Compositions for the treatment of hypertension

Abstract

To provide a new effective and acceptable pharmaceutical composition for reducing hypertension.SOLUTION: (a) telmisartan, (b) indapamide, and (c) amlodipine besylate, wherein the dose of telmisartan is from about 8mg to about 12mg or from about 12mg to about 16mg, the dose of indapamide is from about 0. 5mg to about 0. 75mg or from about 0. 75mg to about 1. 0mg, and the dose of amlodipine besylate is from about 1mg to about 1. or from about 1. to about, and wherein the pharmaceutical composition further comprises one or more cholesterol lowering active agents. 5mg 5mg 2mg.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 703,802, filed July 26, 2018, which is incorporated herein by reference. [Background technology]

[0002] High blood pressure, also known as hypertension, is a leading cause of preventable morbidity and mortality, and the benefits of treatments to lower blood pressure (BP) are well established. However, despite the availability of a plethora of antihypertensive medications, many patients remain inadequately regulated, as evidenced by multiple large population studies. Contributing factors to inadequate BP control include poor adherence, complex guidelines recommending multiple titration steps, and treatment inertia. Furthermore, most treated patients receive only monotherapy, which has limited efficacy even at high doses with increased side effects and reduced tolerability. Therefore, new, effective and tolerable treatments for lowering hypertension are needed. Summary of the Invention

[0003] In one aspect, a pharmaceutical composition is disclosed herein, said pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition further comprises at least one cholesterol-lowering active agent. In some embodiments, the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function-altering agent, a serum homocysteine-lowering agent, or a combination thereof.

[0004] In some embodiments, the diuretic is a thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

[0005] In some embodiments, the calcium channel blocker 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 channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate.

[0006] In some embodiments, the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is telmisartan.

[0007] In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the diuretic is a thiazide-like diuretic, and the dose of the thiazide-like diuretic is about 50% of the minimum hypertension therapeutic dose (LHTD) of the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dose of indapamide is about 0.625 mg. In some embodiments, the dose of the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is about 1.25 mg. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 10 mg. In some embodiments, the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0008] In one aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0009] In some embodiments, the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof.

[0010] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

[0011] In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate.

[0012] In some embodiments, the dose of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of the thiazide-like diuretic is about 100% of the minimum hypertension therapeutic dose (LHTD) of the thiazide diuretic. In some embodiments, the thiazide-like diuretic is indapamide. The dose of indapamide is about 1.25 mg. In some embodiments, the dose of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is about 2.5 mg. In some embodiments, the dose of telmisartan is about 100% of the minimum hypertension therapeutic dose (LHTD) of telmisartan. In some embodiments, the dose of telmisartan is about 20 mg. In some embodiments, the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate. In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg. In some embodiments, the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0013] In some embodiments of the pharmaceutical compositions disclosed herein, (a), (b), and (c) are provided in a single formulation. In some embodiments, (a), (b), and (c) are each provided in separate formulations. In some embodiments, two of (a), (b), and (c) are provided in a single formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0014] Also provided are methods for treating hypertension in a subject, comprising administering any one of the pharmaceutical compositions disclosed herein. In some embodiments, treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) greater than the reduction achieved with a total minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) greater than the reduction achieved with a total minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in longer-term tolerability and reduced risk of side effects compared to treatment with the lowest total antihypertensive dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject has not received any prior treatment for hypertension prior to the treatment.

[0015] In another aspect, provided herein is a pharmaceutical composition, the pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0016] In another aspect, provided herein is a pharmaceutical composition, the pharmaceutical composition comprising: (a) with angiotensin II receptor blockers such as telmisartan; (b) thiazide-like diuretics; (c) a calcium channel blocker, wherein: The dose of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD), wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent. In some embodiments, the dose of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD).

[0017] In some embodiments, the at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0018] In some embodiments, the at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0019] In some embodiments, the at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a statin.

[0020] In some embodiments, the at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

[0021] In some embodiments, the at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0022] In some embodiments, the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[0023] In some embodiments, (a), (b), and (c) are provided in a single formulation.

[0024] In some embodiments, (a), (b), (c) and at least one cholesterol-lowering active agent are provided in a single formulation.

[0025] In another aspect, provided herein is a method for treating at least one of hypertension and dyslipidemia in a subject, comprising administering a pharmaceutical composition disclosed herein. Specifically, the method is a first-line treatment.

[0026] In another aspect, provided herein is a method for treating combined hypertension and dyslipidemia in a subject, comprising administering a pharmaceutical composition disclosed herein. Specifically, the method is a first-line treatment.

[0027] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0028] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0029] [Figure 1] Mean systolic blood pressure (mmHg) over time by treatment is shown. [Figure 2] Mean diastolic blood pressure (mmHg) over time by treatment is shown. [Figure 3] Average heart rate over time by treatment is shown. DETAILED DESCRIPTION OF THE INVENTION

[0030] Provided herein are pharmaceutical compositions for treating hypertension, including an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. In some embodiments, the dose of each component is less than the low dose approved for treating hypertension. The present disclosure recognizes the technical advantages of the low-dose combination therapies described herein, including, but not limited to, the use of low doses that avoid or ameliorate side effects while maintaining or improving benefits, synergistic therapeutic effects of certain drug combinations, and early introduction of combination therapy to improve therapeutic effects. In one aspect, a low-dose combination composition for treating hypertension is described herein, where the treatment includes initial or primary treatment of hypertension.

[0031] 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, a reference to an "agent" includes a plurality of such agents, and a reference to a "composition" includes a reference to one or more compositions (or compositions), and equivalents thereof known to those of skill in the art. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments within the ranges are intended to be encompassed. The term "about," when referring to a numerical value or range, indicates that the stated numerical value or range is approximate within experimental variability (or statistical experimental error), and thus, in some embodiments, the numerical value or range varies by between 1% and 10% of the stated numerical value or range. The term "comprising" (and related words such as "comprise" or "comprises," or "having" or "including") is not intended to exclude that in other embodiments, embodiments such as, for example, any composition, method, or process described herein, may "consist of" or "consist essentially of" the recited features.

[0032] definition As used in this specification and the appended claims, unless expressly stated to the contrary, the following terms have the meanings specified below.

[0033] As used herein, " pharmaceutically acceptable salts " includes both acid and base addition salts. In some embodiments, the pharmaceutically acceptable salt of any one of the compounds described herein is the 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.

[0034] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which salts are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanediol (alkanediol) acids, aromatic acids, and aliphatic and aromatic sulfonic acids, and with, for example, 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, and the like. Thus, exemplary 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, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM 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 to produce the salt according to methods and techniques familiar to those skilled in the art.

[0035] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, and which salts are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base 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, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. 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, such as 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0036] As used herein, a "hydrate" is a compound containing a stoichiometric or non-stoichiometric amount of water, and in some embodiments, is formed during the process of crystallization with water. Hydrate is intended to include any one of the hydrates of the compounds described herein that have been approved for use by the U.S. Food and Drug Administration.

[0037] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health status of the subject being treated.

[0038] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with 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.

[0039] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; domestic animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0040] As used herein, "treatment" or "treating" or "alleviating" or "relieving" are used interchangeably herein. These terms refer to an approach to achieving beneficial or desired results, including, but not limited to, a therapeutic effect and / or a preventative effect. A "therapeutic effect" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic effect is achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement is observed in a patient, even though the patient still suffers from the underlying disease. In the case of a preventative effect, the composition can be administered to a patient at risk of developing a particular disease or to a patient who reports one or more physiological symptoms of the disease, even if no diagnosis of the disease has been made.

[0041] Triple Compositions Described herein are pharmaceutical compositions comprising (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker, wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 60% to about 80% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 66% of the minimum hypertension therapeutic dose (LHTD).

[0042] In some embodiments, the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active agents, wherein said blood pressure lowering active agents consist of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

[0043] In another aspect, described herein are pharmaceutical compositions comprising: (a) an angiotensin II receptor blocker, such as telmisartan; (b) a thiazide-like diuretic; and (c) a calcium channel blocker, wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 95% to about 105% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest hypertension therapeutic dose (LHTD).

[0044] In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of angiotensin-converting enzyme inhibitors (ACE inhibitors) or pharmaceutically acceptable salts thereof. In some embodiments, 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.

[0045] Further described herein are pharmaceutical compositions consisting essentially of (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker, wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 60% to about 80% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 66% of the minimum hypertension therapeutic dose (LHTD).

[0046] Further described herein are pharmaceutical compositions consisting essentially of (a) an angiotensin II receptor blocker, such as telmisartan; (b) a thiazide-like diuretic; and (c) a calcium channel blocker, wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 95% to about 105% of the minimum hypertension therapeutic dose (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest hypertension therapeutic dose (LHTD).

[0047] In some embodiments, the pharmaceutical compositions disclosed herein achieve significant blood pressure reduction in subjects with moderately elevated blood pressure. In some embodiments, the pharmaceutical compositions disclosed herein achieve significant blood pressure reduction in subjects with moderately elevated blood pressure with minimal, minor, or no side effects.

[0048] Beta-blockers In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of beta-blockers or pharmaceutically acceptable salts thereof. In some embodiments, beta-blockers are compounds that inhibit the receptor sites of the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on the adrenergic beta-receptors of the sympathetic nervous system. In some embodiments, beta-blockers include, but are not limited to, beta-adrenergic blockers, beta-antagonists, beta-adrenergic antagonists, beta-adrenergic receptor antagonists, or beta-adrenergic receptor antagonists. In some embodiments, beta-blockers inhibit the activation of all types of beta-adrenergic receptors. In some embodiments, beta-blockers inhibit both beta-adrenergic receptors and alpha-adrenergic receptors. In some embodiments, beta-blockers are selective for one of the following beta-receptors: beta-1, beta-2, and beta-3 receptors.

[0049] 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 that combines beta-adrenergic receptor blocking activity and alpha-adrenergic receptor blocking activity. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the beta-blocker is a beta-1-selective adrenergic receptor antagonist. Examples of beta-1-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 adrenoceptor antagonist, such as butaxamine (butaxamine).

[0050] In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, metipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tertatolol, arotinolol, levobunolol, befunolol, amosulalol, tilisolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta-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 beta-blocker is acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, oxprenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, carvedilol, labetalol, timolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta-blocker is atenolol. In some embodiments, the beta-blocker is bisoprolol or a pharmaceutically acceptable salt thereof.

[0051] Platelet function modifiers In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of platelet function modifiers. In some embodiments, the platelet function modifier is aspirin, ticlopidine, dipyridamole, or clopidogrel. In some embodiments, the platelet function modifier is a glycoprotein IIb / IIIa receptor inhibitor such as abciximab. In some embodiments, the platelet function modifier is a nonsteroidal anti-inflammatory drug such as ibuprofen. In some embodiments, the platelet function modifier is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen. In some embodiments, the platelet function modifier is aspirin.

[0052] Serum homocysteine-lowering agents In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of serum homocysteine-lowering agents. 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.

[0053] Angiotensin II receptor antagonists / blockers As used herein, angiotensin II receptor antagonists or blockers (ARBs) are compounds that modulate the action of angiotensin II by preventing angiotensin II from binding to angiotensin II receptors on the muscles surrounding blood vessels. In some embodiments, the angiotensin II receptor blocker is olmesartan, azilsartan, losartan, valsartan, candesartan, eprosartan, irbesartan, telmisartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is losartan. In some embodiments, the angiotensin II receptor blocker is valsartan. In some embodiments, the angiotensin II receptor blocker is candesartan. In some embodiments, the angiotensin II receptor blocker is eprosartan. In some embodiments, the angiotensin II receptor blocker is irbesartan. In some embodiments, the angiotensin II receptor blocker is telmisartan.

[0054] diuretics As used herein, a diuretic refers to a compound that increases urine flow. Diuretics are classified by chemical structure (such as thiazide and thiazide-like diuretics), site of action (such as loop diuretics), or pharmacological effect (such as osmotic diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics).

[0055] In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide-like diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a loop diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise an osmotic diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a carbonic anhydrase inhibitor. In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium-sparing diuretic.

[0056] Thiazide diuretics As used herein, thiazide diuretics refer to compounds containing a benzothiadiazine molecular structure. In some embodiments, thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubules of the kidney, resulting in increased urinary excretion of sodium and water. Examples of thiazide diuretics include, but are not limited to, altizide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, and trichlormethiazide.

[0057] In some embodiments, the thiazide diuretic is altizide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is altizide. 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 epitizide. 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 trichlormethiazide.

[0058] Thiazide-like diuretics As used herein, a thiazide-like diuretic is a sulfonamide diuretic that has similar physiological properties to thiazide diuretics, but does not possess the chemical properties of a thiazide (i.e., does not possess a benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, and fenquizone.

[0059] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is quinethazone. In some embodiments, the thiazide-like diuretic is clopamide. 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 clofenamide. In some embodiments, the thiazide-like diuretic is metolazone. In some embodiments, the thiazide-like diuretic is meticrane. 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 clorexolone. In some embodiments, the thiazide-like diuretic is fenquizone.

[0060] Loop diuretics As used herein, loop diuretics are agents that inhibit the reabsorption of sodium, chloride, and potassium by blocking the reabsorption of Na in the thick ascending loop of Henle. + / K + / 2Cl -It is a compound that acts on a cotransporter. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, etozolinone, muzolimine, ozolinone, piretanide, tienilic acid, and torasemide. In some embodiments, the loop diuretic is furosemide, bumetanide, ethacrynic acid, etozolinone, muzolimine, ozolinone, piretanide, tienilic acid, torasemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0061] Other diuretics Osmotic diuretics are compounds that retain water in the proximal tubule and the descending limb of the loop of Henle. In some embodiments, osmotic diuretics increase fluid and plasma volume, increasing blood flow to the kidney. Examples include, but are not limited to, mannitol and glycerol.

[0062] Carbonic anhydrase inhibitors As used herein, a carbonic anhydrase inhibitor is a compound that is an inhibitor of carbonic anhydrase. In some embodiments, carbonic anhydrase inhibitors increase the excretion of bicarbonate, including concomitant sodium, potassium, and water, thereby increasing alkaline urine flow. In some embodiments, carbonic anhydrase inhibitors inhibit the transport of bicarbonate into the interstitium of the proximal tubule convolution, resulting in less sodium being reabsorbed and more sodium, bicarbonate, and water being lost in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorphenamide, and methazolamide.

[0063] Potassium-sparing diuretics Potassium-sparing diuretics are compounds that compete with aldosterone for intracellular cytoplasmic receptor sites or that directly block sodium channels, particularly the epithelial sodium channel (ENaC). Examples of potassium-sparing diuretics include, but are not limited to, amiloride, spironolactone, eplerenone, triamterene, and potassium canrenoate.

[0064] Other diuretics contemplated for use further include, but are not limited to, caffeine, theophylline, theobromine, tolvaptan, conivaptan, dopamine, and pamabrom.

[0065] 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.

[0066] Calcium channel blockers As used herein, a calcium channel blocker is a compound that promotes vasodilatation by reducing calcium influx into vascular smooth muscle cells. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate. In some embodiments, the calcium channel blocker is nifedipine. In some embodiments, the calcium channel blocker is diltiazem. In some embodiments, the calcium channel blocker is nimodipine. In some embodiments, the calcium channel blocker is verapamil. In some embodiments, the calcium channel blocker is isradipine. In some embodiments, the calcium channel blocker is felodipine. In some embodiments, the calcium channel blocker is nicardipine. In some embodiments, the calcium channel blocker is nisoldipine. In some embodiments, the calcium channel blocker is clevidipine.

[0067] Minimum hypertension treatment dose As used herein, Lowest Hypertension Therapeutic Dose (LHTD) refers to the lowest strength dose for a single drug for hypertension approved by the U.S. Food and Drug Administration, as of the filing date of this application, as listed in the Orange Book database ("<http: / / www.accessdata.fda.gov / scripts / cder / ob / > "). The lowest hypertension therapeutic dose does not include the lowest manufactured dose if it is not the same as the lowest manufactured dose. Furthermore, the lowest hypertension therapeutic dose does not include the dose recommended by a physician if it is not the same as the dose recommended by a physician. Furthermore, the lowest hypertension dose of an angiotensin II receptor blocker, diuretic, or calcium channel blocker described herein refers to the dose of the form of the angiotensin II receptor blocker, diuretic, or calcium channel blocker approved for use by the U.S. Food and Drug Administration, which forms include the free base, pharmaceutically acceptable salts, or hydrates thereof.

[0068] In some embodiments, the dose of the angiotensin II receptor blocker is about 40% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 40% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 40% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 40% to about 50% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 45% to about 55% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 60% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 60% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker is about 70% to about 80% of the minimum therapeutic dose for hypertension.

[0069] In some embodiments, the dose of the angiotensin II receptor 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor 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 hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor 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 hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 66% of the minimum hypertension therapeutic dose.

[0070] In some embodiments, the diuretic dose is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 60% to about 70% of the minimum hypertension therapeutic dose, hi some embodiments, the diuretic dose is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0071] In some embodiments, the dose 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose 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 hypertension therapeutic dose. In some embodiments, the diuretic dose 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 hypertension therapeutic dose. In some embodiments, the diuretic dose is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dose is about 66% of the minimum hypertension therapeutic dose.

[0072] In some embodiments, the dose of the thiazide diuretic is about 40% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 50% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 45% to about 55% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0073] 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic 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 hypertension therapeutic 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 hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide diuretic is about 66% of the minimum hypertension therapeutic dose.

[0074] In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0075] In some embodiments, the dose 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose 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 hypertension therapeutic dose. In some embodiments, the dose 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 hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 66% of the minimum hypertension therapeutic dose.

[0076] In some embodiments, the loop diuretic dose is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0077] 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose 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 hypertension therapeutic dose. In some embodiments, the loop diuretic dose 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 hypertension therapeutic dose. In some embodiments, the loop diuretic dose is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the loop diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the loop diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the loop diuretic is about 66% of the minimum hypertension therapeutic dose.

[0078] In some embodiments, the dose of the calcium channel blocker is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 60% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the calcium channel blocker is about 60% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the calcium channel blocker is about 70% to about 80% of the minimum therapeutic dose for hypertension.

[0079] In some embodiments, the dose of the calcium channel 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel 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 hypertension therapeutic dose. In some embodiments, the dose of the calcium channel 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 hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 66% of the minimum hypertension therapeutic dose.

[0080] In some embodiments, the lowest hypertension therapeutic doses (LHTD) and corresponding suggested doses and suggested dose ranges for the following compounds are as set forth in the table below:

[0081] [Table 1]

[0082] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 30 mg to about 45 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of irbesartan is about 37.5 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0083] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0084] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 30 mg to about 45 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of irbesartan is about 37.5 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0085] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0086] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of chlorthalidone is about 12.5 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0087] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 30 mg to about 45 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of irbesartan is about 37.5 mg, the dose of chlorthalidone is about 12.5 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0088] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0089] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0090] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0091] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0092] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0093] In some embodiments, the pharmaceutical composition comprises: (a) irbesartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0094] In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 150% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 140% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 130% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 120% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 110% of the minimum therapeutic dose for hypertension.

[0095] In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 145% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 105% of the minimum hypertension therapeutic dose.

[0096] In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 90% to about 140% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 90% to about 130% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 90% to about 120% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 90% to about 110% of the minimum therapeutic dose for hypertension.

[0097] In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 95% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 95% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 95% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker, such as telmisartan, is about 95% to about 105% of the minimum hypertension therapeutic dose.

[0098] In some embodiments, the dose of the angiotensin II receptor blocker is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% of the minimum hypertension therapeutic dose. , about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120%. In some embodiments, the dose of the angiotensin II receptor blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose.

[0099] In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 110% of the minimum hypertension therapeutic dose.

[0100] In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 145% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 105% of the minimum hypertension therapeutic dose.

[0101] In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 110% of the minimum hypertension therapeutic dose.

[0102] In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 105% of the minimum hypertension therapeutic dose.

[0103] In some embodiments, the dose of the thiazide-like diuretic is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the minimum hypertension therapeutic dose. %, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120%. In some embodiments, the dose of the thiazide-like diuretic is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the thiazide-like diuretic blocker is about 100% of the minimum hypertension therapeutic dose.

[0104] In some embodiments, the dose of the calcium channel blocker is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 110% of the minimum hypertension therapeutic dose.

[0105] In some embodiments, the dose of the calcium channel blocker is about 85% to about 145% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 105% of the minimum hypertension therapeutic dose.

[0106] In some embodiments, the dose of the calcium channel blocker is about 90% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 110% of the minimum hypertension therapeutic dose.

[0107] In some embodiments, the dose of the calcium channel blocker is about 95% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 105% of the minimum hypertension therapeutic dose.

[0108] In some embodiments, the dose of the calcium channel blocker is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose.

[0109] In some embodiments, the lowest hypertension therapeutic doses (LHTD) and corresponding suggested doses and suggested dose ranges for the following compounds are as set forth in the table below:

[0110] [Table 2]

[0111] In some embodiments, the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.In some embodiments, the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is substituted at about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is substituted at about 200% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0112] In some embodiments, the doses of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the doses of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.In some embodiments, the doses of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is substituted at about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is substituted at about 200% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0113] In some embodiments, the doses of the angiotensin II receptor blocker, the diuretic (e.g., a thiazide diuretic or thiazide-like diuretic), and the calcium channel blocker are each independently about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the doses of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each independently about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is about 100% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.In some embodiments, the doses of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each independently about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is about 100% of the minimum hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker, hi some embodiments, the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0114] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 16 mg to about 30 mg, the dose of indapamide is about 1 mg to about 1.875 mg, and the dose of amlodipine besylate is about 2 mg to about 3.75 mg.

[0115] In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0116] In some embodiments, the dose of telmisartan is from about 18 mg to about 22 mg, the dose of indapamide is from about 1.125 mg to about 1.375 mg, and the dose of amlodipine besylate is from about 2.25 mg to about 2.75 mg.

[0117] In some embodiments, the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0118] In some embodiments, the pharmaceutical composition comprises: (a) telmisartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 16 mg to about 30 mg, the dose of chlorthalidone is about 20 mg to about 37.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3.75 mg.

[0119] In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of chlorthalidone is about 20 mg to about 30 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0120] In some embodiments, the dose of telmisartan is about 18 mg to about 22 mg, the dose of chlorthalidone is about 22.5 mg to about 27.5 mg, and the dose of amlodipine besylate is about 2.25 mg to about 2.75 mg.

[0121] In some embodiments, the dose of telmisartan is about 20 mg, the dose of chlorthalidone is about 25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0122] formulation In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each provided in separate formulations. In some embodiments, two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker and the diuretic are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker and the calcium channel blocker are provided in a single formulation. In some embodiments, the diuretic and the calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or 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.

[0123] Other suitable formulations include, but are not limited to, formulations suitable for rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although in any event the most suitable mode of administration will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as a unit dose.

[0124] Typical pharmaceutical compositions may be used in the form of pharmaceutical preparations, e.g., solid, semi-solid, or liquid forms, which contain one or more of the disclosed compounds as active ingredients in admixture with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient may be compounded with a typically non-toxic, pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the disease process or condition.

[0125] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tableting 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 such a preformulation composition is referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0126] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or 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) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) humectants, such as, for example, acetyl alcohol and glycerol monostearate; (8) 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 compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0127] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made by molding, in a suitable machine, a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, capsules may be prepared by enclosing a tablet in a hard capsule (e.g., overencapsulation). Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

[0128] In some embodiments, the angiotensin II receptor blocker of the pharmaceutical compositions 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 dose of the angiotensin-converting enzyme inhibitor is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 90% to about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 100% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 60% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 60% to about 70% of the minimum therapeutic dose for hypertension.In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 70% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dose 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%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose 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 hypertension therapeutic dose. In some embodiments, the dose 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 hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 66% of the minimum hypertension therapeutic dose.

[0129] Treatment method The pharmaceutical compositions described herein are useful for treating hypertension in a subject in need thereof. In some embodiments, treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, treatment results in a systolic blood pressure (SBP) of less than about 135 mmHg. In some embodiments, treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg to about 20 mmHg. In some embodiments, treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg to about 30 mmHg. In some embodiments, 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, 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, treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, treatment results in a diastolic blood pressure (DBP) of less than about 85 mmHg. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 10 mmHg. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 15 mmHg. In some embodiments, 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, this results in a reduction 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.

[0130] In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a total minimum hypertension therapeutic dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a total minimum hypertension therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a total minimum hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a total minimum hypertension therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

[0131] In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

[0132] In some embodiments, treatment results in longer-term tolerance and a reduced risk of side effects compared to treatment with the lowest total hypertension therapeutic dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, treatment results in longer-term tolerance and a reduced risk of side effects compared to treatment with the lowest total hypertension therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, treatment results in longer-term tolerance and a reduced risk of side effects compared to treatment with the lowest total hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, treatment results in longer-term tolerance and a reduced risk of side effects compared to treatment with the lowest total hypertension therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

[0133] In some embodiments, the pharmaceutical composition results in a reduction in systolic blood pressure (SBP) greater than or equal to the reduction achieved by a combination of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker, wherein the dose of each of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the pharmaceutical composition results in a reduction in diastolic blood pressure (DBP) greater than or equal to the reduction achieved by a combination of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker, wherein the dose of each of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, this results in longer-term tolerability and reduced risk of side effects compared to treatment with a combination of any two of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker in a pharmaceutical composition, wherein the dose of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose.

[0134] In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject has very mild elevated blood pressure before treatment. In some embodiments, the subject has not received any prior treatment for hypertension before treatment. In some embodiments, the subject has very mild elevated blood pressure before treatment and has not received any prior treatment for hypertension before treatment.

[0135] The present disclosure recognizes that, in some embodiments, the use of an angiotensin II receptor blocker in the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects, including but not limited to, a significant reduction in blood pressure, a significant reduction in blood pressure in subjects with mildly elevated blood pressure, longer-term tolerability, and a reduced risk of side effects. The present disclosure recognizes that, in some embodiments, the omission of 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 reduction in blood pressure, a significant reduction in blood pressure in subjects with mildly elevated blood pressure, longer-term tolerability, and a reduced risk of side effects.

[0136] It is further recognized herein that, in some embodiments, triple combinations described herein that include an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each component at about 40% to about 80% of the minimum hypertension therapeutic dose, provide a greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination that includes an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (e.g., amlodipine besylate), each component at 100% of the minimum hypertension therapeutic dose. In some embodiments, a triple combination described herein that includes an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each component at about 40% to about 60% of the minimum hypertension therapeutic dose, provides a greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination that includes an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (e.g., amlodipine besylate), each component at 100% of the minimum hypertension therapeutic dose.

[0137] It is further recognized herein that, in some embodiments, the triple combination described herein, comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker, each at about 80% to about 150% of the minimum hypertension therapeutic dose, provides a greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate). In some embodiments, the triple combination described herein, comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker, each at about 80% to about 120% of the minimum hypertension therapeutic dose, provides a greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (e.g., amlodipine besylate).

[0138] In one aspect, a method of treating hypertension and / or dyslipidemia in a subject is provided, the method comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) administering to the subject a calcium channel blocker; wherein each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and the method further comprises at least one cholesterol-lowering active agent.

[0139] In some embodiments of the methods provided herein, the methods are essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof. In some embodiments of the methods provided herein, the methods do not include or consist of administration of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof.

[0140] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0141] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan.

[0142] In some embodiments of the methods provided herein, the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD).

[0143] In some embodiments of the methods provided herein, the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

[0144] In some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.625 mg.

[0145] In some embodiments of the methods provided herein, the dose of the calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0146] In some embodiments of the methods provided herein, the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.25 mg.

[0147] In some embodiments of the methods provided herein, the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0148] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 10 mg.

[0149] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0150] In some embodiments of the methods provided herein, 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, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg.

[0151] In some embodiments of the methods provided herein, the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0152] Provided herein are methods for treating hypertension and / or dyslipidemia in a subject, the methods comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) administering to the subject a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and the method further comprises at least one cholesterol-lowering active agent.

[0153] In some embodiments of the methods provided herein, the methods are essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof.

[0154] In some embodiments of the methods provided herein, the diuretic is a thiazide-like diuretic.

[0155] In some embodiments of the methods provided herein, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0156] In some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide or a hydrate thereof.

[0157] In some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide.

[0158] In some embodiments of the methods provided herein, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0159] In some embodiments of the methods provided herein, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments of the methods provided herein, the calcium channel blocker is amlodipine besylate.

[0161] In some embodiments of the methods provided herein, the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD).

[0162] In some embodiments of the methods provided herein, the dose of the thiazide-like diuretic is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

[0163] In some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide and the dose of indapamide is about 1.25 mg.

[0164] In some embodiments of the methods provided herein, the dose of the calcium channel blocker is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0165] In some embodiments of the methods provided herein, the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg.

[0166] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan.

[0167] In some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 20 mg.

[0168] In some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide, the calcium channel blocker is amlodipine besylate, and the angiotensin II receptor blocker is telmisartan.

[0169] In some embodiments of the methods provided herein, the dose of telmisartan is from about 16 mg to about 24 mg, the dose of indapamide is from about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is from about 2 mg to about 3 mg.

[0170] In some embodiments of the methods provided herein, the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0171] In some embodiments of the methods provided herein, the at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0172] In some embodiments of the methods provided herein, the at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a statin.

[0173] In some embodiments of the methods provided herein, at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

[0174] In some embodiments of the methods provided herein, the at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0175] In some embodiments of the methods provided herein, the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[0176] In some embodiments of the methods provided herein, (a), (b), (c) and at least one cholesterol-lowering active agent are provided in a single formulation.

[0177] In some embodiments of the methods provided herein, (a), (b), (c) and the at least one cholesterol-lowering active agent are provided in at least two separate formulations.

[0178] In some embodiments of the methods provided herein, at least two of (a), (b), (c), and the at least one cholesterol-lowering active agent are provided in a single formulation.

[0179] In some embodiments of the methods provided herein, at least three of (a), (b), (c), and the at least one cholesterol-lowering active agent are provided in a single formulation.

[0180] In some embodiments of the methods provided herein, the at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0181] In some embodiments of the methods provided herein, (a), (b), and (c) are provided in a single formulation, and the combination of ezetimibe and rosuvastatin is provided in a separate formulation. [Example]

[0182] Example 1: Cardiovascular measurements in spontaneously hypertensive rats receiving a combination of antihypertensive drugs

[0183] summary The purpose of this study was to evaluate the comparative effects on blood pressure of various triple combinations of angiotensin II receptor blockers, calcium channel blockers, and diuretics (thiazides or thiazide-like diuretics). The primary goal was to evaluate whether there were differences in the effects of combinations using different drugs from the same class, and between combinations using different doses of the same drug, including low doses (i.e., doses below the lowest approved and manufactured dose, e.g., 50% of the lowest hypertension therapeutic dose (LHTD)).

[0184] The specific combinations tested were: · Combination 1: telmisartan, amlodipine besylate, and indapamide (all at 50% of the lowest hypertension therapeutic dose (LHTD) or one-quarter of the FDA-recommended usual maintenance dose (equivalent to telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg)); Combination 2: telmisartan, amlodipine, and indapamide (all at 100% of the lowest hypertension therapeutic dose (LHTD) or half the usual FDA-recommended maintenance dose (equivalent to telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg)); and Combination 3: Losartan, amlodipine besylate, and hydrochlorothiazide (all at 100% of the lowest hypertension therapeutic dose (LHTD) or half the usual FDA-recommended maintenance dose (equivalent to 25 mg losartan, 2.5 mg amlodipine besylate, and 12.5 mg hydrochlorothiazide)).

[0185] This study was conducted in spontaneously hypertensive rats (SHR), the animal model most commonly used in hypertension studies (Pinto YM, Paul M, Ganten D. "Lessons from rat models of hypertension: from Goldblatt to genetic engineering." Cardiovascular Research. 39 (1): 77-88.). Standard allometric scaling methods and the C of each of six antihypertensive drugs were used. max Drug doses were calculated using data from published literature for AUC and . Each animal was exposed to a single dose of all drugs in the complex in a Latin square design.

[0186] method The following was used as vehicle in the following studies: 0.5% methylcellulose (w / v) and 0.25% polysorbate 80 (v / v) in 25 mM phosphate buffer at pH 8+ / -0.2.

[0187] The following animals were used in the study: spontaneously hypertensive rats (strain: SHR / NCrl). Rats were obtained from Charles River Laboratories, Inc., Kingston, New York. The age at the start of dosing was approximately 12 weeks of age. 13 male rats were used for acclimation. 8 male rats were used for testing. Animals were identified by cage cards and tattoos.

[0188] Telemetry Implantation: Animals were implanted with Data Science International transmitters (HD-S10) to collect blood pressure and heart rate data. Animals were not administered any dose formulation until at least 10 days after surgery.

[0189] Housing: Animals were housed individually in solid bottom cages equipped with water bottles.

[0190] Diet: Unless otherwise specified, animals were fed Teklad Global Diet-Rodent 2014 (Envigo RMS, Inc.) ad libitum. In some cases, animals were fed the meal form of this diet when their health status indicated.

[0191] Water: Undeveloped area tap water was provided ad libitum.

[0192] Contaminants: No known contaminants were present in the feed, water, or bedding (where applicable) at levels that would interfere with this study.

[0193] Environment: Environmental controls in the animal housing room were set up to maintain the following indoor conditions: a temperature range of 20–26 °C, a relative humidity of 30–70%, and a 12-h light / dark cycle.

[0194] Acclimatization (pre-administration phase): The acclimation period lasted up to 1 week.

[0195] Environmental and dietary enrichment: Animals were provided with a variety of cage-enrichment devices and dietary enrichment (not required for analysis).

[0196] Randomization: Animals were randomly selected based on mean arterial pressure values ​​during the pre-dose phase.

[0197] The table below shows the group designations of the rats used in the study:

[0198] [Table 3]

[0199] The following table shows the dose levels administered in the study:

[0200] [Table 4]

[0201] Dosing Procedure: For Combinations 1, 2, and 3, each test combination formulation was prepared fresh on each dosing day. A portion of the vehicle (approximately 80%) was added to the test combination formulation and mixed until the preparation was homogeneous. If a homogeneous suspension or solution was not obtained, 1N NaOH and / or 1N HCl was added to adjust the pH to 9 + 0.2. The remaining vehicle was added and mixed with a stir bar. The test combination formulations were continuously stirred at room temperature and protected from light for approximately 30 minutes prior to and throughout dosing. The test combination formulations were stored protected from light and stirred in a refrigerator set to maintain a temperature of 2-8°C.

[0202] Dosing Procedure: For handling prior to dosing, the test combination formulation was equilibrated to near room temperature for at least 30 minutes prior to dosing. Animals were dosed at a volume of 10 mL / kg, with the actual dose based on most recent body weight. Doses were administered using oral gavage. Dosing intervals were once daily on days 1, 8, 15, and 22. After dose administration, the remaining test combination formulation was discarded according to standard handling procedures.

[0203] Telemetry Collection: Animals were not disturbed or manipulated without prior permission immediately prior to and during telemetry data collection. Such disturbances included, but were not limited to, cage changes, bedding changes, mopping, sanitation, or anything that disrupted the natural, quiet environment critical to the collection of cardiovascular telemetry data.

[0204] Animal Observations: Each rat was observed once each morning. Any abnormal findings were recorded. Rats were observed for mortality, abnormalities, and signs of pain or distress. Any abnormal findings observed during unscheduled observation periods were noted.

[0205] Body weight: Body weights were measured at least once during the pre-dose phase and before each scheduled dose. Additional body weights were recorded as needed to monitor animal health. Animals were fitted with transmitters: Prior to weighing for dose calculations, a scale was tared using a representative transmitter and leads.

[0206] Telemetry Data Collection: Raw arterial pressure signals were digitized at a sampling rate of 500 Hz. Derivation parameters were the same for the pre-dose and dosing phases. For pre-dose data collection, all implanted telemetry devices were checked for signal consistency to ensure that the telemetry signal was acceptable for analysis. Signal checks consisted of at least one telemetry recording obtained from each rat in the study. Telemetry data was recorded continuously for approximately 24 hours. Telemetry data was reviewed to determine whether the rat was eligible for the study. Data was retained in the study record and used to calculate a nominal 24-hour mean arterial pressure average to aid in randomized animal selection. For dosing phase data collection, continuous telemetry data was collected during the dosing phase, from at least 90 minutes before dosing through approximately 48 hours after dosing.

[0207] Nominal dosing time: Telemetry collection time points were based on a single nominal dosing time for all animals. The nominal dosing time for each day of the dosing phase was the end of dosing for the first half of the animals dosed that day, as recorded in each computer for all animals in that calculation.

[0208] Telemetry Data Evaluation: Telemetry parameters including heart rate (beats / min), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), mean arterial pressure (mmHg), and arterial blood pressure (mmHg) were analyzed and reported. Telemetry data generated by Ponemah during the dosing phase was analyzed in 1-minute samples. Data was processed into 15-minute averages and provided for data review. The 15-minute average data was further averaged by binning into the following analysis periods: Period 1: 0.5 to 2 hours after administration; Period 2: 2-4 hours after administration; Period 3: 4 to 8 hours after administration; Period 4: 8-12 hours after administration; Period 5: 12-20 hours after administration; Period 6: 20-32 hours after administration (second light cycle); and Period 7: 32-44 hours after administration (second dark cycle).

[0209] analysis Blood pressure was measured over a 44-hour period using an implanted telemetry device.The primary outcome was systolic blood pressure.

[0210] Statistical analyses were performed using all available data points, weighted to reflect the non-constant timing of measurements. To account for repeated measurements within individuals over time, estimates of treatment effect were calculated using estimated differences between treatments using mixed models with a direct product autoregressive correlation structure (SAS 9.4, SAS Institute, Cary, NC).

[0211] result Eight animals were initiated into the study; however, the telemetry transmitter failed in one animal, resulting in complete data being available from seven animals.

[0212] The table below shows the difference in systolic BP (mmHg) between treatments:

[0213] [Table 5]

[0214] Figure 1 shows the average systolic blood pressure (mmHg) over the treatment period. Figure 2 shows the average diastolic blood pressure (mmHg) over the treatment period. Figure 3 shows the average heart rate over the treatment period.

[0215] In this non-limiting example, the results demonstrated that Combination 1 resulted in a greater reduction in systolic blood pressure than Combination 3, and that Combination 2 resulted in a greater reduction in systolic blood pressure than either Combination 3 or 1. These differences persisted over the entire 44-hour observation period. The results demonstrated that both Combination 1 and Combination 2 resulted in a greater reduction in systolic blood pressure than Combination 3. These differences persisted over the entire 44-hour observation period. There were similar differences in reduction in DPB between the three combinations, and no differences in heart rate between the combinations.

[0216] In this non-limiting example, the results demonstrate unexpected differences between the combination of telmisartan, amlodipine besylate, and indapamide and the combination of losartan, amlodipine besylate, and hydrochlorothiazide. Specifically, at equivalent or lower doses, the combination of telmisartan, amlodipine besylate, and indapamide resulted in greater reductions in blood pressure than the combination of losartan, amlodipine besylate, and hydrochlorothiazide. Because the dose of amlodipine besylate is the same in combinations 2 and 3, the results demonstrate previously unknown differences in the effectiveness of certain angiotensin II receptor blockers and certain diuretics (such as thiazide diuretics vs. thiazide-like diuretics) when administered in parallel with amlodipine besylate.

[0217] Example 2: Triple Combination Composition Therapy for the Treatment of Hypertension method The study is a randomized, placebo-controlled, double-blind crossover trial. It will be divided into three phases. During the first phase (4 weeks), participants will be randomized (1:1) to either receive the triple combination composition treatment or a placebo. This will be followed by a 2-week washout (placebo), after which participants will be assigned to the opposite group and receive the other treatment for 4 weeks. Participants will be recruited from the community, primarily through community general practices in western Sydney, Australia.

[0218] participants Participants were eligible if they met the following inclusion criteria: 1) adults aged 18 years or older; 2) office SBP >140 mmHg and / or DBP >90 mmHg on two separate readings; and baseline ambulatory SBP >135 mmHg and / or DBP >85 mmHg; and 3) not receiving medical treatment for hypertension. Exclusion criteria included: no clear contraindication to one or more of the component drugs in the triple combination; the treating physician felt that changing current treatment would put the patient at risk; severe or accelerated hypertension; pregnancy; inability to provide informed consent; and a medical illness with an expected life expectancy of less than 3 months.

[0219] intervention For these studies, either triple combinations where each component is at 50% of the lowest hypertension therapeutic dose (LHTD) or triple combinations where each component is at 100% of the lowest hypertension therapeutic dose (LHTD) will be tested.

[0220] For studies testing triple combinations where each component is 50% of the lowest hypertension therapeutic dose (LHTD), the test compositions are as follows: The triple combination composition is a single encapsulated pill containing the following three components in predetermined amounts: telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg. The placebo capsule appears identical and contains a placebo tablet of similar weight to the tablets in the triple combination composition.

[0221] For studies testing triple combinations where each component is 100% of the lowest hypertension therapeutic dose (LHTD), the test compositions are as follows: The triple combination composition is a single encapsulated pill containing the three following components in predetermined amounts: telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg. The placebo capsule appears identical and contains a placebo tablet of similar weight to the tablets in the triple combination composition.

[0222] Participants will be administered a single pill of either the triple combination composition or placebo throughout the trial. Patients will be instructed to take the pill at the same time each day and encouraged to take the pill in the morning, although the time of day (morning or afternoon) is subject to patient preference.

[0223] All investigational products are prepared by a TGA-cGMP (Therapeutic Goods Australia-certificate of Good Manufacturing Practice) certified manufacturing facility. Where appropriate, a pill-splitting device is used to halve the half-strength dose, without crushing, to obtain a reduced-strength dose, which is then weighed to ensure accuracy of the dose halving. The reduced-strength dose is then encapsulated using gelatin capsules (DBCaps-Capsugel). The capsules are stored in a cool, dry place and monitored using a temperature logger until dispensed.

[0224] Treatment allocation will be blinded to both study staff and participants. In addition to the study medication, all participants will receive education about healthy lifestyle options recommended by guidelines for managing hypertension.

[0225] Randomization A computer-assisted randomization sequence is generated by a statistician and provided to the drug packaging company. This sequence is blinded to the research assistants, recruitment team, and investigators. For each patient, i.e., assigned randomization number, pills are enclosed in three child-resistant packages corresponding to the three phases of the study. The packages have an identical appearance, ensuring blinding of all patients and research staff. The drug packages are then dispensed in an organized sequence.

[0226] Outcomes and data collection The primary outcome was reduction in mean 24-hour systolic blood pressure over 4 weeks using ambulatory blood pressure recording (ABP). Secondary outcomes included: a. Reduction in mean 24-hour diastolic blood pressure and daytime and nighttime SBP and DBP over 4 weeks b. Reduction in office SBP and DBP measured by standardized automated blood cuffs c. Proportion with controlled blood pressure at 4 weeks, defined as 24-hour BP <135 / 85mmHg and office BP <140 / 90mmHg. d. Adverse events and pre-specified adverse events according to laboratory parameters: elevation of transaminases (ALT / AST) more than 3 times the upper limit of normal, or 2 times if baseline is known to be elevated; serum creatinine; a decrease in glomerular filtration rate of >20% as estimated by sodium, potassium, and uric acid levels; e. Assessment of acceptability and tolerability

[0227] Patients undergo 24-hour ABP monitoring four times: baseline (not taking the study drug), 4 weeks (taking the Phase 1 drug), 6 weeks (taking placebo), and 10 weeks (taking the Phase 3 drug). To minimize inconvenience, patients are referred to a laboratory for ABP. ABP units are calibrated by the laboratory at regular intervals according to the manufacturer's specifications. To minimize variability, follow-up readings are repeated from the same collection center using the same brand of device. Participants are reimbursed a nominal amount to cover travel and parking costs. Study drug and surveys are provided to participants free of charge. Office BP is recorded three times at each visit using an OMRON T9P (HEM-759-C1). The second and third readings are averaged for study analysis. Additionally, at weeks 4 and 10, patients undergo blood tests to assess biochemical side effects, complete questionnaires about clinical side effects, and assess compliance by self-report and pill counts. Patients remain blinded to treatment allocation when completing this questionnaire.

[0228] Drug tolerance and tolerability will also be assessed at the end of the study. All adverse events will be recorded. In addition, specific questions will be asked about clinical adverse events potentially related to antihypertensive medications: dizziness, blurred vision, syncope / collapse, chest pain / angina, shortness of breath, cough, wheezing, pedal edema, rash, and itching.

[0229] The trial will have a simplified data safety and management committee consisting of two core members with expertise in clinical medicine, clinical trials, and statistics. When 10 patients have been randomized, one meeting will be held to review the safety of the trial and advise continuing the trial.

[0230] Statistical considerations A sample size of 50 patients is planned to provide 90% power at p = 0.05 to detect an SBP difference of 12 mmHg between intervention and control, taking into account a possible 10% loss to follow-up and assuming an SD of the within-patient difference of 12 mmHg.

[0231] statistical methods Analyses will be performed with intention to treat. All tests will be two-sided, with a nominal alpha of 5%. All statistical analyses will be unadjusted for prognostic covariates. Data on pills taken during the period and missed doses will be used to report compliance with the study drug.

[0232] Following the approach of Kenward and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010;11(1):1-17), we used linear mixed models to estimate the effect of treatment on change in blood pressure from baseline for each treatment period. To appropriately adjust for baseline levels collected at the beginning of each treatment period (weeks 0 and 6), this method uses all measurements (baseline and follow-up for both periods) as outcomes but takes into account covariance between measurements within individuals (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 time period (first / second), type of measurement (baseline / final), and treatment received (placebo / triple combination composition) generate unbiased estimates of the effect of the triple combination composition on change in blood pressure compared to placebo. All available data are included in the model, and missing data are not imputed. If a patient is missing data for a period, data from the available period are used. To determine whether the treatment effect changes, a sensitivity analysis is performed including only patients with available data from both periods. Additionally, the degrees of freedom in the Kenward and Roger denominator are adjusted to optimize for smaller subject numbers (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).

[0233] Tests for carryover will use unpaired t-tests of the primary outcome with order as the effect. Period effects will be tested using paired t-tests, comparing the primary outcome in period 1 with the primary outcome in period 2 for the same patient. Sensitivity analyses will also be performed using ordinary paired t-tests to compare the primary outcome between different periods (different treatments) from the same patient, ignoring the baseline level in each period.

[0234] Continuous secondary endpoints with baseline values ​​(e.g., daytime / nighttime ambulatory SBP / DBP) will be analyzed similarly to the primary endpoint. Other continuous variables without baseline values ​​for each period will be analyzed using paired t-tests. Numbers and rates of all adverse events will be reported. As a sensitivity analysis, the analysis will be repeated with complete cases (i.e., complete data for each measurement period).

[0235] Age (<=60 vs. >60 years), sex, and BMI (<=30 kg / m 2 vs.<30kg / m 2 ) and the interaction between the treatment effect. Subgroup analyses for each variable will also be performed. All analyses will be performed using the software SAS 9.4 (Cary, NC, USA).

[0236] Example 3: Comparative study of low-dose combination composition vs. standard-dose monotherapy for the treatment of hypertension the goal The primary goal of this study is to investigate in a double-blind, randomized, controlled trial whether initiating treatment with low-dose combination therapy reduces blood pressure more effectively and with fewer side effects in hypertensive patients compared with initiating standard-dose monotherapy according to current guidelines. A secondary goal is to assess whether this approach is safe and has fewer side effects than standard treatment.

[0237] research design This will be a 12-week, double-blind, randomized controlled trial (1:1) in 650 patients with grade 1 and 2 essential hypertension. Subjects will be randomized by a central computer-based randomization service to initial treatment with the triple combination composition or an angiotensin receptor blocker (ARB) according to current Australian hypertension guidelines (with an additional option of a calcium channel blocker (CCB) if indicated). The primary outcome is reduction in mean systolic blood pressure using a standardized automated BP cuff at 12 weeks. Secondary outcomes include: proportion with controlled blood pressure at 6 and 12 weeks, ambulatory blood pressure (ABP) measurements, and tolerability / occurrence of adverse events.

[0238] Eligibility Criteria Inclusion criteria were as follows: -Adults (≥18 years old) - Treatment-naive or not currently on treatment (i.e., not in the last 4 weeks) taking one BP-lowering medication (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta-blocker, aldosterone antagonist, alpha-blocker) - SBP 140-179mmHg and / or DBP 90-109mmHg documented twice, at least one week apart - At least one of the above measurements must be documented by study staff using an automated BP device or recorded as a daytime mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg on 24-hour ambulatory BP monitoring -At least one of these measurements should be recent (last 12 weeks) - Documented daytime mean SBP ≥ 135mmHg and / or DBP ≥ 85mmHg on 24-hour ambulatory BP monitoring within 12 weeks prior to randomization. The exclusion criteria were as follows: - Contraindications to telmisartan, amlodipine, or indapamide - Hypertension, evidence of secondary causes, e.g., renal artery stenosis; significant renal dysfunction (eGRF<50), elevated serum potassium (laboratory normal range) - Pregnant women, lactating women, and / or women of childbearing potential who are not using a medically acceptable form of contraception (pharmacological or failure-type contraception) during the study - Any concomitant illness, physical injury, or psychiatric condition that, in the opinion of the study team / family physician, may interfere with the conduct of the study, including outcome assessment - Participation in concurrent interventional medical investigations or clinical trials. Patients in non-interventional observational, natural history, and / or epidemiological studies are eligible. The participant's primary care physician or other responsible physician believes it is not appropriate for the participant to switch from their current monotherapy - Unable or unwilling to provide written informed consent - Unable to complete study procedures including 24-hour ambulatory BP -Clear indication for combination therapy

[0239] Test Procedures For these studies, either triple combinations where each component is at 50% of the lowest hypertension therapeutic dose (LHTD) or triple combinations where each component is at 100% of the lowest hypertension therapeutic dose (LHTD) will be tested.

[0240] For studies testing a triple combination where each component is 50% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients who meet the inclusion criteria will be randomized to: 1) a combination pill containing the following three components - telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg; or 2) telmisartan 40 mg.

[0241] For studies testing a triple combination where each component is 100% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients who meet the inclusion criteria will be randomized to: 1) a combination pill containing the following three components - telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg; or 2) telmisartan 40 mg.

[0242] Patients currently receiving monotherapy will be asked to discontinue that therapy while receiving study treatment. If BP exceeds 140 / 90 mmHg in either group at 6 weeks, amlodipine besylate (5 mg) will be added by study staff.

[0243] Outcome The primary outcome was the between-group difference in mean automated office systolic blood pressure at 12 weeks, adjusted for baseline values.

[0244] Secondary outcomes include: 24-hour ambulatory blood pressure measurements Between-group differences in mean 24-hour SBP and DBP at 12 weeks Between-group differences in mean changes in 24-hour SBP and DBP from 0 to 12 weeks Between-group differences in mean daytime SBP and DBP at 12 weeks Between-group differences in mean nocturnal SBP and DBP at 12 weeks Between-group differences in daytime, nighttime, and 24-hour BP load (percentage of area under the blood pressure curve above normal daytime, nighttime, and 24-hour values ​​according to the NHFA Guide to management of hypertension 2008) Between-group differences in the proportion of nocturnal BP non-dippers (nighttime BP ≤10% lower than mean daytime BP according to the NHFA Guide to management of hypertension 2008) and the coefficient of variation of BP (O'Brien, E., G. Parati, and G. Stergiou, Hypertension, 2013. 62(6): p. 988-94). -Other blood pressure measurements in the triple group vs. the control group: Change in mean diastolic blood pressure from baseline to 12 weeks Control of hypertension (% with SBP<140mmHg and DBP<90mmHg) at 6 and 12 weeks Proportion without need for step-up treatment, with bilateral BP control (as defined above) and no adverse events at 6 weeks. Between-group differences in SBP and DBP variability -Acceptability Between-group differences in potentially relevant side effects (dizziness, blurred vision, fainting / collapse / fall, chest pain / angina, shortness of breath, cough, wheezing, ankle edema, rash, pruritus, gout, hyperkalemia, hypokalemia, hyponatremia, other) Between-group differences in mean potassium, uric acid, blood glucose, cholesterol and fraction, ALT, AST, UACR (urinary albumin-to-creatinine ratio), and creatinine levels. Between-group differences in patients who discontinued treatment.

[0245] statistical method All analyses of study results will be conducted according to the intention-to-treat principle. The primary analysis of change in systolic blood pressure (SBP) at 12 weeks will be performed using analysis of covariance (ANCOVA), including treatment group and baseline SBP as covariates. Continuous secondary outcomes will be analyzed similarly. Further analyses will include both 6- and 12-week measurements in longitudinal models, including treatment group, visit, and treatment by visit interactions, as well as baseline measurements. Generalized estimating equations will be used to model within-patient correlations. A similar approach will be applied to dichotomous endpoints (e.g., hypertension control), with log-binomial regression used instead of linear regression. Analyses of predefined subgroups, including baseline blood pressure, sex, age, and history of hypertension treatment, will also be conducted. A detailed analysis plan will be developed prior to unblinding.

[0246] Example 4: Pharmaceutical Composition 1 The following pharmaceutical compositions are prepared with the specified ingredients and dosages as shown in the table below.

[0247] [Table 6]

[0248] Example 5: Pharmaceutical Composition 2 The following pharmaceutical compositions are prepared with the specified ingredients and dosages as shown in the table below.

[0249] [Table 7-1]

[0250] [Table 7-2]

[0251] Example 6: Pharmaceutical Composition 3 The following pharmaceutical compositions are prepared with the specified ingredients and dosages as shown in the table below.

[0252] [Table 8-1]

[0253] [Table 8-2]

[0254] Example 7: Comparative study of low-dose combination composition versus standard-dose monotherapy and placebo to evaluate effects on blood pressure and cholesterol in subjects with migraine the goal To investigate in a double blind randomized factorial trial whether low-dose combination BP and cholesterol lowering treatment reduces BP and LDL levels, and to determine the safety of the intervention among participating subjects. Study design: A 12-week, double-blind, randomized, controlled, 3x3 factorial trial in participants with migraine. Participants were randomized to either the BP group (low-dose telmisartan, amlodipine, and indapamide vs. standard-dose propranolol vs. placebo) or the cholesterol-lowering group (low-dose rosuvastatin and ezetimibe vs. simvastatin vs. placebo). There was a 4-week screening period and an additional 4-week observation period after the study.

[0255] Eligibility Criteria Inclusion criteria were as follows: Migraine according to IHS ICHD-3 diagnostic criteria ICHD 3b (with or without typical aura) Subject self-reported an average of 2-14 migraine days per month over the past 3 months (90 days) Migraine symptoms must have been present for ≥1 year prior to study enrollment The onset of migraine symptoms must occur before age 50. Adults between 18 and 65 years old Office SBP ≥ 120mmHg and / or DBP ≥ 75mmHg (average of the second and third readings) No clear contraindications to any of the study drugs at the doses used in this trial (Subjects may take other prophylactic and therapeutic medications as long as they have no contraindications to the study drug. Patients are eligible if they are taking medications in the same class as the study treatment.) Medically stable as determined by the investigator. If taking concurrent migraine preventive medication, be on a stable dose at the investigator's discretion - Willingness to continue current migraine preventive medication during the study period Able to take oral medications, adhere to medication regimens, and perform study procedures for the duration of the study.

[0256] The exclusion criteria were as follows: Contraindications to any of the following: telmisartan, amlodipine, indapamide, rosuvastatin, ezetimibe, simvastatin, or propranolol Concurrent use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, or statins Clear indication for any one or more of the study drugs Subject has a history of cluster headaches. Subjects with exclusively headache-free migraine aura, migraine with brainstem aura, hemiplegic migraine, or chronic migraine Medication-overuse headache according to IHS criteria Pregnant female patients, breastfeeding female patients, or female patients who are capable of bearing children and are not using appropriate contraception Chronic medical conditions (e.g., lupus) that may have an impact, as determined by the investigator Alcohol or drug abuse within the last year Any current medical or psychiatric condition that, in the opinion of the investigator, may interfere with the conduct of the study or contraindicate participation. · Abnormal creatinine or electrolytes on screening. · Inability to provide informed consent. Treatment of migraine headaches with botulinum toxin injections or nerve stimulation in the past 3 months. Participation in an interventional medical investigation or clinical trial, currently or within the past 3 months. Subjects in non-interventional observational studies, natural history studies, and / or epidemiological studies are eligible.

[0257] Study design: A 12-week, double-blind, randomized, controlled, 3x3 factorial trial. Participants were randomized to either the BP group (low-dose telmisartan, amlodipine, and indapamide vs. standard-dose propranolol vs. placebo) or the cholesterol-lowering group (low-dose rosuvastatin and ezetimibe vs. simvastatin vs. placebo). There was a 4-week screening period and an additional 4-week observation period after the study.

[0258] [Table 9]

[0259] Participants were randomly assigned to a BP group (low-dose telmisartan, amlodipine, and indapamide vs. standard-dose propranolol vs. placebo) and a cholesterol group (low-dose rosuvastatin and ezetimibe vs. simvastatin vs. placebo) using a computer-generated randomization schedule. Group 1 received a low-dose BP-lowering combination and a low-dose cholesterol-lowering combination (i.e., telmisartan 20 mg + amlodipine 2.5 mg + indapamide 1.25 mg + rosuvastatin 10 mg + ezetimibe 10 mg (Composition N)). Group 2 received a low-dose BP-lowering combination and simvastatin (i.e., telmisartan 20 mg + amlodipine 2.5 mg + simvastatin). Group 3 received a low-dose BP-lowering combination and placebo (i.e., telmisartan 20 mg + amlodipine 2.5 mg + placebo). Group 4 received a low-dose cholesterol-lowering combination plus propranolol (i.e., rosuvastatin 10 mg + ezetimibe 10 mg + propranolol). Group 5 received propranolol plus simvastatin. Group 6 received propranolol plus placebo. Group 7 received a low-dose cholesterol-lowering combination plus placebo (i.e., rosuvastatin 10 mg + ezetimibe 10 mg + placebo). Group 8 received placebo plus simvastatin. Group 9 received double placebo.

[0260] The randomization allocation was blinded to all participants and study team members except the primary study statistician and the investigational drug manufacturer. All individual medications were overwrapped and blinded with identical packaging, labels, and dosing schedules.

[0261] Test Procedures

[0262] Low-dose BP-lowering combination = telmisartan 20 mg + amlodipine 2.5 mg + indapamide 1.25 mg once daily

[0263] Low-dose cholesterol-lowering combination = rosuvastatin 10 mg + ezetimibe 10 mg once daily

[0264] Propranolol dose = 160 mg / day, once daily

[0265] Simvastatin dose = 20 mg / day, once daily

[0266] Outcome Blood pressure and cholesterol outcomes: 1. Changes in DBP and SBP 2. Changes in LDL

[0267] Secondary outcomes: 1. Acceptability: a. Between-group differences in potentially relevant side effects (dizziness, blurred vision, syncope / collapse / fall, ankle edema, rash, pruritus, gout, hyperkalemia, hypokalemia, hyponatremia, muscle pain, insomnia, nightmares, rebound hypertension) b. Difference between groups in patients who discontinued treatment 2. Safety: Proportion of patients with any serious adverse events (SAEs) 3. Medication adherence: self-reported measures, pill counts.

[0268] BP measurement: Office BP measurements were performed according to the recommendations of the Australian National Heart Foundation. Participants rested in a seated position for 5 minutes, the appropriate cuff size was selected, and three BP measurements were recorded using an Omron HEM907 monitor or an equivalent validated automated digital BP monitor. The principles of automated office BP measurement were applied, whereby patients were left alone during BP recording.

[0269] Laboratory Tests: Potassium (K+), sodium (Na+), serum creatinine, and LDL were measured at screening and at a follow-up visit at the end of 12 weeks of treatment.

[0270] Safety: All participants reported SAEs and adverse events of special interest (AESIs) from the time of informed consent until the end of the follow-up period and reported them in case reports. AESIs included: Dizziness Hypotension Leg edema ·headache Muscle cramps Bradycardia ·Flushing Hypersensitivity reactions (rash, itching) Gastrointestinal disorders ·Myalgia Fainting / collapse / fall ·gout ·insomnia ·nightmare Rebound hypertension ·Chest tightness / chest pain Tremors / shaking Arrhythmia / tachycardia

[0271] statistical method Statistical and analytical planning

[0272] All analyses of study results were conducted according to the intention-to-treat principle. Analyses of continuous outcomes, such as SBP and LDL-cholesterol at 12 weeks, were performed using ANCOVA, including treatment group and baseline values ​​as covariates. Further analyses included baseline measurements as well as intermediate measurements in longitudinal models, including treatment group, visit, and treatment by visit interaction. Generalized estimating equations were used to model within-patient correlations. A similar approach was applied to dichotomous endpoints, with log-binomial regression used instead of linear regression. There were also predefined subgroup analyses, including baseline BP, baseline LDL, sex, and age.

[0273] Determining the number of subjects

[0274] With 60 participants randomized to each BP-lowering group and 60 participants randomized to each LDL-lowering group, the trial had 80% power at p = 0.05 to detect an SBP difference of 7 mmHg between groups, assuming an SD of 13; and 80% power at p = 0.05 to detect an LDL difference of 0.5 mmol / l, assuming an SD of 0.7 mmol / l. Given recruitment challenges, an adequate sample size was not achieved.

[0275] [Table 10]

[0276] result

[0277] [Table 11-1]

[0278] [Table 11-2]

[0279] [Table 11-3]

[0280] [Table 11-4]

[0281] [Table 12]

[0282] [Table 13-1]

[0283] [Table 13-2]

[0284] Table 14

[0285] Table 15

[0286] Table 16

[0287] Table 17-1

[0288] Table 17-2

[0289] Table 18-1

[0290] Table 18-2

[0291] Table 18-3

[0292] Table 18-4

[0293] Table 18-5

[0294] [Table 18-6]

[0295] [Table 18-7]

[0296] [Table 18-8]

[0297] Additional Embodiments

[0298] Embodiments include the following embodiments 1-161.

[0299] Embodiment 1. A pharmaceutical composition, the pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) of each of (a), (b), and (c), and the pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

[0300] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active agents, wherein the blood pressure lowering active agents comprise an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

[0301] Embodiment 3. The pharmaceutical composition of embodiment 1 or 2, wherein the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt thereof.

[0302] Embodiment 4. The pharmaceutical composition of any one of embodiments 1-3, wherein said pharmaceutical composition is essentially free of a beta-blocker, or a pharmaceutically acceptable salt thereof.

[0303] Embodiment 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition is essentially free of a platelet function-altering agent, a serum homocysteine-lowering agent, or a combination thereof.

[0304] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein said pharmaceutical composition is essentially free of platelet function-altering agents.

[0305] Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the platelet function modifying agent is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen.

[0306] Embodiment 11. The pharmaceutical composition of embodiment 9 or 10, wherein the platelet function altering agent is aspirin.

[0307] Embodiment 12. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is essentially free of a serum homocysteine-lowering agent.

[0308] Embodiment 13. The pharmaceutical composition of embodiment 12, wherein the serum homocysteine-lowering agent is folic acid, vitamin B6, vitamin B12, or a combination thereof.

[0309] Embodiment 14. The pharmaceutical composition of embodiment 12 or 13, wherein the serum homocysteine-lowering agent is folic acid.

[0310] Embodiment 15. The pharmaceutical composition of any one of embodiments 1-14, wherein the diuretic is an azide diuretic.

[0311] Embodiment 16. The pharmaceutical composition of embodiment 15, wherein the thiazide diuretic is altizide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof.

[0312] Embodiment 17. The pharmaceutical composition of embodiment 16, wherein the thiazide diuretic is hydrochlorothiazide.

[0313] Embodiment 18. The pharmaceutical composition of any one of embodiments 1-14, wherein the diuretic is a thiazide-like diuretic.

[0314] Embodiment 19. The pharmaceutical composition of embodiment 18, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0315] Embodiment 20. The pharmaceutical composition of embodiment 19, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0316] Embodiment 21. The pharmaceutical composition of embodiment 20, wherein the thiazide-like diuretic is indapamide.

[0317] Embodiment 22. The pharmaceutical composition of embodiment 19, wherein the thiazide-like diuretic is chlorthalidone.

[0318] Embodiment 23. The pharmaceutical composition of any one of embodiments 1-14, wherein the diuretic is a loop diuretic.

[0319] Embodiment 24. The pharmaceutical composition of embodiment 23, wherein the loop diuretic is furosemide, bumetanide, ethacrynic acid, etozolin, muzolimine, ozolinone, piretanide, tienilic acid, torasemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0320] Embodiment 25. The pharmaceutical composition of any one of embodiments 1-14, wherein the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof.

[0321] Embodiment 26. The pharmaceutical composition of any one of embodiments 1-25, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0322] Embodiment 27. The pharmaceutical composition of embodiment 26, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 28. The pharmaceutical composition of embodiment 27, wherein the calcium channel blocker is amlodipine besylate.

[0324] Embodiment 29. The pharmaceutical composition of any one of embodiments 1-28, wherein the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0325] Embodiment 30. The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is irbesartan.

[0326] Embodiment 31 The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is telmisartan.

[0327] Embodiment 32. The pharmaceutical composition of any one of embodiments 1-31, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD).

[0328] Embodiment 33. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide diuretic and the dose of the thiazide diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide diuretic.

[0329] Embodiment 34. The pharmaceutical composition of embodiment 33, wherein the thiazide diuretic is hydrochlorothiazide and the dose of hydrochlorothiazide is about 6.25 mg.

[0330] Embodiment 35. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

[0331] Embodiment 36. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.625 mg.

[0332] Embodiment 37. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is chlorthalidone, and the dose of chlorthalidone is about 12.5 mg.

[0333] Embodiment 38. The pharmaceutical composition of embodiment 32, wherein the diuretic is a loop diuretic and the dose of the loop diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the loop diuretic.

[0334] Embodiment 39. The pharmaceutical composition of any one of embodiments 1-38, wherein the dose of the calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0335] Embodiment 40. The pharmaceutical composition of embodiment 39, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.25 mg.

[0336] Embodiment 41. The pharmaceutical composition of any one of embodiments 1-40, wherein the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0337] Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is irbesartan and the dose of irbesartan is about 37.5 mg.

[0338] Embodiment 43. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is telmisartan and the dose of telmisartan is about 10 mg.

[0339] Embodiment 44. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

[0340] Embodiment 45. The pharmaceutical composition of embodiment 44, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0341] Embodiment 46. The pharmaceutical composition of embodiment 45, wherein the dose of irbesartan is about 37.5 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0342] Embodiment 47. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

[0343] Embodiment 48. The pharmaceutical composition of embodiment 47, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0344] Embodiment 49. The pharmaceutical composition of embodiment 48, wherein the dose of telmisartan is about 10 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0345] Embodiment 50. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0346] Embodiment 51. The pharmaceutical composition of embodiment 50, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0347] Embodiment 52. The pharmaceutical composition of embodiment 51, wherein the dose of irbesartan is about 37.5 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine is about 1.25 mg.

[0348] Embodiment 53. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0349] Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0350] Embodiment 55. The pharmaceutical composition of embodiment 54, wherein the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0351] Embodiment 56. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

[0352] Embodiment 57. The pharmaceutical composition of embodiment 56, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0353] Embodiment 58. The pharmaceutical composition of embodiment 57, wherein the dose of telmisartan is about 10 mg, the dose of chlorthalidone is about 12.5 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0354] Embodiment 59. The pharmaceutical composition of embodiment 32, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

[0355] Embodiment 60. The pharmaceutical composition of embodiment 59, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0356] Embodiment 61. The pharmaceutical composition of embodiment 60, wherein the dose of irbesartan is about 37.5 mg, the dose of chlorthalidone is about 12.5 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0357] Embodiment 62. The pharmaceutical composition of any one of embodiments 1-31, wherein the dose of each of (a), (b), and (c) is about 60% to about 80% of the lowest hypertension therapeutic dose (LHTD).

[0358] Embodiment 63. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide diuretic and the dose of the thiazide diuretic is about 66% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide diuretic.

[0359] Embodiment 64. The pharmaceutical composition of embodiment 63, wherein the thiazide diuretic is hydrochlorothiazide and the dose of hydrochlorothiazide is about 8.25 mg.

[0360] Embodiment 65. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 66% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

[0361] Embodiment 66. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.825 mg.

[0362] Embodiment 67. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is chlorthalidone and the dose of chlorthalidone is about 16.5 mg.

[0363] Embodiment 68. The pharmaceutical composition of embodiment 62, wherein the diuretic is a loop diuretic and the dose of the loop diuretic is about 66% of the lowest hypertensive therapeutic dose (LHTD) of the loop diuretic.

[0364] Embodiment 69. The pharmaceutical composition of any one of embodiments 62-68, wherein the dose of the calcium channel blocker is about 66% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0365] Embodiment 70. The pharmaceutical composition of embodiment 69, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.65 mg.

[0366] Embodiment 71. The pharmaceutical composition of any one of embodiments 62-70, wherein the dose of the angiotensin II receptor blocker is about 66% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0367] Embodiment 72. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is irbesartan and the dose of irbesartan is about 49.5 mg.

[0368] Embodiment 73. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is telmisartan and the dose of telmisartan is about 13.2 mg.

[0369] Embodiment 74. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

[0370] Embodiment 75. The pharmaceutical composition of embodiment 74, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0371] Embodiment 76. The pharmaceutical composition of embodiment 75, wherein the dose of irbesartan is about 49.5 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0372] Embodiment 77. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

[0373] Embodiment 78. The pharmaceutical composition of embodiment 77, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0374] Embodiment 79. The pharmaceutical composition of embodiment 78, wherein the dose of telmisartan is about 13.2 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0375] Embodiment 80. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0376] Embodiment 81. The pharmaceutical composition of embodiment 80, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0377] Embodiment 82. The pharmaceutical composition of embodiment 81, wherein the dose of irbesartan is about 49.5 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine is about 1.65 mg.

[0378] Embodiment 83. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0379] Embodiment 84. The pharmaceutical composition of embodiment 83, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0380] Embodiment 85. The pharmaceutical composition of embodiment 84, wherein the dose of telmisartan is about 13.2 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0381] Embodiment 86. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

[0382] Embodiment 87. The pharmaceutical composition of embodiment 86, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0383] Embodiment 88. The pharmaceutical composition of embodiment 87, wherein the dose of telmisartan is about 13.2 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0384] Embodiment 89. The pharmaceutical composition of embodiment 62, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

[0385] Embodiment 90. The pharmaceutical composition of embodiment 89, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0386] Embodiment 91. The pharmaceutical composition of embodiment 90, wherein the dose of irbesartan is about 49.5 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0387] Embodiment 92. The pharmaceutical composition of any one of embodiments 1-91, wherein the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is substituted with about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0388] Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the dose of the angiotensin II receptor blocker is substituted with about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0389] Embodiment 94. The pharmaceutical composition of embodiment 92, wherein the dose of the diuretic is substituted with about 80% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0390] Embodiment 95. The pharmaceutical composition of embodiment 92, wherein the dose of the calcium channel blocker is substituted with about 80% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0391] Embodiment 96. The pharmaceutical composition of any one of embodiments 92-95, wherein the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is substituted with about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0392] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the dose of the angiotensin II receptor blocker is substituted with about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0393] Embodiment 98. The pharmaceutical composition of embodiment 97, wherein the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0394] Embodiment 99. The pharmaceutical composition of embodiment 98, wherein the dose of the diuretic is substituted with about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0395] Embodiment 100. The pharmaceutical composition of embodiment 99, wherein the dose of the diuretic is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0396] Embodiment 101. The pharmaceutical composition of embodiment 96, wherein the dose of the calcium channel blocker is substituted with about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0397] Embodiment 102. The pharmaceutical composition of embodiment 101, wherein the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0398] Embodiment 103. The pharmaceutical composition of any one of embodiments 92-95, wherein the dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is substituted with about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0399] Embodiment 104. The pharmaceutical composition of embodiment 103, wherein the dose of the angiotensin II receptor blocker is substituted with about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0400] Embodiment 105. The pharmaceutical composition of embodiment 104, wherein the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0401] Embodiment 106. The pharmaceutical composition of embodiment 103, wherein the dose of the diuretic is substituted with about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0402] Embodiment 107. The pharmaceutical composition of embodiment 106, wherein the dose of the diuretic is replaced by about 200% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0403] Embodiment 108. The pharmaceutical composition of embodiment 103, wherein the dose of the calcium channel blocker is substituted with about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0404] Embodiment 109. The pharmaceutical composition of embodiment 108, wherein the dose of the calcium channel blocker is substituted with about 200% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0405] Embodiment 110. The pharmaceutical composition of any one of embodiments 1-91, wherein the doses of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are substituted with about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0406] Embodiment 111. The pharmaceutical composition of embodiment 110, wherein the dose of the angiotensin II receptor blocker is substituted with about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0407] Embodiment 112. The pharmaceutical composition of embodiment 110, wherein the dose of the diuretic is substituted with about 80% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0408] Embodiment 113. The pharmaceutical composition of embodiment 110, wherein the dose of the calcium channel blocker is substituted with about 80% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0409] Embodiment 114. The pharmaceutical composition of any one of embodiments 110-113, wherein the doses of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are substituted with about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0410] Embodiment 115. The pharmaceutical composition of embodiment 114, wherein the dose of the angiotensin II receptor blocker is substituted with about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0411] Embodiment 116. The pharmaceutical composition of embodiment 115, wherein the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0412] Embodiment 117. The pharmaceutical composition of embodiment 114, wherein the dose of the diuretic is substituted with about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0413] Embodiment 118. The pharmaceutical composition of embodiment 117, wherein the dose of the diuretic is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0414] Embodiment 119. The pharmaceutical composition of embodiment 114, wherein the dose of the calcium channel blocker is substituted with about 80% to about 150% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0415] Embodiment 120. The pharmaceutical composition of embodiment 119, wherein the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0416] Embodiment 121. The pharmaceutical composition of any one of embodiments 110-113, wherein the doses of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are substituted with about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0417] Embodiment 122. The pharmaceutical composition of embodiment 121, wherein the dose of the angiotensin II receptor blocker is substituted with about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0418] Embodiment 123. The pharmaceutical composition of embodiment 122, wherein the dose of the angiotensin II receptor blocker is substituted with about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0419] Embodiment 124. The pharmaceutical composition of embodiment 121, wherein the dose of the diuretic is substituted with about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0420] Embodiment 125. The pharmaceutical composition of embodiment 124, wherein the dose of the diuretic is replaced by about 200% of the lowest hypertensive therapeutic dose (LHTD) of the diuretic.

[0421] Embodiment 126. The pharmaceutical composition of embodiment 121, wherein the dose of the calcium channel blocker is substituted with about 150% to about 250% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0422] Embodiment 127. The pharmaceutical composition of embodiment 126, wherein the dose of the calcium channel blocker is substituted with about 200% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0423] Embodiment 128: A pharmaceutical composition, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and the pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

[0424] Embodiment 129: The pharmaceutical composition of embodiment 128, wherein the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifying agent, a serum homocysteine-lowering agent, or a combination thereof.

[0425] Embodiment 130: The pharmaceutical composition of embodiment 128 or 129, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0426] Embodiment 131: The pharmaceutical composition of embodiment 130, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0427] Embodiment 132: The pharmaceutical composition of embodiment 131, wherein the thiazide-like diuretic is indapamide.

[0428] Embodiment 133: The pharmaceutical composition of any one of embodiments 128-132, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0429] Embodiment 134: The pharmaceutical composition of embodiment 133, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0430] Embodiment 135: The pharmaceutical composition of embodiment 134, wherein the calcium channel blocker is amlodipine besylate.

[0431] Embodiment 136: A pharmaceutical composition described in any one of embodiments 128-135, wherein the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD).

[0432] Embodiment 137: The pharmaceutical composition of any one of embodiments 128-136, wherein the dose of the thiazide-like diuretic is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

[0433] Embodiment 138: The pharmaceutical composition of embodiment 137, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 1.25 mg.

[0434] Embodiment 139: The pharmaceutical composition of any one of embodiments 128-138, wherein the dose of the calcium channel blocker is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

[0435] Embodiment 140: The pharmaceutical composition of embodiment 139, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg.

[0436] Embodiment 141: The pharmaceutical composition of any one of embodiments 128-139, wherein the dose of the angiotensin II receptor blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0437] Embodiment 142: The pharmaceutical composition of any one of embodiments 128-140, wherein the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan.

[0438] Embodiment 143: The pharmaceutical composition of embodiment 142, wherein the dose of telmisartan is about 20 mg.

[0439] Embodiment 144: The pharmaceutical composition of embodiment 136, wherein the thiazide-like diuretic is indapamide, the calcium channel blocker is amlodipine besylate, and the angiotensin II receptor blocker is telmisartan.

[0440] Embodiment 145: The pharmaceutical composition of embodiment 144, wherein the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0441] Embodiment 146: The pharmaceutical composition of embodiment 145, wherein the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0442] Embodiment 147. A pharmaceutical composition according to any one of embodiments 1-146, wherein (a), (b), and (c) are provided in a single formulation.

[0443] Embodiment 148. The pharmaceutical composition of any one of embodiments 1-146, wherein (a), (b), and (c) are each provided in a separate formulation.

[0444] Embodiment 149. A pharmaceutical composition according to any one of embodiments 1-146, wherein two of (a), (b), and (c) are provided in a single formulation.

[0445] Embodiment 150. The pharmaceutical composition of any one of embodiments 1-149, wherein the pharmaceutical composition is in the form of a pill, tablet, or capsule.

[0446] Embodiment 151. The pharmaceutical composition of any one of embodiments 1-50, wherein the pharmaceutical composition is suitable for oral administration.

[0447] Embodiment 152: A method of treating hypertension in a subject, comprising administering to the subject a pharmaceutical composition according to any one of embodiments 1-151.

[0448] Embodiment 153. The method of embodiment 152, wherein the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg.

[0449] Embodiment 154. The method of embodiment 151 or 152, wherein the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more.

[0450] Embodiment 155. The method of any one of embodiments 151-154, wherein the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg.

[0451] Embodiment 156. The method of any one of embodiments 151-155, wherein the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more.

[0452] Embodiment 157. The method of any one of embodiments 151-156, wherein the treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a total minimum antihypertensive dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0453] Embodiment 158. The method of any one of embodiments 151-157, wherein the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a total minimum antihypertensive therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0454] Embodiment 159. The method of any one of embodiments 151-158, wherein the treatment results in greater long-term tolerability and reduced risk of side effects compared to the total minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0455] Embodiment 160. The method of any one of embodiments 151-159, wherein the treatment is an initial or primary treatment of hypertension.

[0456] Embodiment 161 The method of any one of embodiments 151-160, wherein the subject has not received any prior treatment for hypertension prior to treatment.

[0457] In some or any one of the above embodiments, the at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0458] In some or any one of the above embodiments, the at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0459] In some or any one of the above embodiments, the at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a statin.

[0460] In some or any one of the above embodiments, the at least one cholesterol-lowering active agent is selected from ezetimibe, rosuvastatin, or a combination thereof.

[0461] In some or any one of the above embodiments, the at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0462] In some or any one of the above embodiments, the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[0463] In some or any one of the above embodiments, (a), (b), and (c) are provided in a single formulation.

[0464] In some or any one of the above embodiments, (a), (b), (c) and the at least one cholesterol-lowering active agent are provided in a single formulation.

[0465] In some or any one of the above embodiments, (a), (b), (c) and the at least one cholesterol-lowering active agent are provided in separate formulations.

[0466] The embodiments include the following embodiments P1 to P99.

[0467] Embodiment P1. A pharmaceutical composition, the pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and the pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

[0468] Embodiment P2. The pharmaceutical composition of embodiment P1, wherein the pharmaceutical composition is an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof.

[0469] Embodiment P3. The pharmaceutical composition of Example P1 or P2, wherein said diuretic is a thiazide-like diuretic.

[0470] Embodiment P4. The pharmaceutical composition of embodiment P3, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0471] Embodiment P5. The pharmaceutical composition of Example P4, wherein said thiazide-like diuretic is indapamide or a hydrate thereof.

[0472] Embodiment P6. The pharmaceutical composition of Example P5, wherein said thiazide-like diuretic is indapamide.

[0473] Embodiment P7. The pharmaceutical composition of any one of embodiments P1-P6, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0474] Embodiment P8. The pharmaceutical composition of any one of embodiments P1-P7, wherein said calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0475] Embodiment P9. The pharmaceutical composition of any one of Examples P1-P8, wherein said calcium channel blocker is amlodipine besylate.

[0476] Embodiment P10. The pharmaceutical composition of any one of embodiments P1-P9, wherein said angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0477] Embodiment P11. The pharmaceutical composition of any one of Examples P1-P10, wherein said angiotensin II receptor blocker is telmisartan.

[0478] Embodiment P12. A pharmaceutical composition according to any one of embodiments P1-P11, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD).

[0479] Embodiment P13. The pharmaceutical composition of any one of embodiments P1-P12, wherein said diuretic is a thiazide-like diuretic and the dose of said thiazide-like diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of said thiazide-like diuretic.

[0480] Embodiment P14. The pharmaceutical composition of any one of Embodiments P1-P13, wherein said thiazide-like diuretic is indapamide and the dose of said indapamide is about 0.625 mg.

[0481] Embodiment P15. The pharmaceutical composition of any one of embodiments P1-P14, wherein the dose of said calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of said calcium channel blocker.

[0482] Embodiment P16. The pharmaceutical composition of any one of Embodiments P1-P15, wherein said calcium channel blocker is amlodipine besylate and said dose of amlodipine besylate is about 1.25 mg.

[0483] Embodiment P17. The pharmaceutical composition of any one of embodiments P1-P16, wherein the dose of said angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of said angiotensin II receptor blocker.

[0484] Embodiment P18. The pharmaceutical composition of any one of embodiments P1-P17, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 10 mg.

[0485] Embodiment P19. The pharmaceutical composition of any one of embodiments P1-P18, wherein said angiotensin II receptor blocker is telmisartan, said diuretic is indapamide, and said calcium channel blocker is amlodipine besylate.

[0486] Embodiment P20. The pharmaceutical composition of embodiment P19, wherein the dose of the telmisartan is about 8 mg to about 12 mg, the dose of the indapamide is about 0.5 mg to about 0.75 mg, and the dose of the amlodipine besylate is about 1 mg to about 1.5 mg.

[0487] Embodiment P21. The pharmaceutical composition of embodiment P19, wherein the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0488] Embodiment P22. A pharmaceutical composition, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and the pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

[0489] Embodiment P23. The pharmaceutical composition of embodiment P22, wherein the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifying agent, a serum homocysteine-lowering agent, or combinations thereof.

[0490] Embodiment P24. The pharmaceutical composition of embodiment P22 or P23, wherein said diuretic is a thiazide-like diuretic.

[0491] Embodiment P25. The pharmaceutical composition of embodiment P24, wherein said thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0492] Embodiment P26. The pharmaceutical composition of embodiment P25, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0493] Embodiment P27. The pharmaceutical composition of embodiment P26, wherein said thiazide-like diuretic is indapamide.

[0494] Embodiment P28. The pharmaceutical composition of any one of embodiments P22-P27, wherein said calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0495] Embodiment P29. The pharmaceutical composition of any one of embodiments P22-P28, wherein said calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0496] Embodiment P30. The pharmaceutical composition of any one of embodiments P22-P29, wherein said calcium channel blocker is amlodipine besylate.

[0497] Embodiment P31. The pharmaceutical composition of any one of embodiments P22-P30, wherein the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD).

[0498] Embodiment P32. The pharmaceutical composition of any one of embodiments P22-P31, wherein the dose of said thiazide-like diuretic is about 100% of the lowest hypertensive therapeutic dose (LHTD) of said thiazide-like diuretic.

[0499] Embodiment P33. The pharmaceutical composition of any one of embodiments P22-P32, wherein said thiazide-like diuretic is indapamide and the dose of said indapamide is about 1.25 mg.

[0500] Embodiment P34. The pharmaceutical composition of any one of embodiments P22-P33, wherein the dose of said calcium channel blocker is about 100% of the lowest hypertensive therapeutic dose (LHTD) of said calcium channel blocker.

[0501] Embodiment P35. The pharmaceutical composition of any one of embodiments P22-P34, wherein said calcium channel blocker is amlodipine besylate and said dose of amlodipine besylate is about 2.5 mg.

[0502] Embodiment P36. The pharmaceutical composition of any one of embodiments P22-P35, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of said telmisartan.

[0503] Embodiment P37. The pharmaceutical composition of any one of embodiments P22-P36, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 20 mg.

[0504] Embodiment P38. The pharmaceutical composition of any one of embodiments P22-P37, wherein said thiazide-like diuretic is indapamide, said calcium channel blocker is amlodipine besylate, and said angiotensin II receptor blocker is telmisartan.

[0505] Embodiment P39. The pharmaceutical composition of embodiment P38, wherein the dose of the telmisartan is about 16 mg to about 24 mg, the dose of the indapamide is about 1 mg to about 1.5 mg, and the dose of the amlodipine besylate is about 2 mg to about 3 mg.

[0506] Embodiment P40. The pharmaceutical composition of embodiment P39, wherein the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0507] Embodiment P41. The pharmaceutical composition of any one of embodiments P1-40, wherein said at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0508] Embodiment P42. The pharmaceutical composition of any one of embodiments P1-41, wherein said at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a tatin.

[0509] Embodiment P43. The pharmaceutical composition of any one of embodiments P1-42, wherein said at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

[0510] Embodiment P44. The pharmaceutical composition of any one of embodiments P1-43, wherein said at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0511] Embodiment P45. The pharmaceutical composition of embodiment P43 or P44, wherein the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[0512] Embodiment P46. A method of treating at least one of hypertension and dyslipidemia in a subject, the method comprising administering to the subject a pharmaceutical composition of any one of embodiments P1-P45.

[0513] Embodiment P47. A method of treating combined hypertension and dyslipidemia in a subject, said method comprising administering to said subject a pharmaceutical composition of any one of embodiments P1-P45.

[0514] Embodiment P48. The method of embodiment 46 or 47, wherein said method is a first-line treatment.

[0515] Embodiment P49. A method of treating hypertension and / or dyslipidemia in a subject, the method comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and the method further comprises at least one cholesterol-lowering active agent.

[0516] Embodiment P50. The method of embodiment P49, wherein said method is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifying agent, a serum homocysteine-lowering agent, or combinations thereof.

[0517] Embodiment P51. The method of embodiment P49 or P50, wherein said diuretic is a thiazide-like diuretic.

[0518] Embodiment P52. The method of embodiment P51, wherein said thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0519] Embodiment P53. The method of embodiment P52, wherein said thiazide-like diuretic is indapamide or a hydrate thereof.

[0520] Embodiment P54. The method of embodiment P53, wherein said thiazide-like diuretic is indapamide.

[0521] Embodiment P55. The method of any one of Embodiments P49-P54, wherein said calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0522] Embodiment P56. The method of any one of embodiments P49-P55, wherein said calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0523] Embodiment P57. The method of any one of embodiments P49-P56, wherein said calcium channel blocker is amlodipine besylate.

[0524] Embodiment P58. The method of any one of embodiments P49-P57, wherein said angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0525] Embodiment P59. The method of any one of embodiments P49-P58, wherein said angiotensin II receptor blocker is telmisartan.

[0526] Embodiment P60. The method of any one of embodiments P49-P59, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD).

[0527] Embodiment P61. The method of any one of Embodiments P49-P60, wherein said diuretic is a thiazide-like diuretic and said thiazide-like diuretic dose is about 50% of the lowest hypertensive therapeutic dose (LHTD) of said thiazide-like diuretic.

[0528] Embodiment P62. The method of any one of Embodiments P49-P61, wherein said thiazide-like diuretic is indapamide and said dose of indapamide is about 0.625 mg.

[0529] Embodiment P63. The method of any one of embodiments P49-P62, wherein the dose of said calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of said calcium channel blocker.

[0530] Embodiment P64. The method of any one of embodiments P49-P63, wherein said calcium channel blocker is amlodipine besylate and said dose of amlodipine besylate is about 1.25 mg.

[0531] Embodiment P65. The method of any one of embodiments P49-P64, wherein the dose of said angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of said angiotensin II receptor blocker.

[0532] Embodiment P66. The method of any one of embodiments P49-P65, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 10 mg.

[0533] Embodiment P67. The method of any one of embodiments P49-P66, wherein said angiotensin II receptor blocker is telmisartan, said diuretic is indapamide, and said calcium channel blocker is amlodipine besylate.

[0534] Embodiment P68. The method of embodiment P67, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0535] Embodiment P69. The method of embodiment P67, wherein the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0536] Embodiment P70. A method of treating hypertension and / or dyslipidemia in a subject, the method comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and the method further comprises at least one cholesterol-lowering active agent.

[0537] Embodiment P71. The method of embodiment P70, wherein said method is essentially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a platelet function modifying agent, a serum homocysteine-lowering agent, or combinations thereof.

[0538] Embodiment P72. The method of embodiment P70 or P71, wherein said diuretic is a thiazide-like diuretic.

[0539] Embodiment P73. The method of embodiment P72, wherein said thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0540] Embodiment P74. The method of embodiment P73, wherein said thiazide-like diuretic is indapamide or a hydrate thereof.

[0541] Embodiment P75. The method of embodiment P74, wherein said thiazide-like diuretic is indapamide.

[0542] Embodiment P76. The method of any one of Embodiments P70-P75, wherein said calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverin, or a pharmaceutically acceptable salt or hydrate thereof.

[0543] Embodiment P77. The method of any one of embodiments P70-P76, wherein said calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0544] Embodiment P78. The method of any one of embodiments P70-P77, wherein said calcium channel blocker is amlodipine besylate.

[0545] Embodiment P79. The method of any one of Embodiments P70-P78, wherein the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD).

[0546] Embodiment P80. The method of any one of Embodiments P70-P79, wherein the dose of said thiazide-like diuretic is about 100% of the lowest hypertensive therapeutic dose (LHTD) of said thiazide-like diuretic.

[0547] Embodiment P81. The method of any one of Embodiments P70-P80, wherein said thiazide-like diuretic is indapamide and said dose of indapamide is about 1.25 mg.

[0548] Embodiment P82. The method of any one of embodiments P70-P81, wherein the dose of said calcium channel blocker is about 100% of the lowest hypertensive therapeutic dose (LHTD) of said calcium channel blocker.

[0549] Embodiment P83. The method of any one of embodiments P70-P82, wherein said calcium channel blocker is amlodipine besylate and said dose of amlodipine besylate is about 2.5 mg.

[0550] Embodiment P84. The method of any one of embodiments P70-P83, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) for telmisartan.

[0551] Embodiment P85. The method of any one of embodiments P70-P84, wherein said angiotensin II receptor blocker is telmisartan and said dose of telmisartan is about 20 mg.

[0552] Embodiment P86. The method of any one of embodiments P70-P85, wherein said thiazide-like diuretic is indapamide, said calcium channel blocker is amlodipine besylate, and said angiotensin II receptor blocker is telmisartan.

[0553] Embodiment P87. The method of embodiment P86, wherein the dose of telmisartan is from about 16 mg to about 24 mg, the dose of indapamide is from about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is from about 2 mg to about 3 mg.

[0554] Embodiment P88. The method of embodiment P87, wherein the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0555] Embodiment P89. The method of any one of embodiments P49-P88, wherein said at least one cholesterol-lowering active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[0556] Embodiment P90. The method of any one of embodiments P49-P89, wherein said at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a tatin.

[0557] Embodiment P91. The method of any one of Embodiments P49-90, wherein said at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

[0558] Embodiment P92. The method of any one of embodiments P49-P90, wherein said at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0559] Embodiment P93. The method of embodiment P91 or P92, wherein the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[0560] Embodiment P94. The method of any one of embodiments P49-P93, wherein (a), (b), (c) and the at least one cholesterol-lowering active agent are provided in a single formulation.

[0561] Embodiment P95. The method of any one of embodiments P49-P93, wherein (a), (b), (c) and the at least one cholesterol-lowering active agent are provided in at least two separate formulations.

[0562] Embodiment P96. The method of any one of embodiments P49-P93, wherein at least two of (a), (b), (c), and said at least one cholesterol-lowering active agent are provided in a single formulation.

[0563] Embodiment P97. The method of any one of embodiments P49-P93, wherein at least three of (a), (b), (c), and said at least one cholesterol-lowering active agent are provided in a single formulation.

[0564] Embodiment P98. The method of embodiment P97, wherein said at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[0565] Embodiment P99. The method of embodiment P98, wherein (a), (b), and (c) are provided in a single formulation and the combination of ezetimibe and rosuvastatin is provided in a separate formulation.

[0566] In one aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) at least two of the calcium channel blockers; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0567] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) angiotensin II receptor blockers; (b) diuretics and; (c) at least three calcium channel blockers; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent. In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) at least two of the calcium channel blockers; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0568] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) at least two of the calcium channel blockers; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0569] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) with telmisartan; (b) thiazide-like diuretics; (c) at least three calcium channel blockers; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and wherein the pharmaceutical composition comprises at least one cholesterol-lowering active agent.

[0570] In some embodiments, (a), (b), and (c) are provided in a single formulation and the combination of ezetimibe and rosuvastatin is provided in a separate formulation.

[0571] In another aspect, there is also provided herein a method for treating at least one of hypertension and dyslipidemia in a subject, comprising administering the pharmaceutical composition disclosed in any one or more of the above embodiments. In particular, the method is a first-line treatment.

[0572] In another aspect, there is also provided herein a method for treating a combination of hypertension and dyslipidemia in a subject, comprising administering the pharmaceutical composition disclosed in any one or more of the above embodiments. In particular, the method is a first-line treatment.

[0573] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the disclosure described herein may be utilized in practicing the present disclosure. The following claims define the scope of the disclosure, and it is intended that methods and structures within the scope of the claims and their equivalents be covered thereby.

Claims

1. 1. A pharmaceutical composition, said pharmaceutical composition comprising: (a) an angiotensin II receptor blocker; (b) a diuretic; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD), and said pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

2. 2. The pharmaceutical composition of claim 1, wherein the diuretic is a thiazide-like diuretic, and the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

3. 3. The pharmaceutical composition of claim 2, wherein the thiazide-like diuretic is indapamide.

4. 4. The pharmaceutical composition of claim 1, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the calcium channel blocker is amlodipine besylate.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the angiotensin II receptor blocker is telmisartan.

8. 8. The pharmaceutical composition of any one of claims 1-7, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertensive therapeutic dose (LHTD).

9. 9. The pharmaceutical composition of claim 1, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

10. 10. The pharmaceutical composition of any one of claims 1-9, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.625 mg.

11. 11. The pharmaceutical composition of any one of claims 1-10, wherein the dose of the calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

12. 12. The pharmaceutical composition of any one of claims 1-11, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.25 mg.

13. 13. The pharmaceutical composition of any one of claims 1-12, wherein the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) of the angiotensin II receptor blocker.

14. 14. The pharmaceutical composition of any one of claims 1-13, wherein the angiotensin II receptor blocker is telmisartan and the dose of telmisartan is about 10 mg.

15. 9. The pharmaceutical composition of claim 8, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate; and the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

16. A pharmaceutical composition, the pharmaceutical composition comprising: (a) telmisartan; (b) a thiazide-like diuretic; (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD), and said pharmaceutical composition further comprises at least one cholesterol-lowering active agent.

17. 17. The pharmaceutical composition of claim 16, wherein the diuretic is a thiazide-like diuretic, and the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the thiazide-like diuretic is indapamide.

19. 19. The pharmaceutical composition of any one of claims 16-18, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

20. 20. The pharmaceutical composition of any one of claims 16-19, wherein the calcium channel blocker is amlodipine besylate.

21. 21. The pharmaceutical composition of any one of claims 16-20, wherein the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD).

22. 22. The pharmaceutical composition of any one of claims 16-21, wherein the dose of the thiazide-like diuretic is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the thiazide-like diuretic.

23. 23. The pharmaceutical composition of any one of claims 16-22, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 1.25 mg.

24. 24. The pharmaceutical composition of any one of claims 16-23, wherein the dose of the calcium channel blocker is about 100% of the lowest hypertensive therapeutic dose (LHTD) of the calcium channel blocker.

25. 25. The pharmaceutical composition of any one of claims 16-24, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg.

26. 26. The pharmaceutical composition of any one of claims 16-25, wherein the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan.

27. 27. The pharmaceutical composition of any one of claims 16-26, wherein the angiotensin II receptor blocker is telmisartan and the dose of telmisartan is about 20 mg.

28. 22. The pharmaceutical composition of claim 21, wherein the thiazide-like diuretic is indapamide, the calcium channel blocker is amlodipine besylate; and the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

29. 29. The pharmaceutical composition of any one of claims 1-28, wherein the at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

30. 30. The pharmaceutical composition of any one of claims 1-29, wherein said at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

31. 31. The pharmaceutical composition of claim 29 or 30, wherein the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

32. 32. A method of treating at least one of hypertension and dyslipidemia in a subject, said method comprising administering to said subject a pharmaceutical composition according to any one of claims 1-31.

33. 32. A method of treating combined hypertension and dyslipidemia in a subject, comprising administering to said subject a pharmaceutical composition according to any one of claims 1-31.

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