084] Randomization method

[0085] The randomization codes for this clinical trial were assigned to eight treatment groups in equal proportions (1:1:1:1:1:1:1:1) by a statistician who was not directly involved in this clinical trial. ®(Version 9.4, SAS Institute, Inc., Cary, NC, USA) was used. Before the start of the clinical trial, the statistician delivered the list for packaging the clinical trial drug to the sponsor's packaging manager, and the sponsor packaged the clinical trial drug according to the list and delivered it to the trial site. Afterwards, subjects who met the inclusion / exclusion criteria were assigned to each treatment group in the order of enrollment in the clinical trial according to the randomization code through the Interactive Web Response System (IWRS).

[0086] Validity and safety endpoints

[0087] The validity and safety evaluation variables of this test were set as follows.

[0088] [Effectiveness Assessment Variables]:

[0089] - Primary efficacy endpoint

[0090] Change in MSSBP (Mean Sitting Systolic Blood Pressure) at 8 weeks after administration of the clinical trial drug compared to baseline

[0091] - Secondary validity evaluation variables

[0092] 1. Change in MSSBP at 4 weeks after administration of clinical trial drug compared to baseline

[0093] 2. Change in MSDBP (Mean Sitting Diastolic Blood Pressure) at 4 and 8 weeks of administration of the clinical trial drug compared to baseline

[0094] 3. Blood pressure normalization rate: Target blood pressure at 4 and 8 weeks of clinical trial drug administration * The proportion of subjects who reached

[0095] *Target blood pressure: MSSBP < 140 mmHg and MSDBP < 90 mmHg (except for patients with diabetes or chronic kidney disease: MSSBP < 130 mmHg and MSDBP < 80 mmHg)

[0096] 4. Blood pressure response rate: The proportion of subjects whose MSSBP decreased by 20 mmHg or more and / or whose MSDBP decreased by 10 mmHg or more compared to baseline at weeks 4 and 8 of administration of the clinical trial drug.

[0097] [Stability assessment variables]:

[0098] Adverse reactions, laboratory tests, 12-lead electrocardiogram, vital signs, ankle edema

[0099] Statistical analysis

[0100] In this study, the primary statistical analysis for efficacy was based on the Full Analysis Set (FAS), with the Per Protocol Set (PPS) used as an additional analysis. Safety analysis was based on the Safety Set (SS). SAS version 9.4 was used for statistical analysis.

[0101] The statistical analysis method for this test was set as follows.

[0102] - Validity evaluation variable / Primary validity evaluation variable

[0103] The number of subjects, mean, standard deviation, median, minimum, and maximum values ​​for the MSSBP measurements at baseline (the same meaning as “baseline” in the text) and 8 weeks for each administration group and the change from baseline after 8 weeks are presented, and the differences between each test group and each control group were analyzed using analysis of covariance (ANCOVA) including the baseline MSSBP value as a covariate.

[0104] - Secondary validity evaluation variables

[0105] For continuous variables, the number of subjects, mean, standard deviation, median, minimum, and maximum values ​​for each administration group were presented, and the average change between each test group and each control group was compared using analysis of covariance (ANCOVA) including the baseline value of each evaluation variable as a covariate.

[0106] For categorical variables, frequencies and percentages by administration group were presented, and the difference in proportions between each test group and each control group was analyzed using Pearson's chi-square test or Fisher's exact test depending on whether the number of cells with an expected frequency of less than 5 exceeded 20%.

[0107] The safety evaluation variables were set as follows:

[0108] - Adverse reactions

[0109] The number of subjects, incidence rate, and number of occurrences of treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs) that occurred after administration of the clinical trial drug were presented for each administration group, and the differences between each test group and the control group were analyzed using Fisher's exact test.

[0110] In addition, the number of subjects, incidence rate, and number of occurrences by administration group were presented by coding according to the system organ class (SOC) and preferred term (PT) of the medical dictionary for regulatory activities (MedDRA).

[0111] - Laboratory tests, 12-lead electrocardiogram, vital signs

[0112] For changes at each time point by administration group, continuous variables presented the number of subjects, mean, standard deviation, median, minimum, and maximum, and categorical variables presented the frequency and percentage.

[0113] - Ankle swelling

[0114] The number of subjects, mean, standard deviation, median, minimum, and maximum values ​​for each administration group were presented, and the mean change between each test group and the control group was compared using the Wilcoxon rank-sum test. Additionally, the Wilcoxon signed-rank test was used to analyze whether there were significant differences in the change within the group.

[0115] This evaluation variable was analyzed solely using the FAS, and missing values ​​were replaced using the Last Observation Carried Forward (LOCF) method. Furthermore, between-group comparisons were conducted for each test group (test groups 1, 2, 3, and 4) and the control group (control groups 2 and 3).

[0116]

[0117] <Experimental Example 1> Change in MSSBP at 8 weeks compared to baseline

[0118] The change in MSSBP at 8 weeks compared to baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group.

[0119] As a result of FAS analysis, the change in MSSBP at 8 weeks of administration of the clinical trial drug compared to the baseline, which is the primary efficacy evaluation variable of this clinical trial, was as follows: Example 1: -23.54±15.731 mmHg, Example 3: -21.28±12.973 mmHg, Example 2: -24.36±12.246 mmHg, Example 4: -16.23±15.902 mmHg, Comparative Example 1: -16.04±12.727 mmHg, Comparative Example 2: -16.06±13.586 mmHg, Comparative Example 3: -22.40±14.594 mmHg, Placebo: -6.54±12.013 mmHg (Figure 1).

[0120] The difference in the amount of change in MSSBP between the control group and each dose group of the trial drug at 8 weeks after administration of the trial drug compared to the baseline is shown in Table 4 below.

[0121] Difference in change between the MSSBP control group and the test drug at 8 weeks after administration of the clinical trial drug compared to the baseline FAS analysis results Comparison Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Change p-value Change p-value Change p-value Change p-value Example 1 -7.50±3.570.0400 * -7.68±3.790.0473 * 0.03±3.650.9929-16.97±3.55<0.0001 * Example 3-4.90±3.090.1178-5.21±3.300.12053.03±3.110.3347-14.44±3.08<0.0001 * Example 2-8.72±3.150.0075 * -8.72±3.360.0119 * -1.85±3.240.5704-18.02±3.10<0.0001 * Example 4-0.51±3.340.8799-0.87±3.580.80887.30±3.250.0284 * -9.88±3.370.0047 *

[0122] The difference in the amount of change between each dose group of the test drug compared to the control group showed a statistically significant tendency for the amount of change in MSSBP to decrease in Examples 1 and 2 compared to Comparative Examples 1 and 2, Example 3 showed a tendency to decrease, but statistical significance was not confirmed, and Example 4 showed a minimal difference in the amount of change (<1 mmHg).

[0123] The difference in the amount of change in MSSBP in Example 1 compared to Comparative Example 3 was minimal (<1 mmHg), and in Example 2, the amount of change in MSSBP tended to decrease, but statistical significance was not confirmed. On the other hand, Examples 3 and 4 showed an increasing tendency, and Example 4 showed statistical significance. All test groups showed a statistically significant decreasing tendency compared to the placebo.

[0124]

[0125] <Experimental Example 2> Change in MSSBP at 4 weeks compared to baseline

[0126] The change in MSSBP at 4 weeks compared to baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group.

[0127] As a result of FAS analysis, the mean change (Mean±SD) in MSSBP at 4 weeks of administration of the clinical trial drug compared to the baseline was as follows: Example 1: -19.99±13.668 mmHg, Example 3: -20.87±12.062 mmHg, Example 2: -19.62±13.093 mmHg, Example 4: -20.25±17.201 mmHg, Comparative Example 1: -14.93±10.619 mmHg, Comparative Example 2: -16.36±11.615 mmHg, Comparative Example 3: -20.11±12.087 mmHg, Placebo: -3.21±11.114 mmHg (Fig. 2).

[0128] The difference in the amount of change in MSSBP between the control group and each dose group of the trial drug at 4 weeks after administration of the trial drug compared to the baseline is shown in Table 5 below.

[0129] Difference in change between the control group and the test drug in MSSBP at 4 weeks after administration of the clinical trial drug compared to the baseline Comparison Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Change p-value Change p-value Change p-value Change p-value Example 1 -5.03±3.04 0.1029 -3.65±3.18 0.2557 1.04±3.18 0.7459 -16.52±3.23 <0.0001 * Example 3-5.49±2.530.0336 * -4.05±2.570.12091.15±2.590.6599-16.76±2.77<0.0001 * Example 2-5.05±3.010.0988-3.80±3.180.23670.56±3.150.8591-16.47±3.16<0.0001 * Example 4-5.64±3.290.0912-4.37±3.380.20180.83±3.330.8043-16.77±3.52<0.0001 *

[0130] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 1 was as follows: Example 1: -5.03±3.04 mmHg (p=0.1029), Example 3: -5.49±2.53 mmHg (p=0.0336 * ), Example 2: -5.05±3.01 mmHg (p=0.0988), Example 4: -5.64±3.29 mmHg (p=0.0912). A statistically significant difference was observed between Example 3 and Comparative Example 1, and no statistically significant difference was observed between Examples 1, 2, and 4.

[0131] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 2 was, respectively, Example 1: -3.65±3.18 mmHg (p=0.2557), Example 3: -4.05±2.57 mmHg (p=0.1209), Example 2: -3.80±3.18 mmHg (p=0.2367), Example 4: -4.37±3.38 mmHg (p=0.2018). No statistically significant difference was observed in any test group compared to Comparative Example 2.

[0132] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 3 was Example 1: 1.04±3.18 mmHg (p=0.7459), Example 3: 1.15±2.59 mmHg (p=0.6599), Example 2: 0.56±3.15 mmHg (p=0.8591), Example 4: 0.83±3.33 mmHg (p=0.8043). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0133] The difference in the amount of change between each dose group of the test drug compared to the placebo was -16.52±3.23 mmHg (p<0.0001) for Example 1. * ), Example 3: -16.76±2.77 mmHg(p<0.0001*), Example 2: -16.47±3.16 mmHg(p<0.0001 * ), Example 4: -16.77±3.52 mmHg(p<0.0001 * ) was statistically significant compared to the placebo in all test groups.

[0134]

[0135] <Experimental Example 3> Change in MSDBP at 4 weeks compared to baseline

[0136] The change in MSDBP at 4 weeks compared to baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group.

[0137] As a result of FAS analysis, the mean change (Mean±SD) in MSDBP at 4 weeks after administration of the clinical trial drug compared to the baseline was Example 1: -9.97±6.855 mmHg, Example 3: -7.02±8.924 mmHg, Example 2: -8.17±9.447 mmHg, Example 4: -7.49±7.277 mmHg, Comparative Example 1: -7.91±6.130 mmHg, Comparative Example 2: -6.16±5.170 mmHg, Comparative Example 3: -9.01±5.616 mmHg, Placebo: 0.87±7.484 mmHg (Fig. 3).

[0138] The difference in the amount of change between the control group and the test drug in each dose group at 4 weeks after administration of the clinical trial drug compared to the baseline is shown in Table 6 below.

[0139] Difference in change between each dose group of the MSDBP control group and the test drug at 4 weeks after administration of the clinical trial drug compared to the baseline Comparison Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Change p-value Change p-value Change p-value Change p-value Example 1 -2.69±1.60 0.0975 -3.70±1.42 0.0121 * -1.08±1.560.4920-10.77±1.53<0.0001 * Example 30.18±1.880.9261-0.71±1.760.68771.86±1.860.3208-7.79±1.81<0.0001 * Example 2-1.21±2.000.5461-2.19±1.860.24360.48±1.960.8058-9.40±1.90<0.0001 * Example 40.01±1.790.9937-1.68±1.660.31671.46±1.720.3986-9.11±1.82<0.0001 *

[0140] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 1 was, respectively, Example 1: -2.69±1.60 mmHg (p=0.0975), Example 3: 0.18±1.88 mmHg (p=0.9261), Example 2: -1.21±2.00 mmHg (p=0.5461), Example 4: 0.01±1.79 mmHg (p=0.9937). No statistically significant difference was observed in any test group compared to Comparative Example 1.

[0141] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 2 was -3.70±1.42 mmHg (p=0.0121) for Example 1. * ), Example 3: -0.71±1.76 mmHg (p=0.6877), Example 2: -2.19±1.86 mmHg (p=0.2436), Example 4: -1.68±1.66 mmHg (p=0.3167). A statistically significant difference was observed between Example 1 and Comparative Example 2, and no statistically significant difference was observed in Example 3, Example 2, and Example 4.

[0142] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: -1.08±1.56 mmHg (p=0.4920), Example 3: 1.86±1.86 mmHg (p=0.3208), Example 2: 0.48±1.96 mmHg (p=0.8058), and Example 4: 1.46±1.72 mmHg (p=0.3986). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0143] The difference in the amount of change between each dose group of the test drug compared to the placebo was -10.77±1.53 mmHg (p<0.0001) for Example 1. * ), Example 3: -7.79±1.81 mmHg(p<0.0001 * ), Example 2: -9.40±1.90 mmHg(p<0.0001 * ), Example 4: -9.11±1.82 mmHg(p<0.0001 *) was statistically significant compared to the placebo in all test groups.

[0144]

[0145] <Experimental Example 4> Change in MSDBP at 8 weeks compared to baseline

[0146] The change in MSDBP at 8 weeks compared to baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group.

[0147] As a result of FAS analysis, the mean change (Mean±SD) in MSDBP at 8 weeks of administration of the clinical trial drug compared to the baseline was Example 1: -10.42±8.209 mmHg, Example 3: -8.37±8.291 mmHg, Example 2: -11.64±8.649 mmHg, Example 4: -6.90±7.301 mmHg, Comparative Example 1: -8.18±7.717 mmHg, Comparative Example 2: -8.16±6.814 mmHg, Comparative Example 3: -11.11±6.951 mmHg, Placebo: -0.81±7.764 mmHg (Fig. 4).

[0148] The difference in the amount of change between the control group and the test drug in each dose group at 8 weeks after administration of the clinical trial drug compared to the baseline is shown in Table 7 below.

[0149] Difference in change between the control group and the test drug at 8 weeks after administration of the clinical trial drug compared to the baseline Comparison Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Change p-value Change p-value Change p-value Change p-value Example 1 -2.84±2.010.1622-2.20±1.880.24670.46±1.860.8076-9.88±1.84<0.0001 * Example 2-4.16±2.100.0523-3.57±1.960.0744-0.95±1.950.6262-11.35±1.91<0.0001 *Example 3-0.69±2.020.7327-0.08±1.900.96672.59±1.880.1736-7.72±1.860.0001 * Example 40.61±1.990.76030.88±1.820.63053.56±1.830.0565-7.07±1.820.0003 *

[0150] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 1 was, respectively, Example 1: -2.84±2.01 mmHg (p=0.1622), Example 3: -0.69±2.02 mmHg (p=0.7327), Example 2: -4.16±2.10 mmHg (p=0.0523), Example 4: 0.61±1.99 mmHg (p=0.7603). No statistically significant difference was observed in any test group compared to Comparative Example 1.

[0151] However, in the PPS analysis results, Example 2: -5.71±2.37 mmHg (p=0.0201 * ) showed a statistically significant difference compared to Comparative Example 1.

[0152] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 2 was, respectively, Example 1: -2.20±1.88 mmHg (p=0.2467), Example 3: -0.08±1.90 mmHg (p=0.9667), Example 2: -3.57±1.96 mmHg (p=0.0744), and Example 4: 0.88±1.82 mmHg (p=0.6305). No statistically significant difference was observed in any test group compared to Comparative Example 2.

[0153] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 0.46±1.86 mmHg (p=0.8076), Example 3: 2.59±1.88 mmHg (p=0.1736), Example 3: -0.95±1.95 mmHg (p=0.6262), Example 4: 3.56±1.83 mmHg (p=0.0565). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0154] The difference in the amount of change between each dose group of the test drug compared to the placebo was -9.88±1.84 mmHg (p<0.0001) for Example 1. * ), Example 3: -7.72±1.86 mmHg (p=0.0001 * ), Example 2: -11.35±1.91 mmHg(p<0.0001 * ), Example 4: -7.07±1.82 mmHg (p=0.0003 * ) was statistically significant compared to the placebo in all test groups.

[0155]

[0156] <Experimental Example 5> Blood pressure normalization rate at 4 weeks compared to baseline

[0157] The blood pressure normalization rate at 4 weeks compared to the baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. The target blood pressure was defined as MSSBP less than 140 mmHg and MSDBP less than 90 mmHg (however, for patients with diabetes or chronic kidney disease, MSSBP less than 130 mmHg and MSDBP less than 80 mmHg).

[0158] As a result of FAS analysis, the proportion of subjects who reached the target blood pressure at 4 weeks after administration of the clinical trial drug was Example 1: 73.33% (22 / 30 people), Example 3: 50.00% (16 / 32 people), Example 2: 70.97% (22 / 31 people), Example 4: 58.06% (18 / 31 people), Comparative Example 1: 35.48% (11 / 31 people), Comparative Example 2: 35.71% (10 / 28 people), Comparative Example 3: 53.33% (16 / 30 people), Placebo: 10.34% (3 / 29 people) (Fig. 5).

[0159] The blood pressure normalization rate for each dose group of the test drug compared to the control group at 4 weeks after administration of the clinical trial drug compared to the baseline is shown in Table 8 below.

[0160] Comparison of blood pressure normalization rates between each dose group of the test drug and the control group at 4 weeks after administration of the clinical trial drug compared to the baseline. Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Normalization rate p-value Normalization rate p-value Normalization rate p-value Normalization rate p-value Example 1 37.85% 0.0030 * 37.62%0.0040 * 20.00%0.108062.99%<0.0001 * Example 314.52%0.244414.29%0.2653-3.33%0.793039.66%0.0008 * Example 235.48%0.0051 * 35.25%0.0066 * 17.63%0.155460.62%<0.0001 * Example 422.58%0.074822.35%0.08604.73%0.709947.72%0.0001 *

[0161] The difference in target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 1 was 37.85% (p=0.0030) in Example 1. * ), Example 3: 14.52% (p=0.2444), Example 2: 35.48% (p=0.0051 * ), Example 4: 22.58% (p=0.0748). There was a statistically significant difference between Example 1 and Example 2 compared to Comparative Example 1, and there was no statistically significant difference between Example 3 and Example 4.

[0162] The difference in target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 2 was 37.62% (p=0.0040) in Example 1. * ), Example 3: 14.29% (p=0.2653), Example 2: 35.25% (p=0.0066 *), Example 4: 22.35% (p=0.0860). A statistically significant difference was observed between Example 1 and Example 2 compared to Comparative Example 2, and no statistically significant difference was observed in Example 3 and Example 4.

[0163] The difference in the target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 20.00% (p=0.1080), Example 3: -3.33% (p=0.7930), Example 2: 17.63% (p=0.1554), and Example 4: 4.73% (p=0.7099). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0164] The difference in target blood pressure achievement rate between each dose group of the test drug compared to the placebo was 62.99% (p<0.0001) in Example 1. * ), Example 3: 39.66% (p=0.0008) * ), Example 2: 60.62% (p<0.0001) * ), Example 4: 47.72% (p=0.0001) * ) was statistically significant compared to the placebo in all test groups.

[0165]

[0166] <Experimental Example 6> Blood pressure normalization rate at 8 weeks compared to baseline

[0167] The blood pressure normalization rate at 8 weeks compared to the baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. The target blood pressure was defined as MSSBP less than 140 mmHg and MSDBP less than 90 mmHg (however, for patients with diabetes or chronic kidney disease, MSSBP less than 130 mmHg and MSDBP less than 80 mmHg).

[0168] As a result of FAS analysis, the proportion of subjects who reached the target blood pressure at 8 weeks after administration of the clinical trial drug was Example 1: 67.74% (21 / 31 subjects), Example 3: 56.25% (18 / 32 subjects), Example 2: 77.42% (24 / 31 subjects), Example 4: 41.94% (13 / 31 subjects), Comparative Example 1: 38.71% (12 / 31 subjects), Comparative Example 2: 44.83% (13 / 29 subjects), Comparative Example 3: 60.00% (18 / 30 subjects), Placebo: 19.35% (6 / 31 subjects) (Fig. 6).

[0169] The blood pressure normalization rate for each dose group of the test drug compared to the control group at 8 weeks after administration of the clinical trial drug compared to the baseline is shown in Table 9 below.

[0170] Comparison of blood pressure normalization rates between each dose group of the trial drug compared to baseline at 8 weeks after administration of the trial drug. Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Normalization rate p-value Normalization rate p-value Normalization rate p-value Normalization rate p-value Example 1 29.03% 0.0220 * 22.91%0.07357.74%0.529048.39%0.0001 * Example 317.54%0.163411.42%0.3728-3.75%0.764936.90%0.0026 * Example 238.71%0.0020 * 32.59%0.0095 * 17.42%0.141958.06%<0.0001 * Example 43.23%0.7957-2.89%0.8213-18.06%0.158322.58%0.0538

[0171] The difference in target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 1 was 29.03% (p=0.0220) in Example 1. * ), Example 3: 17.54% (p=0.1634), Example 2: 38.71% (p=0.0020 *), Example 4: 3.23% (p=0.7957). There was a statistically significant difference between Example 1 and Example 2 compared to Comparative Example 1, and there was no statistically significant difference between Example 3 and Example 4.

[0172] The difference in target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 2 was Example 1: 22.91% (p=0.0735), Example 3: 11.42% (p=0.3728), Example 2: 32.59% (p=0.0095). * ), Example 4: -2.89% (p=0.8213). A statistically significant difference was observed between Example 2 and Comparative Example 2, and no statistically significant difference was observed between Examples 1, 3, and 4.

[0173] However, the PPS analysis results showed no statistically significant difference in all test groups compared to Comparative Example 2.

[0174] The difference in the target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 7.74% (p=0.5290), Example 3: -3.75% (p=0.7649), Example 2: 17.42% (p=0.1419), and Example 4: -18.06% (p=0.1583). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0175] The difference in target blood pressure achievement rate between each dose group of the test drug compared to the placebo was 48.39% (p=0.0001) in Example 1. * ), Example 3: 36.90% (p=0.0026) * ), Example 2: 58.06% (p<0.0001) * ), Example 4: 22.58% (p=0.0538). Statistically significant differences were observed only in Example 1, Example 3, and Example 2 compared to the placebo.

[0176]

[0177] <Experimental Example 7> Blood pressure response rate at 4 weeks compared to baseline

[0178] The blood pressure response rate at 4 weeks compared to the baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. The blood pressure response was defined as a decrease of 20 mmHg or more in MSSBP and / or 10 mmHg or more in MSDBP. That is, it was defined as one of the following three cases: 'MSSBP change ≤ -20 mmHg and MSDBP change ≤ -10 mmHg' or 'MSSBP change ≤ -20 mmHg and MSDBP change > -10 mmHg' or 'MSSBP change > -20 mmHg and MSDBP change ≤ -10 mmHg'.

[0179] As a result of FAS analysis, the proportion of subjects who showed a blood pressure response at 4 weeks after administration of the clinical trial drug was Example 1: 60.00% (18 / 30 people), Example 3: 62.50% (20 / 32 people), Example 2: 54.84% (17 / 31 people), Example 4: 58.06% (18 / 31 people), Comparative Example 1: 41.94% (13 / 31 people), Comparative Example 2: 39.29% (11 / 28 people), Comparative Example 3: 60.00% (18 / 30 people), Placebo: 10.34% (3 / 29 people) (Fig. 7).

[0180] The blood pressure response rates for each dose group of the test drug compared to the control group at 4 weeks after administration of the clinical trial drug compared to the baseline are shown in Table 10 below.

[0181] Comparison of blood pressure response rates between each dose group of the trial drug at 4 weeks after administration of the trial drug compared to baseline. Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Response rate p-value Response rate p-value Response rate p-value Response rate p-value Example 1 18.06% 0.1583 20.71% 0.1149 0.00% > 0.9999 49.66% < 0.0001 *Example 320.56%0.102323.21%0.07262.50%0.839952.16%0.0008 * Example 212.90%0.309415.55%0.2322-5.16%0.683644.49%<0.0001 * Example 416.13%0.204118.78%0.1497-1.94%0.877947.72%0.00001 *

[0182] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 1 was, respectively, Example 1: 18.06% (p=0.1583), Example 3: 20.56% (p=0.1023), Example 2: 12.90% (p=0.3094), and Example 4: 16.13% (p=0.2041). No statistically significant difference was observed in any test group compared to Comparative Example 1.

[0183] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 2 was, respectively, Example 1: 20.71% (p=0.1149), Example 3: 23.21% (p=0.0726), Example 2: 15.55% (p=0.2322), and Example 4: 18.78% (p=0.1497). No statistically significant difference was observed in any test group compared to Comparative Example 2.

[0184] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 0.00% (p>0.9999), Example 3: 2.50% (p=0.8399), Example 2: -5.16% (p=0.6836), and Example 4: -1.94% (p=0.8779). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0185] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to the placebo was 49.66% in Example 1 (p<0.0001). * ), Example 3: 52.16% (p<0.0001) *), Example 2: 44.49% (p=0.0003) * ), Example 4: 47.72% (p=0.0001) * ) was statistically significant compared to the placebo in all test groups.

[0186]

[0187] <Experimental Example 8> Blood pressure response rate at 8 weeks compared to baseline

[0188] The blood pressure response rate at 8 weeks compared to the baseline was measured for the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. The blood pressure response was defined as a decrease of 20 mmHg or more in MSSBP and / or 10 mmHg or more in MSDBP. That is, it was defined as one of the following three cases: 'MSSBP change ≤ -20 mmHg and MSDBP change ≤ -10 mmHg' or 'MSSBP change ≤ -20 mmHg and MSDBP change > -10 mmHg' or 'MSSBP change > -20 mmHg and MSDBP change ≤ -10 mmHg'.

[0189] As a result of FAS analysis, the proportion of subjects who showed a blood pressure response at the 8-week point after administration of the clinical trial drug was Example 1: 67.74% (21 / 31 subjects), Example 3: 56.25% (18 / 32 subjects), Example 2: 67.74% (21 / 31 subjects), Example 4: 45.16% (14 / 31 subjects), Comparative Example 1: 45.16% (14 / 31 subjects), Comparative Example 2: 44.83% (13 / 29 subjects), Comparative Example 3: 66.67% (20 / 30 subjects), Placebo: 16.13% (5 / 31 subjects) (Fig. 8).

[0190] The blood pressure response rates for each dose group of the test drug compared to the control group at 8 weeks after administration of the clinical trial drug compared to the baseline are shown in Table 11 below.

[0191] Comparison of blood pressure response rates between each dose group of the trial drug compared to baseline at 8 weeks after administration of the trial drug. Example 1 (Candesartan 8 mg) Comparison Example 2 (Amlodipine 5 mg) Comparison Example 3 (Amlodipine 10 mg) Comparison with placebo Response rate p-value Response rate p-value Response rate p-value Response rate p-value Example 1 22.58% 0.07 30 22.91% 0.07 35 1.08% 0.92 8 75 1.61% <0.0001 * Example 311.09%0.378811.42%0.3728-10.42%0.400140.12%0.0009 * Example 222.58%0.073022.91%0.07351.08%0.928751.61%<0.0001 * Example 40.00%>0.99990.33%0.9793-21.51%0.090929.03%0.00132 *

[0192] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 1 was, respectively, Example 1: 22.58% (p=0.0730), Example 3: 11.09% (p=0.3788), Example 2: 22.58% (p=0.0730), Example 4: 0.00% (p=>0.9999). There was no statistically significant difference in all examples compared to Comparative Example 1. However, as a result of PPS analysis, Example 2: 28.52 (p=0.0452*) showed a statistically significant difference compared to Comparative Example 1.

[0193] The difference in target blood pressure response rate between each dose group of the test drug compared to Comparative Example 2 was, respectively, Example 1: 22.91% (p=0.0735), Example 3: 11.42% (p=0.3728), Example 2: 22.91% (p=0.0735), and Example 4: 0.33% (p=0.9793). No statistically significant difference was observed in any of the examples compared to Comparative Example 2.

[0194] The difference in target blood pressure response rate between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 1.08% (p=0.9287), Example 3: -10.42% (p=0.4001), Example 2: 1.08% (p=0.9287), and Example 4: -21.51% (p=0.0909). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0195] The differences in the target blood pressure response rates between the dose groups of the test drug compared to the placebo were Example 1: 51.61% (p<0.0001*), Example 3: 40.12% (p=0.0009*), Example 2: 51.61% (p<0.0001*), and Example 4: 29.03% (p=0.0132), respectively. Statistically significant differences were observed in all test groups compared to the placebo.

[0196]

[0197] <Experimental Example 9> Change in MSSBP at 8 weeks compared to baseline in patients with early hypertension (ad-hoc)

[0198] In an additional experiment, the change in MSSBP compared to baseline at 8 weeks was measured in patients with early hypertension in the groups administered Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. Patients with early hypertension were subjects with a baseline MSSBP value of less than 160 mmHg.

[0199] As a result of additional analysis, the number of subjects with baseline MSSBP values ​​less than 160 mmHg was 23 in Example 1, 25 in Example 3, 24 in Example 2, 23 in Example 4, 20 in Comparative Example 1, 19 in Comparative Example 2, 23 in Comparative Example 3, and 25 in the placebo group.

[0200] The mean change (Mean±SD) in MSSBP at 8 weeks of administration of the clinical trial drug compared to the baseline in subjects whose baseline MSSBP level was less than 160 mmHg was Example 1: -22.38±16.644 mmHg, Example 3: -19.80±11.438 mmHg, Example 2: -24.00±10.521 mmHg, Example 4: -12.18±13.447 mmHg, Comparative Example 1: -13.32±11.669 mmHg, Comparative Example 2: -14.11±11.385 mmHg, Comparative Example 3: -19.13±14.273 mmHg, Placebo: -7.70±12.359 mmHg (Fig. 9).

[0201] The change in MSSBP between each dose group of the trial drug compared to the control group at 8 weeks after administration of the trial drug compared to the baseline in patients with early hypertension (ad-hoc) is shown in Table 12 below.

[0202] Difference in the change in MSSBP between the control group and the test drug at 8 weeks after administration of the investigational drug compared to the baseline (<160 mmHg) Comparative Example 1 (Candesartan 8 mg) Comparative Example 2 (Amlodipine 5 mg) Comparative Example 3 (Amlodipine 10 mg) Comparative Example 1 (Placebo) Change p-value Change p-value Change p-value Change p-value Example 1 -8.50±4.5 3 0.06 8 1 -7.57±4.6 0 0.10 8 0 -1.68±4.4 8 0.70 8 9 -14.74±4.0 9 0.00 08 * Example 3-5.00±3.460.1561-3.67±3.450.29362.34±3.420.4977-11.41±3.060.0005 * Example 2-10.60±3.280.0024 * -9.90±3.230.0039 * -4.94±3.240.1347-18.07±3.02<0.0001 * Example 41.26±3.840.74472.00±3.840.60457.03±3.780.0699-6.01±3.540.0964

[0203] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 1 was Example 1: -8.50±4.53 mmHg (p=0.0681), Example 3: -5.00±3.46 mmHg (p=0.1561), Example 2: -10.60±3.28 mmHg (p=0.0024 * ), Example 4: 1.26±3.84 mmHg (p=0.7447). There was a statistically significant difference between Example 2 and Comparative Example 1, and there was no statistically significant difference between Examples 1, 3, and 4.

[0204] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 2 was Example 1: -7.57±4.60 mmHg (p=0.1080), Example 3: -3.67±3.45 mmHg (p=0.2936), Example 2: -9.90±3.23 mmHg (p=0.0039 * ), Example 4: 2.00±3.84 mmHg (p=0.6045). A statistically significant difference was observed between Example 2 and Comparative Example 2, and no statistically significant difference was observed between Examples 1, 3, and 4.

[0205] The difference in the amount of change between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: -1.68±4.48 mmHg (p=0.7089), Example 3: 2.34±3.42 mmHg (p=0.4977), Example 2: -4.94±3.24 mmHg (p=0.1347), Example 4: 7.03±3.78 mmHg (p=0.0699). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0206] The difference in the amount of change between each dose group of the test drug compared to the placebo was -14.74±4.09 mmHg (p=0.0008) in Example 1. * ), Example 3: -11.41±3.06 mmHg (p=0.0005 * ), Example 2: -18.07±3.02 mmHg(p<0.0001 *), Example 4: -6.01±3.54 mmHg (p=0.0964). There was a statistically significant difference between Example 1, Example 3, and Example 2 compared to the placebo, and there was no statistically significant difference in Example 4.

[0207]

[0208] <Experimental Example 10> Blood pressure normalization rate at 8 weeks compared to baseline in patients with early hypertension (ad-hoc)

[0209] In an additional experiment, the blood pressure normalization rate at 8 weeks compared to the baseline was measured in patients with early hypertension in the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. Patients with early hypertension were subjects with a baseline MSSBP value of less than 160 mmHg.

[0210] As a result of FAS analysis, the proportion of subjects who reached the target blood pressure at 8 weeks after administration of the clinical trial drug was 78.26% (18 / 23 people) for Example 1, 60.00% (15 / 25 people) for Example 3, 83.33% (20 / 24 people) for Example 2, 43.48% (10 / 23 people) for Example 4, 35.00% (7 / 20 people) for Comparative Example 1, 52.63% (10 / 19 people) for Comparative Example 2, 60.87% (14 / 23 people) for Comparative Example 3, and 24.00% (6 / 25 people) for placebo (Fig. 10).

[0211] The blood pressure normalization rates for each dose group of the trial drug compared to the control group at 8 weeks after administration of the trial drug compared to the baseline in patients with early hypertension (ad-hoc) are shown in Table 13 below.

[0212] Blood pressure normalization rate (<160 mmHg: ad-hoc) between each dose group of the investigational drug compared to the control group in MSSBP at 8 weeks after administration of the investigational drug compared to the baseline. Comparative Example 1 (Candesartan 8 mg) Comparative Example 2 (Amlodipine 5 mg) Comparative Example 3 (Amlodipine 10 mg) Comparative Example 3 (Amlodipine 10 mg) Normalization rate compared to placebo p-value Normalization rate p-value Normalization rate p-value Normalization rate p-value Example 1 43.26% 0.0041 * 25.63%0.079517.39%0.199954.26%0.0002 * Example 325.00%0.09557.37%0.6250-0.87%0.950936.00%0.0099 * Example 248.33%0.0010 * 30.70%0.0295 * 22.46%0.085259.33%<0.0001 * Example 48.48%0.5706-90.15%0.05544-17.39%0.237719.48%0.1527

[0213] The difference in target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 1 was 43.26% (p=0.0041) in Example 1. * ), Example 3: 25.00% (p=0.0955), Example 2: 48.33% (p=0.0010 * ), Example 4: 8.48% (p=0.5706). There was a statistically significant difference between Example 1 and Example 2 compared to Comparative Example 1, and there was no statistically significant difference between Example 3 and Example 4.

[0214] The difference in the target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 2 was Example 1: 25.63% (p=0.0795), Example 3: 7.37% (p=0.6250), Example 2: 30.70% (p=0.0295). *), Example 4: -9.15% (p=0.5544). There was a statistically significant difference between Example 2 and Comparative Example 2, and there was no statistically significant difference between Examples 1, 3, and 4.

[0215] However, the PPS analysis results showed no statistically significant difference between Example 2 and Comparative Example 2 (p=0.2764).

[0216] The difference in the target blood pressure achievement rate between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 17.39% (p=0.1999), Example 3: -0.87% (p=0.9509), Example 2: 22.46% (p=0.0852), and Example 4: -17.39% (p=0.2377). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0217] The difference in target blood pressure achievement rate between each dose group of the test drug compared to the placebo was 54.26% (p=0.0002) in Example 1. * ), Example 3: 36.00% (p=0.0099) * ), Example 2: 59.33% (p<0.0001) * ), Example 4: 19.48% (p=0.1527).

[0218]

[0219] <Experimental Example 11> Blood pressure response rate at 8 weeks compared to baseline in patients with early hypertension (ad-hoc)

[0220] In an additional experiment, the blood pressure response rate at 8 weeks was measured compared to the baseline in patients with early hypertension in the above Examples 1 to 4, Comparative Examples 1 to 3, and the placebo group. Patients with early hypertension were subjects with a baseline MSSBP value of less than 160 mmHg.

[0221] As a result of FAS analysis, among subjects with baseline MSSBP values ​​less than 160 mmHg, the proportion of subjects who showed a blood pressure response at 8 weeks of administration of the clinical trial drug was 65.22% (15 / 23 subjects) for Example 1, 52.00% (13 / 25 subjects) for Example 3, 70.83% (17 / 24 subjects) for Example 2, 30.43% (7 / 23 subjects) for Example 4, 40.00% (8 / 20 subjects) for Comparative Example 1, 42.11% (8 / 19 subjects) for Comparative Example 2, 56.52% (13 / 23 subjects) for Comparative Example 3, and 20.00% (5 / 25 subjects) for placebo (Fig. 11).

[0222] The blood pressure response rates for each dose group of the trial drug compared to the control group at 8 weeks after administration of the trial drug compared to the baseline in patients with early hypertension (ad-hoc) are shown in Table 14 below.

[0223] Blood pressure response rate (<160 mmHg: ad-hoc) between each dose group of the trial drug compared to baseline at 8 weeks after administration of the trial drug. Comparative Example 1 (Candesartan 8 mg) Comparative Example 2 (Amlodipine 5 mg) Comparative Example 3 (Amlodipine 10 mg) Comparative Example 3 (Amlodipine 10 mg) Placebo Comparative Example Response Rate p-value Response Rate p-value Response Rate p-value Example 1 25.22% 0.098 2 2 3.11% 0.134 2 8.70% 0.545 745.22% 0.0015 * Example 312.00%0.42279.89%0.5151-4.52%0.753432.00%0.0184 * Example 230.83%0.0398 * 28.73%0.057914.31%0.307450.83%0.0003 * Example 4-9.57%0.5116-11.67%0.4321-26.09%0.074310.43%0.4042

[0224] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 1 was Example 1: 25.22% (p=0.0982), Example 3: 12.00% (p=0.4227), Example 2: 30.83% (p=0.0398). * ), Example 4: -9.57% (p=0.5116). There was a statistically significant difference between Example 2 and Comparative Example 1, and there was no statistically significant difference between Examples 1, 3, and 4.

[0225] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 2 was, respectively, Example 1: 23.11% (p=0.1342), Example 3: 9.89% (p=0.5151), Example 2: 28.73% (p=0.0579), and Example 4: -11.67% (p=0.4321). No statistically significant difference was observed in any test group compared to Comparative Example 2.

[0226] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to Comparative Example 3 was, respectively, Example 1: 8.70% (p=0.5457), Example 3: -4.52% (p=0.7534), Example 2: 14.31% (p=0.3074), and Example 4: -26.09% (p=0.0743). No statistically significant difference was observed in any test group compared to Comparative Example 3.

[0227] The difference in the proportion of subjects who showed a blood pressure response between each dose group of the test drug compared to the placebo was 45.22% in Example 1 (p=0.0015). * ), Example 3: 32.00% (p=0.0184) * ), Example 2: 50.83% (p=0.0003) * ), Example 4: 10.43% (p=0.4042).

[0228]

[0229] <Experimental Example 12> Safety Evaluation

[0230] The total number of adverse reactions occurring before administration of the clinical trial drug was 23 in 19 patients (7.54%, 19 / 252 patients), and the total number of adverse reactions (TEAEs) occurring after administration of the clinical trial drug was 60 in 44 patients (17.46%, 44 / 252 patients). As a result of checking the TEAE incidence rate by each administration group, there were 10 cases in 7 subjects (21.88%, 7 / 32 subjects) in Example 1, 6 cases in 5 subjects (15.63%, 5 / 32 subjects) in Example 3, 3 cases in 3 subjects (9.38%, 3 / 32 subjects) in Example 2, 4 cases in 3 subjects (10.00%, 3 / 30 subjects) in Example 4, 12 cases in 9 subjects (28.13%, 9 / 32 subjects) in Comparative Example 1, 6 cases in 3 subjects (9.68%, 3 / 31 subjects) in Comparative Example 2, 7 cases in 7 subjects (21.88%, 7 / 32 subjects) in Comparative Example 3, and 12 cases in 7 subjects (22.58%, 7 / 31 subjects) in the placebo group. There was no statistically significant difference in the incidence rate of adverse reactions (TEAE) between administration groups.

[0231] The overall adverse drug reaction (ADR) incidence rate causally related to the administration of the clinical trial drug was reported to be 14 cases in 10 subjects (3.97%, 10 / 252 subjects), and as a result of checking by each administration group, there were 3 cases in 1 subject each (3.13%, 3.13%, 3.23%, 1 / 32 subjects, 1 / 32 subjects, 1 / 31 subjects) in Example 1, Example 2, and Comparative Example 2, 2 cases and 4 cases in 2 subjects (6.25%, 2 / 32 subjects) in Example 3 and Comparative Example 1, respectively, and 3 cases in 3 subjects (9.68%, 3 / 31 subjects) in the placebo group. No ADRs occurred in Example 4 and Comparative Example 3. There was no statistically significant difference in the ADR incidence rate between administration groups.

[0232] The overall serious adverse reaction (SAE) incidence was reported as 2 cases in 2 subjects (0.79%, 2 / 252 subjects), 1 case in 1 subject (3.13%, 1 / 32 subjects) of Example 1, which required hospitalization or extended hospitalization period, and 1 case in 1 subject (3.13%, 1 / 32 subjects) of Comparative Example 1, which caused permanent or serious disability and functional decline. There were no serious adverse drug reactions (SADRs).

[0233] Adverse reactions that caused overall dropout were reported in 4 cases in 4 people (1.59%, 4 / 252 people), and when checked for each administration group, there was 1 case in 1 person each in Example 1, Example 2, Comparative Example 3, and placebo (3.13%, 3.13%, 3.13%, 3.23%, 1 / 32 people, 1 / 32 people, 1 / 32 people, 1 / 31 people). There was no statistically significant difference in the incidence of adverse reactions that caused dropout between administration groups.

[0234] No clinically significant (CS) abnormal findings or clinically significant changes were identified in hematology, coagulation, vital signs, or electrocardiography after baseline.

[0235]

[0236] In conclusion, after administering the clinical trial drug to patients with essential hypertension, in Examples 1 and 2, a statistically significant blood pressure reduction effect was confirmed in MSSBP at 8 weeks compared to placebo, Comparative Example 1 (candesartan 8 mg), and Comparative Example 2 (amlodipine 5 mg), and a similar blood pressure reduction effect was observed compared to Comparative Example 3 (amlodipine 10 mg).

[0237] In Examples 1 and 2, the MSSBP / MSDBP reduction effect and blood pressure response rate at 4 and 8 weeks compared to the placebo and monotherapy (active control) tended to be similar or higher, and the blood pressure normalization rate was the highest, confirming that it was a dose that showed a clinically significant level of effect in the treatment of subjects with essential hypertension.

[0238] In addition, as a result of the safety evaluation, all adverse drug reactions that occurred in the clinical trial drugs were confirmed to be adverse reactions that could be predicted in monotherapy (active control drug), so no new adverse reactions requiring special attention were observed, confirming that sufficient tolerability was secured for all dose groups in Examples 1 to 4.

[0239] Accordingly, the low-dose triple combination drug (Examples 1 and 2) showed similar blood pressure reduction rates and blood pressure normalization rates at 4 and 8 weeks compared to the approved single therapy (candesartan 8 mg, amlodipine 5 / 10 mg). Therefore, it is predicted that it will be possible to prevent the occurrence of adverse reactions that may occur due to excessive blood pressure reduction caused by high-dose monotherapy administration. In addition, since sufficient tolerability and therapeutic effect were confirmed through this clinical trial when administering the low-dose triple combination drug, it is expected that a higher therapeutic effect can be shown through the convenience of taking it in the future. In addition, sufficient tolerability was confirmed in the results of an additional analysis targeting subjects with early hypertension (<160 mmHg).

Claims

1. A pharmaceutical combination preparation comprising, as active ingredients, candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof; and indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof.

2. A pharmaceutical combination preparation according to claim 1, wherein the candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 0.1 to 7 mg when converted to the candesartan free base form.

3. A pharmaceutical combination preparation in the second paragraph, wherein the candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 1 to 5 mg when converted to the candesartan free base form.

4. A pharmaceutical combination preparation in accordance with claim 3, wherein the candesartan, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 2 to 4 mg when converted to the candesartan free base form.

5. A pharmaceutical combination preparation according to claim 1, wherein the amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 0.1 to 4 mg when converted to the amlodipine free base form.

6. A pharmaceutical combination preparation according to claim 5, wherein the amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 1 to 3 mg when converted to the amlodipine free base form.

7. A pharmaceutical combination preparation according to claim 6, wherein the amlodipine, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 1.25 to 2.5 mg when converted to the amlodipine free base form.

8. A pharmaceutical combination preparation according to claim 1, wherein the indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 0.1 to 1.4 mg when converted to the indapamide free base form.

9. A pharmaceutical combination preparation according to claim 8, wherein the indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 0.5 to 1.3 mg when converted to the indapamide free base form.

10. A pharmaceutical combination preparation according to claim 9, wherein the indapamide, or a pharmaceutically acceptable salt, optical isomer, hydrate, or solvate thereof, is included in an amount of 0.625 to 1.25 mg when converted to the indapamide free base form.

11. A pharmaceutical combination preparation in claim 1, wherein the candesartan or a pharmaceutically acceptable salt thereof is candesartan cilexetil.

12. A pharmaceutical combination preparation according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is amlodipine besylate.

13. A pharmaceutical combination preparation according to claim 1, further comprising a pharmaceutical additive selected from a diluent, a disintegrant, a lubricant, and a combination thereof.

14. A pharmaceutical combination preparation in claim 13, wherein the diluent is any one selected from among microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate (DCP), lactose, low-substituted hydroxypropyl cellulose, and combinations thereof.

15. A pharmaceutical combination preparation in claim 13, wherein the disintegrant is any one selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.

16. A pharmaceutical combination preparation according to claim 13, wherein the lubricant is any one selected from magnesium stearate, palmitic acid, talc, magnesium stearate, zinc stearate, calcium stearate, or a combination thereof.

17. In the first paragraph, the pharmaceutical combination preparation is a pharmaceutical combination preparation for preventing or treating hypertension.

18. In paragraph 1, the pharmaceutical combination preparation is selected from the group consisting of tablets, orally disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, dispersible tablets, dissolving tablets, capsules, granules, effervescent granules, powders, oral liquids, elixirs, suspensions, emulsions, lemonades, aromatic waters, preparations and infusions, alcoholic beverages, tinctures, syrups, syrup preparations, oral jellies, polypharmacy products, extracts, fluid extracts, and pills.

19. A pharmaceutical combination preparation in accordance with paragraph 1, which is essentially free of an angiotensin converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta blocker or a pharmaceutically acceptable salt thereof, a lipid-regulating agent, a platelet function-altering agent, a serum homocysteine ​​lowering agent, or a combination thereof.

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