Compositions for treatment of hypertension

Abstract

To provide new treatments for lowering hypertension that are efficacious and tolerable.SOLUTION: There are provided herein, pharmaceutical compositions that are useful for the treatment of hypertension, comprising an angiotensin II receptor blocker, a diuretic, a calcium antagonist, and a β-blocker, wherein the dose of each component is below the lowest dose approved for the treatment of hypertension for the component.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] <Cross-reference> This application is a continuation of U.S. Patent Application No. 15 / 352,425, filed on November 15, 2016, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Hypertension, also known as high blood pressure, is a major cause of preventable morbidity and mortality, and it is well established that treatment to lower blood pressure (BP) is beneficial. However, despite the availability of numerous blood pressure-lowering medications, many patients continue to have inadequate blood pressure control, as demonstrated by a number of large-scale population studies. Factors contributing to poor blood pressure control include poor adherence, complex guidelines recommending multiple up-titration steps, treatment inertia, etc. Furthermore, the majority of treated patients receive only monotherapy, which has limited efficacy even at high doses where side effects increase and tolerance decreases. Therefore, there is a need for new, effective and tolerable treatments for lowering blood pressure.

Summary of the Invention

[0003] As used herein, (a) an angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; are included, and a pharmaceutical composition is provided wherein the dose of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dose (LHTD) of each of (a), (b), (c), and (d).

[0004] In some embodiments, the dosages of (a), (b), (c), and (d) are each about 40% to about 60% of the lowest hypertensive treatment dosage (LHTD) of (a), (b), (c), and (d), respectively. In some embodiments, the pharmaceutical composition essentially does not contain a lipid regulator, a platelet function altering agent, a serum homocysteine lowering agent, or a combination thereof.

[0005] In some embodiments, the diuretic is a thiazide diuretic, and the thiazide diuretic is ariditide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof.

[0006] In some embodiments, the dosage of the thiazide diuretic is about 50% of the lowest hypertensive treatment dosage (LHTD) of the thiazide diuretic. In some embodiments, the thiazide diuretic is hydrochlorothiazide, and the dosage of hydrochlorothiazide is about 6.25 mg.

[0007] In some embodiments, the diuretic is a thiazide-like diuretic, and the thiazide-like diuretic is quinethazone, chlorthalidone, mefruside, clofenamide, metolazone, meclan, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the dosage of the thiazide-like diuretic is about 50% of the lowest hypertensive treatment dosage (LHTD) of the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dosage of indapamide is about 0.625 mg. In some embodiments, the thiazide-like diuretic is chlorthalidone, and the dosage of chlorthalidone is about 12.5 mg.

[0008] In some embodiments, the dosage of the calcium antagonist is about 50% of the lowest hypertensive treatment dosage (LHTD) of the calcium antagonist. In some embodiments, the calcium antagonist is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotarizine, diprotenerine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium antagonist is amlodipine besylate, and the dosage of amlodipine besylate is about 1.25 mg.

[0009] In some embodiments, the dosage of the β-blocker is about 50% of the lowest hypertensive treatment dosage (LHTD) of the β-blocker. In some embodiments, the β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, mecipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tertatolol, alotiolol, levobetaxolol, befunolol, amosulalol, tilisolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the β-blocker is atenolol, and the dosage of atenolol is about 12.5 mg. In some embodiments, the β-blocker is bisoprolol fumarate, and the dosage of bisoprolol fumarate is about 2.5 mg.

[0010] In some embodiments, the dosage of the angiotensin II receptor antagonist is about 50% of the lowest hypertensive treatment dosage (LHTD) of the angiotensin II receptor antagonist. In some embodiments, the angiotensin II receptor antagonist is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor antagonist is irbesartan, and the dosage of irbesartan is about 37.5 mg. In some embodiments, the angiotensin II receptor antagonist is telmisartan, and the dosage of telmisartan is about 10 mg.

[0011] In some embodiments, the angiotensin II receptor antagonist is irbesartan, the diuretic is hydrochlorothiazide, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg.

[0012] In some embodiments, the angiotensin II receptor antagonist is irbesartan, the diuretic is indapamide, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of indapamide is from about 0.5 mg to about 0.75 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg.

[0013] In some embodiments, (a), (b), (c), and (d) are provided in one formulation. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0014] Furthermore, in the present specification, (a) Irbesartan; (b) Hydrochlorothiazide; (c) Amlodipine besylate; and (d) Atenolol; are included, and a pharmaceutical composition is provided, wherein the dosage of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d).

[0015] In some embodiments, the dosages of (a), (b), (c), and (d) are each about 40% to about 60% of the lowest hypertensive treatment dosage (LHTD) of (a), (b), (c), and (d), respectively. In some embodiments, the pharmaceutical composition essentially does not contain a lipid regulator, a platelet function modifier, a serum homocysteine reducing agent, or a combination thereof. In some embodiments, the dosage of hydrochlorothiazide is about 50% of the lowest hypertensive treatment dosage (LHTD) of hydrochlorothiazide. In some embodiments, the dosage of hydrochlorothiazide is about 6.25 mg. In some embodiments, the dosage of amlodipine besylate is about 50% of the lowest hypertensive treatment dosage (LHTD) of amlodipine besylate. In some embodiments, the dosage of amlodipine besylate is about 1.25 mg. In some embodiments, the dosage of atenolol is about 50% of the lowest hypertensive treatment dosage (LHTD) of atenolol. In some embodiments, the dosage of atenolol is about 12.5 mg. In some embodiments, the dosage of irbesartan is about 50% of the lowest hypertensive treatment dosage (LHTD) of irbesartan. In some embodiments, the dosage of irbesartan is about 37.5 mg. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. In some embodiments, (a), (b), (c), and (d) are provided in one formulation. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0016] Furthermore, herein, (a) an angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; A method for treating hypertension in a subject in need thereof, comprising the step of administering a pharmaceutical composition comprising (a), (b), (c), and (d) each dosage is about 20% to about 60% of the respective lowest hypertension treatment dosage (LHTD) of (a), (b), (c), and (d), and a method is provided as another aspect.

[0017] Furthermore, herein, (a) Irbesartan; (b) Hydrochlorothiazide; (c) Amlodipine besylate; and (d) Atenolol; A method for treating hypertension in a subject in need thereof, comprising the step of administering a pharmaceutical composition comprising (a), (b), (c), and (d) each dosage is about 20% to about 60% of the respective lowest hypertension treatment dosage (LHTD) of (a), (b), (c), and (d), and a method is provided.

[0018] In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, the treatment is the first or first-choice treatment for hypertension.

[0019] <Incorporation by reference> All publications, patents, and patent applications mentioned herein are incorporated herein by reference to the extent that each individual publication, patent, patent application is specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0020] The novel features of the present disclosure are described in detail in the appended claims. A better understanding of the features and advantages of the present disclosure can be obtained by referring to the following detailed description that explains exemplary embodiments in which the principles of the present disclosure are used and the accompanying drawings.

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0021] There is provided herein a pharmaceutical composition for treating hypertension, comprising an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker, wherein the dosage of each component is less than the lowest dosage approved for the treatment of hypertension. The present disclosure includes, but is not limited to, benefits such as the use of low dosages to avoid or improve side effects while maintaining or improving benefits, the synergistic treatment of specific drug combinations, and the early introduction of combination therapies to enhance therapeutic effects, and recognizes the technical effects of the low-dose combination therapies described herein. Described herein is a low-dose combination composition for the treatment of hypertension, including the initial or primary treatment of hypertension.

[0022] <Specific Terms> As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "agent" includes a plurality of such agents, reference to "composition" includes one or more compositions (or plural compositions), and reference to equivalents known to those skilled in the art, and the like. When ranges are used herein with respect to physical properties such as molecular weight or chemical properties such as chemical formula, it is intended that all combinations of ranges and specific embodiments within the ranges and sub-combinations thereof are encompassed. The term "about" when referring to a numerical value or numerical range means that the referenced numerical value or numerical range is an approximation within the range of experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary between 1% and 10% of the recited numerical value or numerical range. The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is not intended to exclude, in other embodiments, for example, embodiments of any composition, composition, method, or process described herein, from being "consisting of" or "consisting essentially of" the recited features.

[0023] <Definition> As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0024] As used herein, "pharmaceutically acceptable salts" include both acid and base addition salts. In some embodiments, a pharmaceutically acceptable salt of any one of the compounds described herein is in a form approved for use by the U.S. Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0025] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effects and properties of the free base, which are not biologically or otherwise undesirable, and are made with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. It is formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, alkanoic acids substituted with phenyl, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and salts are also included, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Similarly, salts of amino acids such as alginates, gluconates, and galacturonates are also contemplated (see, for example, "Berge S.M. et al., ”Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)", which is incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid according to methods and techniques well-known to those skilled in the art to form the salt.

[0026] "Pharmaceutically acceptable basic addition salts" refers to salts that retain the biological effects and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable basic addition salts may be formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0027] As used herein, "hydrate" is a compound that contains a stoichiometric or non-stoichiometric amount of water and, in some embodiments, is formed during a crystallization process using water. Hydrate means including any one of the hydrates of the compounds described herein that have been approved for use by the United States Food and Drug Administration.

[0028] As used herein, the term "acceptable" with respect to a formulation, composition, or component means that it has no persistent adverse effect on the health of the subject being treated.

[0029] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to effect delivery of a compound or composition to a desired site of a biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intracascular, or infusion), topical administration, and rectal administration. In some embodiments, those skilled in the art are proficient in the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0030] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following mammalian classes: humans; non-human primates such as chimpanzees, and other apes as well as monkeys; livestock such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; and experimental animals including rodents such as rats, mice and guinea pigs. In one aspect, the mammal is a human.

[0031] As used herein, "treatment" or "treating" or "alleviating" or "reducing" are used interchangeably herein. Such terms refer to a procedure for obtaining a beneficial or desired result, including, but not limited to, therapeutic utility and / or prophylactic benefit. A "therapeutic effect" means eradication or remission of the underlying disease being treated. Similarly, a therapeutic effect is achieved by eradication or remission of one or more of the physiological symptoms associated with the underlying disease such that improvement in the patient is observed, even though the patient may still be affected by the underlying disease. With respect to a prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease or to a patient reporting one or more of the physiological symptoms of the disease, even in the absence of a diagnosis of the disease.

[0032] <Compositions Containing Four Components (Quadruple Compositions)> (a) An angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; are included, and the dosage of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d). A pharmaceutical composition is disclosed herein. In some embodiments, the dosage of each of (a), (b), (c), and (d) is about 40% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d). In some embodiments, the dosage of each of (a), (b), (c), and (d) is about 50% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d).

[0033] (a) An angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; consisting essentially of, and the dosage of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d). A pharmaceutical composition is further described herein. In some embodiments, the dosage of each of (a), (b), (c), and (d) is about 40% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d). In some embodiments, the dosage of each of (a), (b), (c), and (d) is about 50% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d).

[0034] In some embodiments, the pharmaceutical composition disclosed herein achieves a significant blood pressure reduction in a subject having moderately high blood pressure. In some embodiments, the pharmaceutical composition disclosed herein achieves a significant blood pressure reduction in a subject having moderately high blood pressure with minimal, slight, or no side effects.

[0035] <Lipid-Regulating Agent> In some embodiments, the pharmaceutical compositions disclosed herein essentially do not contain a lipid regulator, a platelet function altering agent, a serum homocysteine reducing agent, or a combination thereof.

[0036] In some embodiments, the pharmaceutical compositions disclosed herein essentially do not contain a lipid regulator. In some embodiments, the lipid regulator is a 3-hydroxy-3-methylglutaryl) coenzyme A (HMG CoA) reductase inhibitor, also known as a statin. In some embodiments, the lipid regulator is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin. In some embodiments, the lipid regulator is atorvastatin or simvastatin. In some embodiments, the lipid regulator is atorvastatin. In some embodiments, the lipid regulator is simvastatin.

[0037] In some embodiments, the pharmaceutical compositions disclosed herein essentially do not contain a platelet function altering agent. In some embodiments, the platelet function altering agent is aspirin, ticlopidine, dipyridamole, or clopidogrel. In some embodiments, the platelet function altering agent is a glycoprotein IIb / IIIa receptor inhibitor such as abciximab. In some embodiments, the platelet function altering agent is a non-steroidal anti-inflammatory drug such as ibuprofen. In some embodiments, the platelet function altering agent is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen. In some embodiments, the platelet function altering agent is aspirin.

[0038] In some embodiments, the pharmaceutical composition disclosed herein essentially does not contain a serum homocysteine-lowering agent. In some embodiments, the serum homocysteine-lowering agent is folic acid, vitamin B6, or vitamin B12, or a combination thereof. In some embodiments, the serum homocysteine-lowering agent is folic acid.

[0039] <Angiotensin II receptor antagonist / blocker> As used herein, an angiotensin II receptor antagonist or blocker (ARB) is a compound that modulates the action of angiotensin II by preventing angiotensin II from binding to angiotensin II receptors on the muscles around blood vessels. In some embodiments, the angiotensin II receptor antagonist is losartan, valsartan, candesartan, eprosartan, irbesartan, telmisartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor antagonist is losartan. In some embodiments, the angiotensin II receptor antagonist is valsartan. In some embodiments, the angiotensin II receptor antagonist is candesartan. In some embodiments, the angiotensin II receptor antagonist is eprosartan. In some embodiments, the angiotensin II receptor antagonist is irbesartan. In some embodiments, the angiotensin II receptor antagonist is telmisartan.

[0040] <Diuretic> As used herein, a diuretic refers to a compound that increases urine flow. Diuretics are classified by chemical structure (thiazide diuretics and thiazide-like diuretics), site of action (loop diuretics, etc.) or pharmacological effect (osmotic diuretics, carbonic anhydrase inhibitors and potassium-sparing diuretics, etc.).

[0041] In some embodiments, the pharmaceutical compositions disclosed herein include thiazide diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include thiazide-like diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include loop diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include osmotic diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include carbonic anhydrase inhibitors. In some embodiments, the pharmaceutical compositions disclosed herein include potassium-sparing diuretics.

[0042] <Thiazide diuretics> As used herein, thiazide diuretics refer to compounds that include a benzothiadiazine molecular structure. In some embodiments, thiazide diuretics inhibit the reabsorption of sodium and chloride in the distal renal tubule, resulting in increased urinary excretion of sodium and water. Examples of thiazide diuretics include, but are not limited to, altiudide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, and trichlormethiazide.

[0043] In some embodiments, the thiazide diuretic is althidone, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichloromethiazide, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is althidone. In some embodiments, the thiazide diuretic is bendroflumethiazide. In some embodiments, the thiazide diuretic is chlorothiazide. In some embodiments, the thiazide diuretic is cyclopenthiazide. In some embodiments, the thiazide diuretic is cyclothiazide. In some embodiments, the thiazide diuretic is epithiazide. In some embodiments, the thiazide diuretic is hydrochlorothiazide. In some embodiments, the thiazide diuretic is hydroflumethiazide. In some embodiments, the thiazide diuretic is mebutizide. In some embodiments, the thiazide diuretic is methyclothiazide. In some embodiments, the thiazide diuretic is polythiazide. In some embodiments, the thiazide diuretic is trichloromethiazide.

[0044] <Thiazide-like diuretics> As used herein, a thiazide-like diuretic is a sulfonamide diuretic that has physiological properties similar to those of thiazide diuretics but does not have the chemical properties of thiazides (i.e., does not have a benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, quinethazone, clopamide, chlorthalidone, mefruside, chlorfenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, and fenquizone. In some embodiments, the thiazide-like diuretics are quinethazone, chloropamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meclofenamic acid, xipamide, indapamide, chlorexolone, fenquizone, or pharmaceutically acceptable salts or hydrates thereof. In some embodiments, the thiazide-like diuretic is quinethazone. In some embodiments, the thiazide-like diuretic is chloropamide. In some embodiments, the thiazide-like diuretic is chlorthalidone. In some embodiments, the thiazide-like diuretic is mefruside. In some embodiments, the thiazide-like diuretic is chlorphenamide. In some embodiments, the thiazide-like diuretic is metolazone. In some embodiments, the thiazide-like diuretic is meclofenamic acid. In some embodiments, the thiazide-like diuretic is xipamide. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide. In some embodiments, the thiazide-like diuretic is chlorexolone. In some embodiments, the thiazide-like diuretic is fenquizone.

[0045] <Loop diuretics> As used herein, a loop diuretic is a compound that acts on the Na+ / K+ / 2Cl− cotransporter in the thick ascending limb of Henle to inhibit the reabsorption of sodium, chloride, and potassium. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, ethoxzolamide, muzolimine, ozolinone, piretanide, tienilic acid, and torsemide. In some embodiments, the loop diuretic is furosemide, bumetanide, ethacrynic acid, ethoxzolamide, muzolimine, ozolinone, piretanide, tienilic acid, torsemide, or pharmaceutically acceptable salts or hydrates thereof.

[0046] <Other diuretics> Osmotic diuretics are compounds that cause water retention in the proximal tubule of Henle and the descending limb of the loop. In some embodiments, osmotic diuretics expand the volume of body fluids and plasma and increase blood flow to the kidneys. Examples include, but are not limited to, mannitol and glycerol.

[0047] <Carbonic anhydrase inhibitors> As used herein, carbonic anhydrase inhibitors are compounds that are inhibitors of carbonic anhydrase. In some embodiments, carbonic anhydrase inhibitors increase the excretion of bicarbonate along with sodium, potassium, and water, resulting in an increased flow of alkaline urine. In some embodiments, carbonic anhydrase inhibitors suppress the transport of bicarbonate from the proximal convoluted tubule to the interstitium, which leads to a decrease in the reabsorbed sodium and results in more loss of sodium, bicarbonate, and water in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorphenamide, and methazolamide.

[0048] <Potassium-sparing diuretics> Potassium-sparing diuretics are compounds that compete with aldosterone for intracellular cytoplasmic receptor sites or directly block sodium channels, particularly epithelial sodium channels (ENaC). Examples of potassium-sparing diuretics include, but are not limited to, amiloride, spironolactone, eplerenone, triamterene, and potassium canrenoate.

[0049] Other diuretics that may be considered for use include, but are not limited to, caffeine, theophylline, theobromine, tolvaptan, conivaptan, dopamine, caffeine, theophylline, theobromine, and pamabrom.

[0050] In some embodiments, the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the diuretic is dichlorphenamide. In some embodiments, the diuretic is amiloride. In some embodiments, the diuretic is pamabrom. In some embodiments, the diuretic is mannitol. In some embodiments, the diuretic is acetazolamide. In some embodiments, the diuretic is methazolamide. In some embodiments, the diuretic is spironolactone. In some embodiments, the diuretic is triamterene.

[0051] <Calcium antagonist> As used herein, a calcium antagonist is a compound that promotes vasodilation by reducing calcium influx into vascular smooth muscle cells. In some embodiments, the calcium antagonist is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotarizine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium antagonist is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium antagonist is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium antagonist is amlodipine besylate. In some embodiments, the calcium antagonist is nifedipine. In some embodiments, the calcium antagonist is diltiazem. In some embodiments, the calcium antagonist is nimodipine. In some embodiments, the calcium antagonist is verapamil. In some embodiments, the calcium antagonist is isradipine. In some embodiments, the calcium antagonist is felodipine. In some embodiments, the calcium antagonist is nicardipine. In some embodiments, the calcium antagonist is nisoldipine. In some embodiments, the calcium antagonist is clevidipine.

[0052] <β-blocker> As used herein, a beta blocker is a compound that inhibits the receptor sites of the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on the adrenergic beta receptors of the sympathetic nervous system. Synonyms include, but are not limited to, beta blocker, beta-adrenergic blocker, beta-antagonist, beta-adrenergic antagonist, beta-adrenergic receptor antagonist, or beta adrenergic receptor antagonist. In some embodiments, the beta blocker inhibits the activation of all types of beta-adrenergic receptors. In some embodiments, the beta blocker inhibits both beta-adrenergic receptors and alpha-adrenergic receptors. In some embodiments, the beta blocker is selective for one of the following beta receptors: beta1, beta2, and beta3 receptors. In some embodiments, the beta blocker is a non-selective beta-adrenergic receptor antagonist. Examples of non-selective beta-adrenergic receptor antagonists include, but are not limited to, pindolol, propranolol, oxprenolol, sotalol, timolol, carteolol, penbutolol, and nadolol. In some embodiments, the beta blocker is a compound having both beta- and alpha-adrenergic receptor blocking effects. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the beta blocker is a beta1-selective adrenergic receptor antagonist. Examples of beta1-selective adrenergic receptor antagonists include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nebivolol, and acebutolol. In some embodiments, the beta blocker is a beta2-selective adrenergic receptor antagonist such as butaxamine.

[0053] In some embodiments, the β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, mecipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tertatolol, alocinolol, levobetaxolol, befunolol, amosulalol, tilisolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the β-blocker is atenolol. In some embodiments, the β-blocker is bisoprolol or a pharmaceutically acceptable salt thereof. In some embodiments, the β-blocker is bisoprolol fumarate.

[0054] <Lowest Hypertension Therapeutic Dose> As used herein, the lowest hypertensive treatment dose (LHTD) refers to the lowest strength dose of a single agent for hypertension approved by the U.S. Food and Drug Administration and marked as "discontinued" by the Orange Book database (http: / / www.accessdata.fda.gov / scripts / cder / ob / ). The lowest hypertensive treatment dose does not include the lowest manufacturing dose if the lowest hypertensive treatment dose is not the same as the lowest manufacturing dose. Further, the lowest hypertensive treatment dose does not include the dose recommended by a physician for cases where the lowest hypertensive treatment dose is not the same as that recommended by the physician. Further, the lowest hypertensive treatment dose of an angiotensin II receptor antagonist, diuretic, calcium antagonist, or β-blocker described herein refers to the dose in the form used by the U.S. Food and Drug Administration, including the free base, pharmaceutically acceptable salt, or hydrate of the angiotensin II receptor antagonist, diuretic, calcium antagonist, or β-blocker.

[0055] In some embodiments, the dosage of the angiotensin II receptor antagonist is about 20% to about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 20% to about 50% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 20% to about 40% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 20% to about 30% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor is about 30% to about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor is about 30% to about 50% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 30% to about 40% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 40% to about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 40% to about 50% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 45% to about 55% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin II receptor antagonist is about 50% to about 60% of the minimum antihypertensive treatment dosage.

[0056] In some embodiments, the dose of the angiotensin II receptor antagonist is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the angiotensin II receptor antagonist is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the angiotensin II receptor antagonist is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the angiotensin II receptor antagonist is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the angiotensin II receptor antagonist is about 25% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the angiotensin II receptor antagonist is about 50% of the minimum antihypertensive treatment dose.

[0057] In some embodiments, the dosage of the diuretic is from about 20% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 20% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 20% to about 40% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 20% to about 30% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 30% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 30% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 30% to about 40% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 40% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 40% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 45% to about 55% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the diuretic is from about 50% to about 60% of the minimum hypertensive treatment dosage.

[0058] In some embodiments, the dosage of the diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the diuretic is about 25% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the diuretic is about 50% of the minimum antihypertensive treatment dosage.

[0059] In some embodiments, the dose of the thiazide diuretic is from about 20% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 20% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 20% to about 40% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 20% to about 30% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 30% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 30% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 30% to about 40% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 40% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 40% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 45% to about 55% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 50% to about 60% of the minimum hypertensive treatment dose.

[0060] In some embodiments, the dose of the thiazide diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is about 25% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is about 50% of the minimum hypertensive treatment dose.

[0061] In some embodiments, the dose of the thiazide-like diuretic is from about 20% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 20% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 20% to about 40% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 20% to about 30% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 30% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 30% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 30% to about 40% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide diuretic is from about 40% to about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 40% to about 50% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 45% to about 55% of the minimum hypertensive treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 50% to about 60% of the minimum hypertensive treatment dose.

[0062] In some embodiments, the dosage of the thiazide-like diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the thiazide-like diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the thiazide-like diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the thiazide-like diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the thiazide-like diuretic is about 25% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the thiazide-like diuretic is about 50% of the minimum hypertensive treatment dosage.

[0063] In some embodiments, the dose of the loop diuretic is from about 20% to about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 20% to about 50% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 20% to about 40% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 20% to about 30% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 30% to about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 30% to about 50% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 30% to about 40% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 40% to about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 40% to about 50% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 45% to about 55% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the loop diuretic is from about 50% to about 60% of the minimum antihypertensive treatment dose.

[0064] In some embodiments, the dose of the loop diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the loop diuretic is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum hypertensive treatment dose. In some embodiments, the dose of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dose. In some embodiments, the dose of the loop diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertensive treatment dose. In some embodiments, the dose of the loop diuretic is about 25% of the minimum hypertensive treatment dose. In some embodiments, the dose of the loop diuretic is about 50% of the minimum hypertensive treatment dose.

[0065] In some embodiments, the dosage of the calcium antagonist is from about 20% to about 60% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 20% to about 50% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 20% to about 40% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 20% to about 30% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 30% to about 60% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 30% to about 50% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 30% to about 40% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 40% to about 60% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 40% to about 50% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 45% to about 55% of the minimum hypertension treatment dosage. In some embodiments, the dosage of the calcium antagonist is from about 50% to about 60% of the minimum hypertension treatment dosage.

[0066] In some embodiments, the dosage of the calcium antagonist is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the calcium antagonist is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the calcium antagonist is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the calcium antagonist is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the calcium antagonist is about 25% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the calcium antagonist is about 50% of the minimum hypertensive treatment dosage.

[0067] In some embodiments, the dosage of the β-blocker is from about 20% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 20% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 20% to about 40% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 20% to about 30% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 30% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 30% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 30% to about 40% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 40% to about 60% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 40% to about 50% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 45% to about 55% of the minimum hypertensive treatment dosage. In some embodiments, the dosage of the β-blocker is from about 50% to about 60% of the minimum hypertensive treatment dosage.

[0068] In some embodiments, the dose of the β-blocker is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the β-blocker is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the β-blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the β-blocker is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the β-blocker is about 25% of the minimum antihypertensive treatment dose. In some embodiments, the dose of the β-blocker is about 50% of the minimum antihypertensive treatment dose.

[0069] In some embodiments, the minimum antihypertensive treatment dose (LHTD) and the corresponding proposed doses and proposed dose ranges for the following compounds are as set forth in the following table.

[0070] [Table 1]

[0071] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor antagonist; (b) hydrochlorothiazide as a thiazide diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) atenolol as a β-blocker. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. In some embodiments, the dosage of irbesartan is about 37.5 mg, the dosage of hydrochlorothiazide is about 6.25 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg.

[0072] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor antagonist; (b) hydrochlorothiazide as a thiazide diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) atenolol as a β-blocker. In some embodiments, the dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of hydrochlorothiazide is about 6.25 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg.

[0073] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor antagonist; (b) indapamide as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) bisoprolol fumarate as a β-blocker. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of indapamide is from about 0.5 mg to about 0.75 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. In some embodiments, the dosage of irbesartan is about 37.5 mg, the dosage of indapamide is about 0.625 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg.

[0074] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor antagonist; (b) indapamide as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) bisoprolol fumarate as a β-blocker. In some embodiments, the dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of indapamide is from about 0.5 mg to about 0.75 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of indapamide is about 0.625 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg.

[0075] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor antagonist; (b) chlorthalidone as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) bisoprolol fumarate as a β-blocker. In some embodiments, the dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg.

[0076] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor antagonist; (b) chlorthalidone as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) atenolol as a β-blocker. In some embodiments, the dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg.

[0077] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor antagonist; (b) chlorthalidone as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) bisoprolol fumarate as a β-blocker. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. In some embodiments, the dosage of irbesartan is about 37.5 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg.

[0078] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor antagonist; (b) chlorthalidone as a thiazide-like diuretic; (c) amlodipine besylate as a calcium antagonist; and (d) atenolol as a β-blocker. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 10 mg. In some embodiments, the dosage of irbesartan is about 37.5 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg.

[0079] Further provided herein is a pharmaceutical composition comprising: (a) irbesartan; (b) hydrochlorothiazide; (c) amlodipine besylate; and (d) atenolol, wherein the dosage of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dose (LHTD) of each of (a), (b), (c), and (d).

[0080] In some embodiments, the dosages of (a), (b), (c), and (d) are each about 40% to about 60% of the lowest hypertensive treatment dosage (LHTD) of (a), (b), (c), and (d) respectively. In some embodiments, the pharmaceutical composition essentially does not contain a lipid regulator, a platelet function modifier, a serum homocysteine reducing agent, or a combination thereof. In some embodiments, the dosage of hydrochlorothiazide is about 50% of the lowest hypertensive treatment dosage (LHTD) of hydrochlorothiazide. In some embodiments, the dosage of hydrochlorothiazide is about 6.25 mg. In some embodiments, the dosage of amlodipine besylate is about 50% of the lowest hypertensive treatment dosage (LHTD) of amlodipine besylate. In some embodiments, the dosage of amlodipine besylate is about 1.25 mg. In some embodiments, the dosage of atenolol is about 50% of the lowest hypertensive treatment dosage (LHTD) of atenolol. In some embodiments, the dosage of atenolol is about 12.5 mg. In some embodiments, the dosage of irbesartan is about 50% of the lowest hypertensive treatment dosage (LHTD) of irbesartan. In some embodiments, the dosage of irbesartan is about 37.5 mg. In some embodiments, the dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. In some embodiments, (a), (b), (c) and (d) are provided in one formulation. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0081] <Formulation> In some embodiments, an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker are provided in one formulation. In some embodiments, each of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker is provided in a separate formulation. In some embodiments, two of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker are provided in one formulation. In some embodiments, the angiotensin II receptor and the diuretic are provided in one formulation. In some embodiments, the angiotensin II receptor antagonist and the calcium antagonist are provided in one formulation. In some embodiments, the angiotensin II receptor antagonist and the β-blocker are provided in one formulation. In some embodiments, the diuretic and the calcium antagonist are provided in one formulation. In some embodiments, the diuretic and the β-blocker are provided in one formulation. In some embodiments, the calcium antagonist and the β-blocker are provided in one formulation. In some embodiments, three of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker are provided in one formulation. In some embodiments, the angiotensin II receptor antagonist, the diuretic, and the calcium antagonist are provided in one formulation. In some embodiments, the diuretic, the calcium antagonist, and the β-blocker are provided in one formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, a tablet, or a capsule. In some embodiments, the pharmaceutical composition is in the form of a pill. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0082] Other suitable formulations include, but are not limited to, those suitable for rectal, topical, oral, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, intravaginal, or aerosol administration. However, the most suitable form of administration for any given case depends on the degree and severity of the disease being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as unit dosages.

[0083] Typical pharmaceutical compositions may be used in the form of pharmaceutical preparations, e.g., in solid, semi-solid, or liquid form, which are admixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use and contain one or more of the compounds disclosed as active ingredients. The active ingredient may be compounded, for example, with a normally non-toxic, pharmaceutically acceptable carrier in the form of tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. The active subject compound is included in a pharmaceutical composition in an amount sufficient to produce the desired effect against the disease process or condition.

[0084] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules since the active ingredient is uniformly dispersed therein.

[0085] For solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition is one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or is mixed with any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution relaxants such as paraffin; (6) absorption promoting substances such as quaternary ammonium compounds; (7) wetting agents such as, for example, acetyl alcohol or glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the composition may also contain a buffering agent. Excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol can also be used as fillers for soft and hard gelatin capsules for the same kind of solid composition.

[0086] Tablets may optionally be made by compression or molding, together with one or more accessory ingredients. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross - linked sodium carboxymethylcellulose), or a surfactant or dispersing agent. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent using a suitable machine. In some embodiments, capsules are prepared by encapsulation of tablets in hard capsules (e.g., overencapsulation). Other solid dosage forms such as tablets, dragees, capsules, pills, and granules may optionally be scored or prepared using coatings or shells such as enteric coatings or other coatings well - known in the art of pharmaceutical formulation.

[0087] In some embodiments, the angiotensin II receptor antagonist of the pharmaceutical composition described herein can be replaced with an angiotensin-converting enzyme inhibitor (ACE inhibitor). Examples of suitable angiotensin-converting enzyme inhibitors include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or pharmaceutically acceptable salts or hydrates thereof. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is from about 20% to about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is from about 40% to about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is from about 45% to about 55% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum antihypertensive treatment dosage. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 50% of the minimum antihypertensive treatment dosage.

[0088] <Treatment method> The pharmaceutical composition described herein is useful for treating hypertension in a subject in need thereof. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 135 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) from about 10 mmHg to about 20 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) from about 10 mmHg to about 30 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, or about 20 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 85 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) from about 5 mmHg to about 10 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) from about 5 mmHg to about 15 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, or about 10 mmHg.In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, or about 15 mmHg.

[0089] In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full minimum antihypertensive treatment dose of any one of an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker in a pharmaceutical composition. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full minimum antihypertensive treatment dose of an angiotensin II receptor antagonist in a pharmaceutical composition. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full minimum antihypertensive treatment dose of a diuretic in a pharmaceutical composition. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full minimum antihypertensive treatment dose of a calcium antagonist in a pharmaceutical composition. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full minimum antihypertensive treatment dose of a β-blocker in a pharmaceutical composition.

[0090] In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of any one of the angiotensin II receptor antagonist, diuretic, calcium antagonist, and β-blocker in the pharmaceutical composition. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of the angiotensin II receptor antagonist in the pharmaceutical composition. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of the calcium antagonist in the pharmaceutical composition. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of the β-blocker in the pharmaceutical composition.

[0091] In some embodiments, when compared to treatment with the full minimum antihypertensive treatment dose of any one of the angiotensin II receptor antagonist, diuretic, calcium antagonist, and β-blocker in the pharmaceutical composition, the treatment enhances longer-term tolerance and reduces the risk of side effects. In some embodiments, when compared to treatment with the full minimum antihypertensive treatment dose of the angiotensin II receptor antagonist in the pharmaceutical composition, the treatment enhances longer-term tolerance and reduces the risk of side effects. In some embodiments, when compared to treatment with the full minimum antihypertensive treatment dose of the diuretic or calcium antagonist in the pharmaceutical composition, the treatment enhances longer-term tolerance and reduces the risk of side effects. In some embodiments, when compared to treatment with the full minimum antihypertensive treatment dose of the calcium antagonist in the pharmaceutical composition, the treatment enhances longer-term tolerance and reduces the risk of side effects. In some embodiments, when compared to treatment with the full minimum antihypertensive treatment dose of the β-blocker in the pharmaceutical composition, the treatment enhances longer-term tolerance and reduces the risk of side effects.

[0092] In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP), which is greater than the decrease obtained with any combination of two of an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker in the pharmaceutical composition, and the dose of each of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker is about 50% of the minimum hypertension treatment dose. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with any combination of two of an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker in the pharmaceutical composition, and the dose of each of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker is about 50% of the minimum hypertension treatment dose. In some embodiments, when compared to treatment with any combination of two of an angiotensin II receptor antagonist, a diuretic, a calcium antagonist, and a β-blocker in the pharmaceutical composition, the treatment enhances long-term tolerance, reduces the risk of side effects, and the dose of each of the angiotensin II receptor antagonist, the diuretic, the calcium antagonist, and the β-blocker is about 50% of the minimum hypertension treatment dose.

[0093] In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject exhibits a very mild blood pressure elevation prior to treatment. In some embodiments, the subject has not received previous hypertension treatment prior to treatment. In some embodiments, the subject exhibits a very mild blood pressure elevation prior to treatment and has not received previous hypertension treatment prior to treatment.

[0094] In some embodiments, the present disclosure recognizes that the use of an angiotensin II receptor antagonist in the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects including, but not limited to, a significant decrease in blood pressure, a significant decrease in blood pressure in subjects with a gradual increase in blood pressure, longer-term tolerance, and a reduced risk of side effects. In some embodiments, the present disclosure recognizes that the elimination of a lipid regulator, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof in the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects including, but not limited to, a significant decrease in blood pressure, a significant decrease in blood pressure in subjects with a gradual increase in blood pressure, longer-term tolerance, and a reduced risk of side effects.

[0095] In further embodiments, the present disclosure recognizes that a greater number of subjects taking any one of the four-component combination compositions described herein achieve a target blood pressure (<140 / 90 mmHg) than subjects using a four-component combination having an ACE inhibitor instead of an angiotensin II receptor antagonist. In some examples, 100% of the subjects taking any one of the four-component combination compositions described herein that feature an angiotensin II receptor antagonist achieve a target blood pressure (<140 / 90 mmHg). In some examples, 100% of the subjects taking any one of the four-component combination compositions described herein, such as a composition comprising an angiotensin II receptor antagonist; a diuretic (e.g., a thiazide diuretic); a calcium antagonist; and a β-blocker, achieve a target blood pressure (<140 / 90 mmHg). In some examples, 100% of the subjects taking any one of the four-component combination compositions described herein, such as a composition comprising irbesartan; hydrochlorothiazide; amlodipine besylate; and atenolol, achieve a target blood pressure (<140 / 90 mmHg).

Example

[0096] <Example 1> Four-Component Combination Composition Therapy (Quadpill) for the Treatment of Hypertension

[0097] <Method> The Quadpill trial was a randomized placebo-controlled double-blind crossover trial. The trial was divided into three stages (Figure 1). During the first stage (4 weeks), participants were randomized (1:1) to receive either Quadpill or placebo. This was followed by a 2-week washout (placebo), after which participants were crossed over to the other arm and received the other treatment for 4 weeks (Figure 1). Participants were recruited from the community, mainly through general practices in western Sydney, Australia.

[0098] <Participants> Participants were eligible if they met the following selection criteria: 1) Adults aged 18 years or older; 2) Office SBP > 140 mmHg and / or DBP > 90 mmHg on two readings on different days; Plus baseline ambulatory SBP > 135 and / or DBP > 85; 3) Not receiving treatment for hypertension. Exclusion criteria: No definite contraindication to one or more of the component therapies in Quadpill; The attending clinician felt that the patient would be put at risk by a change in current therapy; Severe or accelerated hypertension; Pregnancy; Unable to provide informed consent; and Medical conditions with an expected life expectancy of less than 3 months.

[0099] <Intervention> Quadpill was a single capsule containing the following four components in specified amounts: irbesartan (37.5 mg), amlodipine besylate (1.25 mg), hydrochlorothiazide (6.25 mg), and atenolol (12.5 mg). The placebo capsule appeared identical and contained four placebo tablets of the same weight as those in Quadpill.

[0100] Through the trial, participants were administered a single pill, Quadpill or placebo. Patients were instructed to take the tablets at the same time each day and were encouraged to take them in the morning, although the time of day (morning or evening) was at the patient's preference.

[0101] All investigational drugs were prepared by a manufacturing facility approved under TGA-cGMP (Therapeutic Goods Australia-certificate of Good Manufacturing Practice). The low-strength dosage was obtained by splitting the half-strength dosage in half using a pill-splitting device without crushing, and was weighed to ensure accuracy of half the dosage. The low-strength dosage was then encapsulated using gelatin capsules (DBCaps-Capsugel). The capsules were stored in a cool, dry place and monitored using a temperature logger until they were dispensed.

[0102] Treatment allocation was blinded to both the trial staff and the participants. In addition to the investigational drugs, all participants were provided with education on healthy lifestyle options as recommended by guidelines for hypertension management.

[0103] <Randomization> A computer-assisted randomization sequence was generated by a statistician and supplied to a pharmaceutical packaging company. The research assistant, recruitment team, and researchers were not informed of this sequence. For each patient, i.e., assigned randomization number, the pills were packaged in three child-resistant packs corresponding to the third stage of the trial. All packs had the same appearance, ensuring blinding of the patients and the research staff. The drug packs were then dispensed in the sorted order.

[0104] <Results and data collection> The primary outcome was the reduction in mean 24-hour systolic pressure over four weeks using ambulatory blood pressure monitoring (ABP). Secondary outcomes included the following: a. Average 24-hour extended blood pressure and reduction of SBP and DBP during the day and at night over 4 weeks b. Reduction of outpatient SBP and DBP measured by a standardized automated blood pressure cuff c. Proportion of controlled blood pressure over 4 weeks defined as <135 / 85 mmHg 24-hour blood pressure and <140 / 90 mmHg outpatient blood pressure d. Adverse events by test parameters and pre-specified adverse events: When the baseline level is known to be elevated, the upper limit of transaminase (ALT / AST) increases by more than 3 times or more than 2 times the normal; when estimated from serum creatinine, the estimated glomerular filtration rate decreases by >20%; sodium, potassium, and uric acid levels e. Evaluation of acceptability and tolerance

[0105] Patients underwent 24-hour ABP monitoring 4 times - at baseline (without study drug), 4 weeks (first-stage drug), 6 weeks (placebo), and 10 weeks (third-stage drug). To minimize inconvenience, patients were referred to the laboratory for ABP. The ABP unit was regularly calibrated by the laboratory according to the manufacturer's specifications. To minimize variability, readings for follow-up were repeated from the same collection center using the same brand of device. Participants were reimbursed the face value to cover transportation and parking costs. The study drug and investigations were provided to participants free of charge. Outpatient blood pressure was recorded 3 times at each visit using an OMRON T9P (HEM-759-C1). The second and third readings were averaged for study analysis. Additionally, blood tests were performed at weeks 4 and 10 to evaluate biochemical side effects, questionnaires were conducted for clinical side effects, and compliance was evaluated by self-report and pill count. When completing this questionnaire, patients remained blinded to treatment assignment.

[0106] The acceptability and tolerance of the drug were also evaluated at the end of the trial. All adverse events were recorded. Additionally, clinical adverse events possibly related to the blood pressure lowering drug: dizziness, blurred vision, syncope / fainting, chest pain / angina, shortness of breath, cough, wheezing, pedal edema, skin rash, and itching were specifically questioned.

[0107] In this trial, a Simplified Data Safety and Monitoring Committee consisting of two core members with expertise in clinical medicine, trials, and statistics was established. A single meeting was called when 10 patients were randomly assigned to the trial to review safety, and the study was advised to continue.

[0108] <Statistical Considerations> A sample size of 50 patients was planned to provide 90% power at p = 0.05 to detect a 12 mmHg SBP difference between intervention and control, assuming an SD of the within-patient difference of 12 mmHg, considering a 10% possibility of loss to follow-up. The trial ended in one year at the end of the budget, staff allocation time was assigned, and the original sample size was not reached.

[0109] <Statistical Approach> The analysis was conducted with the intention of dealing with the basis. All trials were two-sided, and the nominal level of α was 5%. All statistical analyses were not adjusted for prognostic covariates. The trialists reported compliance with the investigational drug using data on the pills (doses) taken and missed doses during the period.

[0110] Following the approach of Kenward and Roger, a linear mixed model was used to estimate the treatment effect on the change in blood pressure from baseline for each treatment period (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010; 11(1): 1-17.). To appropriately adjust for the baseline levels collected at the start of each treatment period (week 0, week 6), this method uses all measurements (baseline and follow-up, both periods) as outcomes, taking into account the covariance between measurements within an individual (Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analyses of change from baseline in clinical trials? Stat Med 2009; 28(20): 2509-30). Linear contrasts between variables representing period (period 1 / period 2), type of measurement (baseline / final), and treatment received (placebo / Quadpill) produce an unbiased estimate of the effect of Quadpill on the change in blood pressure compared to placebo. Since all available data were included in the model, missing data were not included. If a patient missed data during a period, the data from the available period were used. To check if the treatment effect had changed, a sensitivity analysis was performed including only patients with data from both periods. There was also an adjustment of the denominator degrees of freedom of Kenward and Roger (2009) optimal for small sample sizes (Kenward MG, Roger JH. An improved approximation to the precision of fixed effects from restricted maximum likelihood. Computational Statistics & Data Analysis 2009; 53(7): 2583-95).

[0111] For the carry-over test, a non-paired t-test of the main ordered results was used as the effect. The period effect was tested by using a paired t-test comparing the main results in period 1 and the main results in period 2 from the same patients. Sensitivity analysis was also performed using the ordinary paired t-test to compare the main results between different periods (different treatments) from the same patients, ignoring the baseline level of each patient.

[0112] Continuous secondary evaluation items with baseline values (e.g., daytime / nighttime outpatient SBP / DBP) were analyzed in the same way as the main evaluation items. Other continuous variables without baseline values in each period were analyzed with a paired t-test. The number and percentage of all adverse events were reported. As sensitivity analysis, the analysis was repeated for the data of 18 complete cases (i.e., complete data for each measurement period), and showed findings similar to those reported here.

[0113] Test for the interaction of treatment effect with age (<=60 years vs. >60 years), gender, and BMI (<=30 vs. >30 kg / m2). Subgroup analysis was also performed for each variable. All analyses were performed using SAS 9.4 (Cary, NC, USA) on software.

[0114] <Results> Of the 55 screened patients, 21 participants were eligible and 1 patient withdrew before drug initiation. Twenty patients were randomized between November 2014 and December 2015, and 2 withdrew at the end of the first treatment period for social reasons (Figure 2). The baseline characteristics of the study population are shown in Table 1.

[0115]

Table 2

[0116] The difference in mean 24-hour SBP between the Quadpill period and the placebo period was -18.7 mmHg, 95% CI -23.0; -14.3. (Table 2) The placebo-corrected decrease in mean 24-hour SBP / DBP was 22 / 15 mmHg during the day and 10 / 12 mmHg overnight. Office SBP decreased by 22.4 mmHg, 95% CI 16.5 - 28.3, and DBP decreased by 13.1 mmHg, 95% CI 8.8 - 17.3. Overall, 15 / 18 (83%) of the participants achieved mean ambulatory SBP < 135 and DBP < 85 mmHg when taking Quadpill, compared with 7 / 18 (39%) when taking placebo (p = 0.0053). All participants achieved office SBP < 140 and DBP < 90 mmHg on Quadpill compared with 6 / 18 (33%) in the placebo group (p = 0.0013). (Table 3) Mean heart rate was lower with Quadpill treatment (between-group difference of -6.5 beats per minute (-10.6, -2.3).

[0117]

Table 3

[0118]

Table 4

[0119] Neither the carry-over effect (t = -0.17, p = 0.868) nor the period effect (t = -1.05, p = 0.308) was significant. There was no significant interaction by age, sex, or BMI. In sensitivity analyses using standard comparisons (paired t-tests), the results were substantially the same as the difference in mean 24-hour SBP between the Quadpill period and the placebo period of -18.7 mmHg, 95% CI -23.1; -14.2. Similarly, in a second sensitivity analysis including only patients with complete data (n = 18) from both periods, the results were substantially the same as the difference in mean 24-hour SBP of -18.7, 95% CI -23.2; -14.2.

[0120] Compliance with treatment was high. The mean number of tablets missed last week was 0.2 (SD 0.4) with Quadpill and 0.3 (SD 0.6) with placebo. All 18 participants who completed the trial answered the end-of-trial acceptability questionnaire, and all found it very easy (n = 13) or easy (n = 5) to swallow the study drug. Furthermore, all 18 participants reported that they would be very likely (n = 10) or likely (n = 8) to take Quadpill if it were commercially available.

[0121] There were no serious adverse events. One patient reported dizziness during Quadpill, causing temporary treatment discontinuation. One patient complained of vestibular dizziness during the placebo washout period. One patient reported frequency of micturition with both Quadpill and placebo phases (Table 4). Mean creatinine levels were higher at the end of Quadpill than during the placebo treatment period: creatinine 78 mmol / L (SD 14) vs 71 (SD 14), p = 0.02; similarly for urate levels: 0.4 (0.1) vs 0.3 (0.1), p = 0.003. (Table 5) The absolute changes in creatinine (4.4, 95% CI 0.9 - 7.8) and urate (0.03, 95% CI 0.001 - 0.04) were small (no patient had an increase of more than 12% for either variable) and appeared reversible (e.g., for those who received Quadpill first, mean creatinine was x, y, and z at baseline, 4 weeks, and 10 weeks respectively). There were no significant differences in ALT, AST, sodium, potassium, total cholesterol, or LDL cholesterol.

[0122]

Table 5

[0123]

Table 6

[0124] <Discussion> In this trial, it was found that Quadpill, which contains four blood pressure-lowering components, reduced the 24-hour ambulatory SBP by 18 mmHg and achieved office blood pressure <140 / 90 mmHg in 100% of the participants. This trial demonstrates some of the potential benefits of an approach that uses multiple drugs at very low doses to achieve efficacy.

[0125] In this trial, a small but statistically significant increase in creatinine and urate was observed, and no patient experienced an increase of more than 12%. Since creatinine is affected not only by renal function but also by perfusion of the kidneys, especially the glomeruli, which can be reduced reversibly either systemically or locally, the increase in creatinine may not be clinically important. Both approaches reduce the risk of renal failure in people with increased glomerular pressure (manifesting clinically as proteinuria), despite the reversible increase in creatinine levels. Therefore, the creatinine effect of blood pressure lowering is expected and may not suggest long-term kidney damage, and may lead to kidney benefits for participants with high glomerular pressure and proteinuria. Placebo-controlled data were first published showing that ultra-low-dose combination therapy can be very effective in lowering blood pressure even in patients with very mild hypertension who have never been treated before. This justifies further studies on long-term efficacy and safety, both for initial treatment and among patients who have inadequate control and / or side effects while on monotherapy.

[0126] <Example 2> Comparative trial of a four-component combination therapy for hypertension and standard-dose monotherapy

[0127] The primary objective of this trial is to investigate, in a double-blind randomized controlled trial, whether starting treatment of hypertension with a four-component combination therapy is more effective and has fewer side effects compared to starting standard-dose monotherapy according to current guidelines. The second objective is to evaluate whether this approach is safe and has fewer side effects compared to standard treatment.

[0128] <Study Design> This is a 12-week double-blind randomized comparative trial (1:1) involving 650 patients with grade 1 and 2 essential hypertension. Subjects are randomized to initial treatment with a 4-component combination composition or an angiotensin receptor blocker (ARB) using a central computer-based randomization service with the option of adding a calcium channel blocker (CCB) as needed according to current Australian hypertension guidelines. The primary outcome is the reduction in mean systolic blood pressure using an automated BP cuff standardized at 12 weeks. Secondary outcomes include: controlled blood pressure at 6 and 12 weeks, measurements of ambulatory blood pressure (ABP), and the ratio of tolerability / occurrence of adverse events.

[0129] <Eligibility Criteria> The inclusion criteria are as follows: - Adults (≥18 years old) - Naïve, or not currently receiving treatment (not taken within the past 4 weeks), or taking one blood pressure lowering medication (angiotensin-converting enzyme inhibitor, angiotensin receptor antagonist, calcium channel blocker, β-blocker, aldosterone antagonist, α-blocker) - SBP 140 - 179 mmHg or DBP 90 - 109 mmHg, or both recorded on two occasions more than 1 week apart - At least one of the measurements should be documented by study staff using a study automated BP device or recorded as mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg during the day in 24-hour ambulatory blood pressure monitoring - At least one of these measures should be recent (past 12 weeks) - mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg in 24-hour ambulatory blood pressure monitoring during the day should be documented within 12 weeks after randomization

[0130] The exclusion criteria are as follows: - Contraindications to irbesartan, amlodipine, indapamide or bisoprolol - Evidence of predisposing factors for hypertension (e.g., renal artery stenosis); marked renal impairment (eGFR < 50), elevated serum potassium levels (above laboratory normal limits) - Women who are pregnant, breastfeeding, and / or of childbearing potential and not using a medically acceptable method of contraception (pharmacological or barrier methods) throughout the study - Concurrent illnesses, physical disabilities, or mental states that, in the opinion of the study team / primary care physician, may interfere with the conduct of the study, including outcome assessment - Participation in concurrent interventional medical research or clinical trials. Patients in observational, natural history, and / or epidemiological studies without interventions are eligible - Participants who, in the opinion of the primary care or other responsible physician, are not suitable for switching from their current monotherapy - Inability or unwillingness to provide written informed consent - Inability to complete study procedures, including 24-hour ambulatory BP - Clear indication for combination therapy

[0131] <Study Treatment> Patients meeting the inclusion criteria are randomly assigned to one of the following: a combination tablet containing the following 4 components - irbesartan (37.5 mg), amlodipine besylate (1.25 mg), indapamide (0.625 mg), bisoprolol fumarate (2.5 mg); or 2) irbesartan (150 mg).

[0132] Patients currently on monotherapy are requested to discontinue their treatment during the study treatment. If BP is greater than 140 / 90 mmHg in either group, amlodipine besylate (5 mg) will be added by the study staff at 6 weeks

[0133] <Results> The primary outcome would be the between-group difference in mean automated office systolic blood pressure over 12 weeks adjusted for baseline values.

[0134] The second outcome would include the following: - 24-hour ambulatory blood pressure monitoring a. Between-group differences in mean 24-hour SBP and DBP at 12 weeks b. Between-group differences in mean change in 24-hour SBP and DBP from 0 to 12 weeks c. Between-group differences in mean daytime SBP and DBP over 12 weeks and between-group differences in mean nighttime SBP and DBP over 12 weeks d. Between-group differences in daytime, nighttime, and 24-hour blood pressure load (area under the blood pressure curve ratio above weekday, nighttime, and 24-hour values according to the 2008 hypertension management guidelines) e. Between-group differences in the proportion of non-dippers (nighttime blood pressure is 10% or less lower than mean daytime blood pressure for hypertension management in 2008) and coefficient of variation of blood pressure (O’Brien, E., G. Parati, and G. Stergiou, Hypertension, 2013. 62(6): p. 988-94). - Other blood pressure measurements in the four-component combination group versus control group: a. Change in mean diastolic blood pressure from baseline to 12 weeks b. Hypertension management at 6 and 12 weeks (% of cases where SBP < 140 mmHg and DBP < 90 mmHg) c. Proportion requiring step-up treatment at 6 weeks d. Proportion of both blood pressure control (as defined above) and no adverse events e. Between-group differences in variability of SBP and DBP - Tolerability a. Between-group differences in potentially related side effects (potentially related side effects (dizziness, blurred vision / fainting, chest pain / angina, shortness of breath, cough, wheezing, ankle swelling, skin rash, itching, gout, hyperkalemia, hypokalemia, hyponatremia, others)) b. Differences among groups in mean potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UACR (urinary albumin-to-creatinine ratio), and creatinine levels c. Differences among groups in participant withdrawal from treatment

[0135] <Statistical methods> All analyses of the trial results are conducted in accordance with the principles of the trial intent. The primary analysis of the change in systolic blood pressure (SBP) at 12 weeks is performed using analysis of covariance (ANCOVA) that includes treatment arm and baseline SBP as covariates. The continuous secondary outcomes are analyzed similarly. The additional analysis includes both 6-week and 12-week measurements in a long-term model that includes treatment by treatment group, visit, and visit interaction, as well as baseline measurements. The within-patient correlation is modeled using generalized estimating equations. A similar approach is applied to secondary endpoints (such as hypertension control) using log-binomial regression instead of linear regression. There are also pre-defined subgroup analyses, such as by baseline blood pressure, gender, age, and hypertension treatment history. A detailed analysis plan is created before unblinding.

[0136] <Example 3> <Pharmaceutical composition> The following pharmaceutical compositions are prepared with specific ingredients and dosages as shown in the following table.

[0137]

Table 7

[0138] <Embodiment> Embodiment 1: (a) An angiotensin II receptor antagonist; (b) A diuretic; (c) A calcium antagonist; and (d) A β-blocker; wherein the dosages of (a), (b), (c), and (d) are each about 20% to about 60% of the lowest hypertension treatment dose (LHTD) of (a), (b), (c), and (d), respectively, a pharmaceutical composition.

[0139] Embodiment 2: The pharmaceutical composition according to Embodiment 1, wherein the dosages of (a), (b), (c), and (d) are each about 40% to about 60% of the lowest hypertension treatment dosage (LHTD) of (a), (b), (c), and (d) respectively.

[0140] Embodiment 3: The pharmaceutical composition according to Embodiment 1 or 2, wherein the pharmaceutical composition essentially does not contain a lipid regulator, a platelet function modifier, a serum homocysteine lowering agent, or a combination thereof.

[0141] Embodiment 4: The pharmaceutical composition according to Embodiment 3, wherein the pharmaceutical composition essentially does not contain a lipid regulator.

[0142] Embodiment 5: The pharmaceutical composition according to Embodiment 4, wherein the lipid regulator is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin.

[0143] Embodiment 6: The pharmaceutical composition according to Embodiment 4 or 5, wherein the lipid regulator is atorvastatin or simvastatin.

[0144] Embodiment 7: The pharmaceutical composition according to Embodiment 3, wherein the pharmaceutical composition essentially does not contain a platelet function modifier.

[0145] Embodiment 8: The pharmaceutical composition according to Embodiment 7, wherein the platelet function modifier is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen.

[0146] Embodiment 9: The pharmaceutical composition according to Embodiment 7 or 8, wherein the platelet function modifier is aspirin.

[0147] Embodiment 10: The pharmaceutical composition according to Embodiment 10, wherein the pharmaceutical composition essentially does not contain a serum homocysteine lowering agent.

[0148] Embodiment 11: The pharmaceutical composition according to Embodiment 10, wherein the serum homocysteine - lowering agent is folic acid, vitamin B6, or vitamin B12, or a combination thereof.

[0149] Embodiment 12: The pharmaceutical composition according to Embodiment 10 or 11, wherein the serum homocysteine - lowering agent is folic acid.

[0150] Embodiment 13: The pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the diuretic is a thiazide diuretic.

[0151] Embodiment 14: The pharmaceutical composition according to Embodiment 13, wherein the dose of the thiazide diuretic is about 50% of the lowest hypertensive treatment dose (LHTD) of the thiazide diuretic.

[0152] Embodiment 15: The pharmaceutical composition according to Embodiment 13 or 14, wherein the thiazide diuretic is alticide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof.

[0153] Embodiment 16: The pharmaceutical composition according to any one of Embodiments 13 to 15, wherein the thiazide diuretic is hydrochlorothiazide.

[0154] Embodiment 17: The pharmaceutical composition according to Embodiment 16, wherein the dose of hydrochlorothiazide is about 6.25 mg.

[0155] Embodiment 18: The pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the diuretic is a thiazide - like diuretic.

[0156] Embodiment 19: The pharmaceutical composition according to Embodiment 18, wherein the dose of the thiazide - like diuretic is about 50% of the lowest hypertensive treatment dose (LHTD) of the thiazide - like diuretic.

[0157] Embodiment 20: The thiazide-like diuretic is kinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meclofenamic acid, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof, and is the pharmaceutical composition according to Embodiment 18 or 19.

[0158] Embodiment 21: The thiazide-like diuretic is indapamide or a hydrate thereof, and is the pharmaceutical composition according to any one of Embodiments 18 to 20.

[0159] Embodiment 22: The thiazide-like diuretic is indapamide, and is the pharmaceutical composition according to Embodiment 21.

[0160] Embodiment 23: The dose of indapamide is about 0.625 mg, and is the pharmaceutical composition according to Embodiment 22.

[0161] Embodiment 24: The thiazide-like diuretic is chlorthalidone, and is the pharmaceutical composition according to any one of Embodiments 18 to 20.

[0162] Embodiment 25: The dose of chlorthalidone is about 12.5 mg, and is the pharmaceutical composition according to Embodiment 24.

[0163] Embodiment 26: The diuretic is a loop diuretic, and is the pharmaceutical composition according to any one of Embodiments 1 to 12.

[0164] Embodiment 27: The dose of the loop diuretic is about 50% of the lowest hypertensive treatment dose (LHTD) of the loop diuretic, and is the pharmaceutical composition according to Embodiment 26.

[0165] Embodiment 28: The loop diuretic is furosemide, bumetanide, ethacrynic acid, ethoxzolamide, muzolimine, ozolinone, pyritanide, tienilic acid, torasemide or a pharmaceutically acceptable salt or hydrate thereof, and is the pharmaceutical composition according to Embodiment 26 or 27.

[0166] Embodiment 29: The diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof, and the pharmaceutical composition according to any one of Embodiments 1 to 12.

[0167] Embodiment 30: The dosage of the diuretic is about 50% of the lowest hypertensive treatment dosage (LHTD) of the diuretic, and the pharmaceutical composition according to Embodiment 29.

[0168] Embodiment 31: The dosage of the calcium antagonist is about 50% of the lowest hypertensive treatment dosage (LHTD) of the calcium antagonist, and the pharmaceutical composition according to any one of Embodiments 1 to 30.

[0169] Embodiment 32: The calcium antagonist is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotarizine, diprotverine, or a pharmaceutically acceptable salt or hydrate thereof, and the pharmaceutical composition according to Embodiment 31.

[0170] Embodiment 33: The calcium antagonist is amlodipine or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to Embodiment 31 or 32.

[0171] Embodiment 34: The calcium antagonist is amlodipine besylate, and the pharmaceutical composition according to Embodiment 33.

[0172] Embodiment 35: The dosage of amlodipine besylate is about 1.25 mg, and the pharmaceutical composition according to Embodiment 34.

[0173] Embodiment 36: The dosage of the β-blocker is about 50% of the lowest hypertensive treatment dosage (LHTD) of the β-blocker, and the pharmaceutical composition according to any one of Embodiments 1 to 35.

[0174] Embodiment 37: The β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, mecipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tertatolol, arotinolol, levobetaxolol, befunolol, amosulalol, chlorthalidone, or a pharmaceutically acceptable salt or hydrate thereof, and is the pharmaceutical composition according to Embodiment 36.

[0175] Embodiment 38: The β-blocker is atenolol, and is the pharmaceutical composition according to Embodiment 36 or 37.

[0176] Embodiment 39: The dosage of atenolol is about 12.5 mg, and is the pharmaceutical composition according to Embodiment 38.

[0177] Embodiment 40: The β-blocker is bisoprolol or a pharmaceutically acceptable salt thereof, and is the pharmaceutical composition according to Embodiment 36 or 37.

[0178] Embodiment 41: The β-blocker is bisoprolol fumarate, and is the pharmaceutical composition according to Embodiment 40.

[0179] Embodiment 42: The dosage of bisoprolol fumarate is about 2.5 mg, and is the pharmaceutical composition according to Embodiment 41.

[0180] Embodiment 43: The dosage of the angiotensin II receptor antagonist is about 50% of the lowest hypertensive treatment dose (LHTD) of the angiotensin II receptor antagonist, and is the pharmaceutical composition according to any one of Embodiments 1 to 42.

[0181] Embodiment 44: The angiotensin II receptor antagonist is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof, and the pharmaceutical composition according to any one of Embodiments 1 to 43.

[0182] Embodiment 45: The angiotensin II receptor antagonist is irbesartan, and the pharmaceutical composition according to Embodiment 43 or 44.

[0183] Embodiment 46: The dose of irbesartan is about 37.5 mg, and the pharmaceutical composition according to Embodiment 45.

[0184] Embodiment 47: The angiotensin II receptor antagonist is telmisartan, and the pharmaceutical composition according to Embodiment 43 or 44.

[0185] Embodiment 48: The dose of telmisartan is about 10 mg, and the pharmaceutical composition according to Embodiment 47.

[0186] Embodiment 49: The angiotensin II receptor antagonist is irbesartan, the diuretic is hydrochlorothiazide, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol, and the pharmaceutical composition according to Embodiment 1.

[0187] Embodiment 50: The dose of irbesartan is from about 30 mg to about 45 mg, the dose of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of atenolol is from about 10 mg to about 15 mg, and the pharmaceutical composition according to Embodiment 49.

[0188] Embodiment 51: The dose of irbesartan is about 37.5 mg, the dose of hydrochlorothiazide is about 6.25 mg, the dose of amlodipine besylate is about 1.25 mg, and the dose of atenolol is about 12.5 mg, and the pharmaceutical composition according to Embodiment 49.

[0189] Embodiment 52: The angiotensin II receptor antagonist is telmisartan, the diuretic is hydrochlorothiazide, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol. The pharmaceutical composition according to Embodiment 1.

[0190] Embodiment 53: The dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. The pharmaceutical composition according to Embodiment 52.

[0191] Embodiment 54: The dosage of telmisartan is about 10 mg, the dosage of hydrochlorothiazide is about 6.25 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg. The pharmaceutical composition according to Embodiment 52.

[0192] Embodiment 55: The angiotensin II receptor antagonist is irbesartan, the diuretic is indapamide, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate. The pharmaceutical composition according to Embodiment 1.

[0193] Embodiment 56: The dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of indapamide is from about 0.5 mg to about 0.75 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. The pharmaceutical composition according to Embodiment 55.

[0194] Embodiment 57: The dosage of irbesartan is about 37.5 mg, the dosage of indapamide is about 0.625 mg, the dosage of amlodipine is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg. The pharmaceutical composition according to Embodiment 55.

[0195] Embodiment 58: The angiotensin II receptor antagonist is telmisartan, the diuretic is indapamide, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate. The pharmaceutical composition according to Embodiment 1.

[0196] Embodiment 59: The dose of telmisartan is from about 8 mg to about 12 mg, the dose of indapamide is from about 0.5 mg to about 0.75 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of bisoprolol fumarate is from about 2 mg to about 3 mg. The pharmaceutical composition according to Embodiment 58.

[0197] Embodiment 60: The dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, the dose of amlodipine besylate is about 1.25 mg, and the dose of bisoprolol fumarate is about 2.5 mg. The pharmaceutical composition according to Embodiment 58.

[0198] Embodiment 61: The angiotensin II receptor antagonist is telmisartan, the diuretic is chlorthalidone, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate. The pharmaceutical composition according to Embodiment 1.

[0199] Embodiment 62: The dose of telmisartan is from about 8 mg to about 12 mg, the dose of chlorthalidone is from about 10 mg to about 15 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of bisoprolol fumarate is from about 2 mg to about 3 mg. The pharmaceutical composition according to Embodiment 61.

[0200] Embodiment 63: The dose of telmisartan is about 10 mg, the dose of chlorthalidone is about 12.5 mg, the dose of amlodipine besylate is about 1.25 mg, and the dose of bisoprolol fumarate is about 2.5 mg. The pharmaceutical composition according to Embodiment 61.

[0201] Embodiment 64: The angiotensin II receptor antagonist is telmisartan, the diuretic is chlorthalidone, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol. The pharmaceutical composition according to Embodiment 1.

[0202] Embodiment 65: The dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of atenolol is from about 10 mg to about 15 mg. The pharmaceutical composition according to Embodiment 64.

[0203] Embodiment 66: The dosage of telmisartan is about 10 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine besylate is about 1.25 mg, and the dosage of atenolol is about 12.5 mg. The pharmaceutical composition according to Embodiment 64.

[0204] Embodiment 67: The angiotensin II receptor antagonist is irbesartan, the diuretic is chlorthalidone, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate. The pharmaceutical composition according to Embodiment 1.

[0205] Embodiment 68: The dosage of irbesartan is from about 30 mg to about 45 mg, the dosage of chlorthalidone is from about 10 mg to about 15 mg, the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dosage of bisoprolol fumarate is from about 2 mg to about 3 mg. The pharmaceutical composition according to Embodiment 67.

[0206] Embodiment 69: The dosage of irbesartan is about 37.5 mg, the dosage of chlorthalidone is about 12.5 mg, the dosage of amlodipine is about 1.25 mg, and the dosage of bisoprolol fumarate is about 2.5 mg. The pharmaceutical composition according to Embodiment 67.

[0207] Embodiment 70: The angiotensin II receptor antagonist is irbesartan, the diuretic is chlorthalidone, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol. The pharmaceutical composition according to Embodiment 1.

[0208] Embodiment 71: The dose of irbesartan is from about 30 mg to about 45 mg, the dose of chlorthalidone is from about 10 mg to about 15 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of atenolol is from about 10 mg to about 15 mg. The pharmaceutical composition according to Embodiment 70.

[0209] Embodiment 72: The dose of irbesartan is about 37.5 mg, the dose of chlorthalidone is about 12.5 mg, the dose of amlodipine is about 1.25 mg, and the dose of atenolol is about 12.5 mg. The pharmaceutical composition according to Embodiment 70.

[0210] Embodiment 73: (a), (b), (c), and (d) are provided in one formulation. The pharmaceutical composition according to any one of Embodiments 1 to 72.

[0211] Embodiment 74: (a), (b), (c), and (d) are provided in separate formulations respectively. The pharmaceutical composition according to any one of Embodiments 1 to 72.

[0212] Embodiment 75: Two of (a), (b), (c), and (d) are provided in one formulation. The pharmaceutical composition according to any one of Embodiments 1 to 72.

[0213] Embodiment 76: Three of (a), (b), (c), and (d) are provided in one formulation. The pharmaceutical composition according to any one of Embodiments 1 to 72.

[0214] Embodiment 77: The pharmaceutical composition is in the form of pills, tablets or capsules. The pharmaceutical composition according to any one of Embodiments 1 to 76.

[0215] Embodiment 78: The pharmaceutical composition is the pharmaceutical composition according to any one of Embodiments 1 to 77, which is suitable for oral administration.

[0216] Embodiment 79: A method for treating hypertension in a subject in need thereof, comprising the step of administering the pharmaceutical composition according to any one of Embodiments 1 to 78.

[0217] Embodiment 80: The method according to Embodiment 79, wherein the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg.

[0218] Embodiment 81: The method according to Embodiment 79 or 80, wherein the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more.

[0219] Embodiment 82: The method according to any one of Embodiments 79 to 81, wherein the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg.

[0220] Embodiment 83: The method according to any one of Embodiments 79 to 82, wherein the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more.

[0221] Embodiment 84: The method according to any one of Embodiments 79 to 83, wherein the treatment results in a decrease in systolic blood pressure (SBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of any one of (a), (b), (c), and (d) in the pharmaceutical composition.

[0222] Embodiment 85: The method according to any one of Embodiments 79 to 84, wherein the treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with the full minimum antihypertensive treatment dose of any one of (a), (b), (c), and (d) in the pharmaceutical composition.

[0223] Embodiment 86: The method according to any one of Embodiments 79 to 85, wherein when compared with treatment with the full minimum antihypertensive treatment dose of any one of (a), (b), (c), and (d) in a pharmaceutical composition, the treatment enhances long-term tolerance and reduces the risk of side effects.

[0224] Embodiment 87: The treatment results in a decrease in systolic blood pressure (SBP), which is greater than the decrease obtained with any combination of two of (a), (b), (c), and (d) in a pharmaceutical composition, and the dose of each of (a), (b), (c), and (d) is about 50% of the minimum antihypertensive treatment dose. The method according to any one of Embodiments 79 to 83.

[0225] Embodiment 88: The treatment results in a decrease in diastolic blood pressure (DBP), which is greater than the decrease obtained with any combination of two of (a), (b), (c), and (d) in a pharmaceutical composition, and the dose of each of (a), (b), (c), and (d) is about 50% of the minimum antihypertensive treatment dose. The method according to any one of Embodiments 79 to 84.

[0226] Embodiment 89: When compared with treatment with any combination of two of (a), (b), (c), and (d) in a pharmaceutical composition, the treatment enhances long-term tolerance and reduces the risk of side effects, and the dose of each of (a), (b), (c), and (d) is about 50% of the minimum antihypertensive treatment dose. The method according to any one of Embodiments 79 to 85.

[0227] Embodiment 90: The treatment is the initial treatment or primary treatment of hypertension. The method according to any one of Embodiments 79 to 89.

[0228] Embodiment 91: The subject has not received previous antihypertensive treatment before the treatment. The method according to any one of Embodiments 79 to 90.

[0229] Embodiment 92: (a) An angiotensin II receptor antagonist; (b) A diuretic; (c) Calcium antagonist; and (d) β-blocker; consisting essentially of, The dosage of each of (a), (b), (c), and (d) is about 20% to about 60% of the lowest hypertensive treatment dosage (LHTD) of each of (a), (b), (c), and (d), a pharmaceutical composition.

[0230] Preferred embodiments of the present disclosure have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be utilized in the practice of the present disclosure. The following claims define the scope of the present disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be thereby encompassed.

Claims

1. (a) an angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; comprising, the dosages of (a), (b), (c), and (d) respectively are about 20% to about 60% of the respective lowest hypertension treatment dosages (LHTDs) of (a), (b), (c), and (d), a pharmaceutical composition.

2. the dosages of (a), (b), (c), and (d) respectively are about 40% to about 60% of the respective lowest hypertension treatment dosages (LHTDs) of (a), (b), (c), and (d), the pharmaceutical composition according to Claim 1.

3. the pharmaceutical composition essentially does not contain a lipid regulator, a platelet function modifier, a serum homocysteine lowering agent, or a combination thereof, the pharmaceutical composition according to Claim 1.

4. the diuretic is a thiazide diuretic, and the thiazide diuretic is alticide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof, the pharmaceutical composition according to Claim 1.

5. the dosage of the thiazide diuretic is about 50% of the lowest hypertension treatment dosage (LHTD) of the thiazide diuretic, the pharmaceutical composition according to Claim 4.

6. the thiazide diuretic is hydrochlorothiazide, and the dosage of hydrochlorothiazide is about 6.25 mg, the pharmaceutical composition according to Claim 4.

7. the diuretic is a thiazide-like diuretic, and the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorfenamide, metolazone, meclan, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof, the pharmaceutical composition according to Claim 1.

8. the dosage of the thiazide-like diuretic is about 50% of the lowest hypertension treatment dosage (LHTD) of the thiazide-like diuretic, the pharmaceutical composition according to Claim 7.

9. the thiazide-like diuretic is indapamide, and the dosage of indapamide is about 0.625 mg, the pharmaceutical composition according to Claim 7.

10. the thiazide-like diuretic is chlorthalidone, and the dosage of chlorthalidone is about 12.5 mg, the pharmaceutical composition according to Claim 7.

11. The pharmaceutical composition according to claim 1, wherein the dosage of the calcium antagonist is about 50% of the lowest hypertension treatment dosage (LHTD) of the calcium antagonist.

12. The pharmaceutical composition according to claim 11, wherein the calcium antagonist is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotarizine, diprotverine, or a pharmaceutically acceptable salt or hydrate thereof.

13. The pharmaceutical composition according to claim 12, wherein the calcium antagonist is amlodipine besylate, and the dosage of amlodipine besylate is about 1.25 mg.

14. The pharmaceutical composition according to claim 1, wherein the dosage of the β-blocker is about 50% of the lowest hypertension treatment dosage (LHTD) of the β-blocker.

15. The pharmaceutical composition according to claim 14, wherein the β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, mecipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tertatolol, alotiolol, levobetaxolol, befunolol, amosulalol, tilisolol, or a pharmaceutically acceptable salt or hydrate thereof.

16. The pharmaceutical composition according to claim 15, wherein the β-blocker is atenolol, and the dosage of atenolol is about 12.5 mg.

17. The pharmaceutical composition according to claim 15, wherein the β-blocker is bisoprolol fumarate, and the dosage of bisoprolol fumarate is about 2.5 mg.

18. The pharmaceutical composition according to claim 1, wherein the dosage of the angiotensin II receptor antagonist is about 50% of the lowest hypertension treatment dosage (LHTD) of the angiotensin II receptor antagonist.

19. The pharmaceutical composition according to claim 18, wherein the angiotensin II receptor antagonist is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

20. The pharmaceutical composition according to claim 19, wherein the angiotensin II receptor antagonist is irbesartan and the dose of irbesartan is about 37.5 mg.

21. The pharmaceutical composition according to claim 19, wherein the angiotensin II receptor antagonist is telmisartan and the dose of telmisartan is about 10 mg.

22. The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor antagonist is irbesartan, the diuretic is hydrochlorothiazide, the calcium antagonist is amlodipine besylate, and the β-blocker is atenolol.

23. The pharmaceutical composition according to claim 22, wherein the dose of irbesartan is from about 30 mg to about 45 mg, the dose of hydrochlorothiazide is from about 5 mg to about 7.5 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of atenolol is from about 10 mg to about 15 mg.

24. The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor antagonist is irbesartan, the diuretic is indapamide, the calcium antagonist is amlodipine besylate, and the β-blocker is bisoprolol fumarate.

25. The pharmaceutical composition according to claim 24, wherein the dose of irbesartan is from about 30 mg to about 45 mg, the dose of indapamide is from about 0.5 mg to about 0.75 mg, the dose of amlodipine besylate is from about 1 mg to about 1.5 mg, and the dose of bisoprolol fumarate is from about 2 mg to about 3 mg.

26. The pharmaceutical composition according to claim 1, wherein (a), (b), (c), and (d) are provided in one formulation.

27. The pharmaceutical composition according to claim 1, which is suitable for oral administration.

28. (a) an angiotensin II receptor antagonist; (b) a diuretic; (c) a calcium antagonist; and (d) a β-blocker; A method for treating hypertension in a subject in need thereof, comprising the step of administering a pharmaceutical composition comprising the same. A method wherein the dosages of (a), (b), (c), and (d) are each about 20% to about 60% of the respective lowest hypertensive treatment dosage (LHTD) of (a), (b), (c), and (d). [

29. ] The method according to claim 28, wherein the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more. [

30. ] The method according to claim 28, wherein the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more.

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