RU2828226C2 - Compositions for treating hypertension - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutics, specifically to embodiments of a pharmaceutical composition for treating hypertension and a method of treating hypertension in a subject in need thereof by oral administration of said composition to the subject. In one embodiment, the pharmaceutical composition contains: 8–12 mg of telmisartan; 0.5–0.75 mg of indapamide; 1–1.5 mg of amlodipine besylate; at least one hypocholesterolemic active agent containing a combination of ezetimibe 10 mg and rosuvastatin 10 mg. In another embodiment, the pharmaceutical composition contains: Telmisartan 16–24 mg; 1–1.5 mg of indapamide; 2–3 mg of amlodipine besylate; at least one hypocholesterolemic active agent containing a combination of ezetimibe 10 mg and rosuvastatin 10 mg.

EFFECT: group of inventions provides preventing or reducing side effects due to the use of active agents in low doses, as well as improved therapeutic effects in treating hypertension due to synergetic action.

9 cl, 3 dwg, 18 tbl, 7 ex

Description

[1] This application claims priority from U.S. Provisional Application No. 62/703,802, filed July 26, 2018, which is incorporated herein by reference.

Prior art of the present invention

[2] High blood pressure, also known as hypertension, is a leading cause of preventable morbidity and mortality, and treatments that lower blood pressure (BP) are well known to be effective. However, despite the many available blood pressure-lowering drugs, many patients still have poor blood pressure control, as documented in numerous large population-based studies. Factors contributing to poor blood pressure control include poor adherence to treatment, complex instructions recommending multiple increases in drug dose, and delays in treatment. Moreover, most treated patients receive only monotherapy, which has limited efficacy even at high doses, when side effects are increased and tolerability is reduced. Accordingly, there is a need for new effective and tolerable treatments to lower high blood pressure.

The essence of the present invention

[3] The present document, in accordance with one aspect, provides a pharmaceutical composition comprising:

(a) angiotensin II receptor blocker;

(b) a diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent. According to some embodiments, the pharmaceutical composition is substantially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, an agent that modifies platelet function, an agent that lowers serum homocysteine levels, or a combination thereof.

[4] According to some embodiments, the diuretic is a thiazide-like diuretic. According to some embodiments, the thiazide-like diuretic is quinetazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, clorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. According to some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. According to some embodiments, the thiazide-like diuretic is indapamide.

[5] According to 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof. According to some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. According to some embodiments, the calcium channel blocker is amlodipine besylate.

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

[7] According to some embodiments, the dose of each of (a), (b), and (c) is from about 40% to about 60% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, the diuretic is a thiazide-like diuretic, and the dose of the thiazide-like diuretic is about 50% of the lowest therapeutic dose for hypertension (LHTD) for the thiazide-like diuretic. According to some embodiments, the thiazide-like diuretic is indapamide, and the dose of indapamide is about 0.625 mg. According to some embodiments, the dose of the calcium channel blocker is about 50% of the lowest therapeutic dose for hypertension (LHTD) for 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 lowest therapeutic dose for the treatment of hypertension (LHTD) for 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. According to some embodiments, 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. According to 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.

[8] According to one aspect, there is provided a pharmaceutical composition comprising:

(a) telmisartan;

(b) thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[9] According to some embodiments, the pharmaceutical composition is substantially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, an agent that alters platelet function, an agent that lowers serum homocysteine levels, or a combination thereof.

[10] According to some embodiments, the thiazide-like diuretic is quinetazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, clorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. According to some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. According to some embodiments, the thiazide-like diuretic is indapamide.

[11] According to 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof. According to some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. According to some embodiments, the calcium channel blocker is amlodipine besylate.

[12] According to some embodiments, the dose of each of (a), (b), and (c) is from about 80% to about 120% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, the dose of the thiazide-like diuretic is about 100% of the lowest therapeutic dose for hypertension (LHTD) for the thiazide-like diuretic. According to some embodiments, the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg. According to some embodiments, the dose of the calcium channel blocker is about 100% of the lowest therapeutic dose for hypertension (LHTD) for the calcium channel blocker. According to 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 lowest therapeutic dose for hypertension (LHTD) for 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 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. 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.

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

[14] Also provided herein is a method of treating hypertension in a subject in need thereof comprising administering any of the pharmaceutical compositions disclosed herein. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by about 10 mmHg or more. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) by about 5 mmHg or more. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) that is greater than the decrease obtained with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition. According to some embodiments, the treatment results in longer tolerability and a reduced risk of adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition. According to some embodiments, the treatment is an initial or first-line hypertension therapy. According to some embodiments, the subject does not receive any previous hypertension therapy prior to the treatment.

[15] In accordance with another aspect, the present document provides a pharmaceutical composition consisting essentially of:

(a) angiotensin II receptor blocker;

(b) diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[16] In accordance with another aspect, the present document provides a pharmaceutical composition consisting essentially of:

(a) an angiotensin II receptor blocker such as telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b), and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 80% to about 120% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent. According to some embodiments, the dose of each of (a), (b), and (c) is from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[17] According to some embodiments, the at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[18] According to some embodiments, the at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[19] According to some embodiments, the at least one hypocholesterolemic active agent is a combination of an NPC1L1 inhibitor and a statin.

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

[21] According to some embodiments, the at least one hypocholesterolemic active agent is a combination of ezetimibe and rosuvastatin.

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

[23] According to some embodiments, (a), (b) and (c) are provided in a single composition.

[24] According to some embodiments, (a), (b), (c) and at least one hypocholesterolemic active agent are provided in a single formulation.

[25] Also provided herein in accordance with another aspect is a method for treating at least one of hypertension and dyslipidemia in a subject in need thereof, comprising administering the pharmaceutical compositions disclosed herein. In a clarification, the method is a first-line therapy.

[26] Also provided herein in accordance with another aspect is a method for treating at least a combination of hypertension and dyslipidemia in a subject in need thereof, comprising administering the pharmaceutical compositions disclosed herein. In a clarification, the method is a first-line therapy.

Incorporation of information into the description of the invention by reference

[27] 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 in its entirety.

Brief description of the drawings

[28] 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, which sets forth illustrative embodiments that utilize the principles of the present disclosure, as well as the accompanying drawings:

[29] Fig. 1 shows the mean systolic blood pressure (mmHg) at different time periods during treatment.

[30] Fig. 2 shows the mean diastolic blood pressure (mmHg) at different time periods during the treatment.

[31] Fig. 3 shows the average heart rate at different time periods during treatment.

Detailed description of the present invention

[32] Provided herein are pharmaceutical compositions for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. In some embodiments, the dose of each component is below the lowest dose approved for the treatment of hypertension. The present disclosure recognizes the technical effects of low-dose combination therapy set forth herein, including, but not limited to, the use of low doses to prevent or reduce side effects while maintaining or enhancing benefits, synergistic therapeutic benefits of certain drug combinations, early administration of combination therapy to enhance therapeutic effects, etc. Disclosed herein, in accordance with one aspect, are low-dose combination compositions for the treatment of hypertension, including initial or first-line therapy for hypertension.

Defined Terminology

[33] As used herein and in the appended claims, the singular forms "a", "an", and "the" include reference to the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "a composition" includes reference to one or more compositions (or a plurality of compositions) and equivalents thereof known to those skilled in the art, etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended that all combinations and subcombinations of the ranges and specific embodiments are included therein. The term "about", when referring to a number or numerical range, means that the recited number or numerical range is an approximation within the limits of experimental variability (or within the limits of statistical experimental error), and thus, in accordance with some embodiments, the number or numerical range varies between 1% and 10% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that, according to other specific embodiments, for example, an embodiment of any substance, composition, method or process or the like described herein, may "consist of" or "consist essentially of" the described characteristics.

Definitions

[34] As used in the specification and appended claims, unless otherwise indicated, the following terms have the meanings set forth below.

[35] The term "pharmaceutically acceptable salt" includes both acid addition and base addition salts. According to some embodiments, a pharmaceutically acceptable salt of any of the compounds described herein is a form approved for use by the U.S. Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[36] “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness and properties of the free bases, that are not biologically or otherwise undesirable, and that are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts which are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, 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, ptoluenesulfonic acid, salicylic acid, etc. Thus, illustrative salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are amino acid salts such as arginates, gluconates, and galacturonates (see, e.g., S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997), which is incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base forms with a sufficient amount of the desired acid to form the salt according to methods and techniques familiar to those skilled in the art.

[37] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an 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, 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 and etc. See Berge et al., above.

[38] As used herein, "hydrates" are compounds that contain stoichiometric or non-stoichiometric amounts of water and, in some embodiments, are formed by a crystallization process with water. Hydrates are intended to include hydrates of any of the compounds described herein that are approved for use by the U.S. Food and Drug Administration.

[39] The term “acceptable” with respect to a composition, formulation or ingredient as used herein means not having a persistent adverse effect on the general health of the subject being treated.

[40] The terms "administer," "to be administered," "administering," and the like refer to methods that can be used to ensure delivery of the compounds or compositions to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used with the compounds and methods described herein. According to some embodiments, the compounds and compositions described herein are administered orally.

[41] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: non-primate humans, such as chimpanzees and other species of apes and monkeys; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. According to one aspect, the mammal is a human.

[42] As used herein, the terms "treating" or "treatable" or "alleviating" or "normalizing" are used interchangeably herein. These terms refer to an approach to obtaining effective or desired results, including, without limitation, a therapeutic effect and/or a prophylactic effect. By "therapeutic effect" is meant the elimination or normalization of the underlying disorder being treated. In addition, a therapeutic effect is achieved by eliminating or normalizing one or more physiological symptoms associated with the underlying disorder such that improvement is observed in the patient, although the patient may still suffer from the underlying disorder. For a prophylactic effect, the compositions can be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of that disease has not been made.

Triple compositions

[43] Disclosed 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 from about 40% to about 80% of the lowest therapeutic dose for treating hypertension (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is about 50% of the lowest therapeutic dose for treating hypertension (LHTD). In some embodiments, the dose of each of (a), (b), and (c) is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is about 66% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

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

[45] According to 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 from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 80% to about 120% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 95% to about 105% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[46] According to some embodiments, the pharmaceutical compositions are substantially free of an angiotensin-converting enzyme inhibitor (ACE inhibitor) or a pharmaceutically acceptable salt thereof. According to some embodiments, the angiotensin-converting enzyme inhibitor includes, but is not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or a pharmaceutically acceptable salt or hydrate thereof.

[47] Also 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 from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 40% to about 60% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is about 50% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 60% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is about 66% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[48] Also 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 from about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 80% to about 120% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 90% to about 110% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is from about 95% to about 105% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[49] According to some embodiments, the pharmaceutical compositions disclosed herein can significantly reduce blood pressure in a subject with moderately elevated blood pressure. According to some embodiments, the pharmaceutical compositions disclosed herein can significantly reduce blood pressure in a subject with moderately elevated blood pressure with minimal, minor, or no side effects.

Beta blockers

[50] According to some embodiments, the pharmaceutical compositions described herein are substantially free of a beta-blocker or a pharmaceutically acceptable salt thereof. According to some embodiments, beta-blockers are compounds that inhibit the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on the adrenergic beta receptors of the sympathetic nervous system. According to some embodiments, beta-blockers include, but are not limited to, beta-blockers, beta-antagonists, beta-adrenergic antagonists, beta-adrenergic receptor antagonists, or beta-adrenergic receptor antagonists. According to some embodiments, beta-blockers inhibit the activation of all types of β-adrenergic receptors. According to some embodiments, beta-blockers inhibit both β-adrenergic receptors and α-adrenergic receptors. According to some embodiments, beta blockers are selective for one of the following beta receptors: β ₁ -, β ₂ -, and β ₃ - receptors.

[51] According to 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, cartolol, penbutolol, and nadolol. According to some embodiments, the beta blocker is a compound with combined β- and α-adrenergic receptor blocking activity. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetolol. According to some embodiments, the beta blocker is a β ₁ -selective adrenoceptor antagonist. Examples of a selective β ₁ -adrenergic receptor antagonist include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nebivolol, and acebutolol. According to some embodiments, the beta blocker is a β ₂ -selective adrenoceptor antagonist such as butaxamine.

[52] According to some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, cartolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, metipranolol, landiolol, bopindolol, pronethalol, butaxamine, bevantolol, tretatolol, arotinolol, levobetaxolol, befunolol, amosulalol, tilizolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, cartolol, 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. Platelet function altering agent

[53] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of an agent that modifies platelet function. In some embodiments, the agent that modifies platelet function is aspirin, ticlopidine, dipyridamole, or clopidogrel. In some embodiments, the agent that modifies platelet function is a glycoprotein IIb/IIIa receptor inhibitor, such as abciximab. In some embodiments, the agent that modifies platelet function is a nonsteroidal anti-inflammatory drug, such as ibuprofen. In some embodiments, the agent that modifies platelet function is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen. In some embodiments, the agent that modifies platelet function is aspirin.

A drug that reduces the level of homocysteine in the blood serum

[54] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of a serum homocysteine lowering agent. In some embodiments, the serum homocysteine lowering agent is folic acid, vitamin B6, or vitamin B12, or a combination thereof. In some embodiments, the serum homocysteine lowering agent is folic acid.

Angiotensin II receptor aptagonist/blocker

[55] 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.

Diuretics

[56] As used herein, diuretics refer to compounds that increase the rate of urination. Diuretics are classified by chemical structure (thiazide diuretics and thiazide-like diuretics), site of action (eg, loop diuretic), or pharmacologic effect (eg, osmotic diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics).

[57] 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.

Thiazide diuretics

[58] As used herein, thiazide diuretics refer to compounds that contain the benzothiadiazine molecular structure. According to some embodiments, thiazide diuretics inhibit the reabsorption of sodium and chloride in the distal tubule of the kidney, resulting in an increase in the excretion of sodium and water in the urine. Examples of thiazide diuretics include, but are not limited to, altiside, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyllothiazide, polychlorazide, and trithiazide.

[59] 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 epithiazide. In some embodiments, the thiazide diuretic is hydrochlorothiazide. In some embodiments, the thiazide diuretic is hydroflumethiazide. In some embodiments, the thiazide diuretic is mebutizide. In some embodiments, the thiazide diuretic is methylthiazide. In some embodiments, the thiazide diuretic is polythiazide. In some embodiments, the thiazide diuretic is trichlormethiazide.

Thiazide-like diuretics

[60] As used herein, a thiazide-like diuretic is a sulfonamide diuretic that has physiological properties similar to a thiazide diuretic but does not have the chemical properties of a thiazide (i.e., does not have a benzothiadiazine nucleus). Examples of thiazide-like diuretics include, but are not limited to, quinetazone, clopamide, chlorthalidone, mefruside, clofenanamide, metolazone, meticrane, xipamide, indapamide, clorexolone, and fenquizone.

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

Loop diuretics

[62] As used herein, loop diuretics are compounds that act on the Na ⁺ /K ⁺ /2Cl ^- cotransporter in the thick ascending loop of Henle to inhibit the reabsorption of sodium, chloride, and potassium. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, etozolin, muzolimine, ozolinone, piretanide, thienylic acid, torasemide. According to some embodiments, the loop diuretic is furosemide, bumetanide, ethacrynic acid, etozolin, muzolimine, ozolinone, piretanide, thienylic acid, torasemide, or a pharmaceutically acceptable salt or hydrate thereof.

Other diuretics

[63] Osmotic diuretics are compounds that cause water retention in the proximal tubule and the descending end of the loop of Henle. In some embodiments, an osmotic diuretic increases fluid and plasma volume and increases blood flow to the kidneys. Examples include, but are not limited to, mannitol and glycerol.

Carbonic anhydrase inhibitors

[64] Carbonic anhydrase inhibitors, as used herein, are compounds that are inhibitors of carbonic anhydrase. In some embodiments, a carbonic anhydrase inhibitor increases the excretion of bicarbonate with its accompanying sodium, potassium, and water, resulting in an increase in the flow of alkaline urine. In some embodiments, a carbonic anhydrase inhibitor inhibits the transport of bicarbonate into the interstitium from the proximal convoluted tubule, resulting in less sodium reabsorption and allowing for a greater loss of sodium, bicarbonate, and water in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorphenamide, and methazolamide.

Potassium-sparing diuretics

[65] Potassium-sparing diuretics are compounds that either compete with aldosterone for intracellular cytoplasmic receptor sites or 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, potassium canrenoate.

[66] Other diuretics indicated for use also include, but are not limited to, caffeine, theophylline, theobromine, tolvaptan, conivaptan, dopamine, and pamabromine.

[67] 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.

Calcium channel blockers

[68] As used herein, calcium channel blockers are compounds that promote vasodilatory activity by reducing the influx of calcium into vascular smooth muscle cells. According to 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, dotarizin, diproterene, 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.

Lowest therapeutic dose for the treatment of hypertension

[69] As used herein, lowest therapeutic dose for hypertension (LHTD) refers to the lowest dose of a single agent for hypertension that is approved by the U.S. Food and Drug Administration and is not labeled as "withdrawn" in the Orange Book database (http://www.accessdata.fda.gov/scripts/cder/ob/) as of the filing date of this application. The lowest therapeutic dose for hypertension does not include the lowest manufactured dose for cases where the lowest therapeutic dose for hypertension is not the same as the lowest manufactured dose. Additionally, the lowest therapeutic dose for hypertension does not include the dose recommended by a physician for cases where the lowest therapeutic dose for hypertension is not the same as the dose recommended by a physician. In addition, the lowest dose for the treatment of hypertension 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 that includes the free base, a pharmaceutically acceptable salt, or a hydrate thereof.

[70] According to some embodiments, the dose of the angiotensin II receptor blocker is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 70% to about 80% of the lowest therapeutic dose for the treatment of hypertension.

[71] According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for the treatment of hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is about 66% of the lowest therapeutic dose for treating hypertension.

[72] According to some embodiments, the dose of the diuretic is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is from about 70% to about 80% of the lowest therapeutic dose for treating hypertension.

[73] According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to 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%, or about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the diuretic is about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the 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 lowest therapeutic dose for treating hypertension. In some embodiments, the dose of the diuretic is about 66% of the lowest therapeutic dose for the treatment of hypertension.

[74] According to some embodiments, the dose of the thiazide diuretic is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is from about 70% to about 80% of the lowest therapeutic dose for the treatment of hypertension.

[75] According to 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is about 50% of the lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for the treatment of hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide diuretic is about 66% of the lowest therapeutic dose for treating hypertension.

[76] According to some embodiments, the dose of the thiazide-like diuretic is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 70% to about 80% of the lowest therapeutic dose for the treatment of hypertension.

[77] According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of a 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is about 50% of the lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for the treatment of hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is about 66% of the lowest therapeutic dose for treating hypertension.

[78] According to some embodiments, the dose of the loop diuretic is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is from about 70% to about 80% of the lowest therapeutic dose for the treatment of hypertension.

[79] According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is about 50% of the lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for the treatment of hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the loop diuretic is about 66% of the lowest therapeutic dose for treating hypertension.

[80] According to some embodiments, the dose of the calcium channel blocker is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 70% to about 80% of the lowest therapeutic dose for the treatment of hypertension.

[81] According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is about 50% of the lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for the treatment of hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is about 66% of the lowest therapeutic dose for treating hypertension.

[82] According to some embodiments, the lowest therapeutic dose for the treatment of hypertension (LHTD) and the corresponding proposed dose and proposed dose range for the following compounds are presented in the following table.

[83] According to 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. According to some embodiments, the dose of irbesartan is from about 30 mg to about 45 mg, the dose of hydrochlorothiazide is from about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg. According to 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.

[84] According to 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. According to some embodiments, the dose of telmisartan is from about 8 mg to about 12 mg, the dose of hydrochlorothiazide is from about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg. According to 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.

[85] According to 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. According to some embodiments, the dose of irbesartan is from about 30 mg to about 45 mg, the dose of indapamide is from about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg. According to 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.

[86] According to 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. According to some embodiments, 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. According to 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.

[87] According to 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. According to some embodiments, the dose of telmisartan is from about 8 mg to about 12 mg, the dose of chlorthalidone is from about 10 mg to about 15 mg, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg. According to 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.

[88] According to 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. According to some embodiments, the dose of irbesartan is from about 30 mg to about 45 mg, the dose of chlorthalidone is from about 10 mg to about 15 mg, and the dose of amlodipine besylate is from about 1 mg to about 1.5 mg. According to 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.

[89] According to 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. According to some embodiments, the dose of irbesartan is from about 45 mg to about 60 mg, the dose of hydrochlorothiazide is from about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[90] According to 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. According to some embodiments, the dose of telmisartan is from about 12 mg to about 16 mg, the dose of hydrochlorothiazide is from about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[91] According to 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. According to some embodiments, the dose of irbesartan is from about 45 mg to about 60 mg, the dose of indapamide is from about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[92] According to 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. According to some embodiments, the dose of telmisartan is from about 12 mg to about 16 mg, the dose of indapamide is from about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[93] According to 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. According to some embodiments, the dose of telmisartan is from about 12 mg to about 16 mg, the dose of chlorthalidone is from about 15 mg to about 20 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[94] According to 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. According to some embodiments, the dose of irbesartan is from about 45 mg to about 60 mg, the dose of chlorthalidone is from about 15 mg to about 20 mg, and the dose of amlodipine besylate is from about 1.5 mg to about 2 mg. According to 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.

[95] According to some embodiments, the dose of an angiotensin II receptor blocker, such as telmisartan, is from about 80% to about 150% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 80% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 80% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is from about 80% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 80% to about 110% of the lowest therapeutic dose for the treatment of hypertension.

[96] According to some embodiments, the dose of an angiotensin II receptor blocker, such as telmisartan, is from about 85% to about 145% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 85% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 85% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is from about 85% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin II receptor blocker is from about 85% to about 105% of the lowest therapeutic dose for the treatment of hypertension.

[97] According to some embodiments, the dose of an angiotensin II receptor blocker, such as telmisartan, is from about 90% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 90% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 90% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is from about 90% to about 110% of the lowest therapeutic dose for treating hypertension.

[98] According to some embodiments, the dose of an angiotensin II receptor blocker, such as telmisartan, is from about 95% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 95% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of an angiotensin II receptor blocker is from about 95% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is from about 95% to about 105% of the lowest therapeutic dose for treating hypertension.

[99] According to some embodiments, the dose of 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%, 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin II receptor blocker is about 100% of the lowest therapeutic dose for treating hypertension.

[100] According to some embodiments, the dose of the thiazide-like diuretic is from about 80% to about 150% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 80% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 80% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 80% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 80% to about 110% of the lowest therapeutic dose for treating hypertension.

[101] According to some embodiments, the dose of the thiazide-like diuretic is from about 85% to about 145% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 85% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 85% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 85% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 85% to about 105% of the lowest therapeutic dose for treating hypertension.

[102] According to some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 110% of the lowest therapeutic dose for treating hypertension.

[103] According to some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 105% of the lowest therapeutic dose for treating hypertension.

[104] According to 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%, 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 lowest therapeutic dose for the treatment of hypertension. According to some embodiments, the dose of a 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 lowest therapeutic dose for the treatment of hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the thiazide-like diuretic is about 100% of the lowest therapeutic dose for treating hypertension.

[105] According to some embodiments, the dose of the calcium channel blocker is from about 80% to about 150% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 80% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 80% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 80% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 80% to about 110% of the lowest therapeutic dose for treating hypertension.

[106] According to some embodiments, the dose of the calcium channel blocker is from about 85% to about 145% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 85% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 85% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 85% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 85% to about 105% of the lowest therapeutic dose for treating hypertension.

[107] According to some embodiments, the dose of the calcium channel blocker is from about 90% to about 140% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 90% to about 130% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 90% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 90% to about 110% of the lowest therapeutic dose for treating hypertension.

[108] According to some embodiments, the dose of the calcium channel blocker is from about 95% to about 135% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 95% to about 125% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 95% to about 115% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is from about 95% to about 105% of the lowest therapeutic dose for treating hypertension.

[109] According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the calcium channel blocker is about 100% of the lowest therapeutic dose for treating hypertension.

[110] According to some embodiments, the lowest therapeutic dose for the treatment of hypertension (LHTD) and the corresponding proposed dose and proposed dose range for the following compounds are presented in the following table.

[111] According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any of the angiotensin II receptor blocker, a diuretic, and a calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest therapeutic dose for the treatment of hypertension (LHTD). In some embodiments, for a diuretic, the dose of the diuretic is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a diuretic, the dose of the diuretic is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD).

[112] According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest therapeutic dose for the treatment of hypertension (LHTD). In some embodiments, for a diuretic, the dose of the diuretic is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a diuretic, the dose of the diuretic is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD). In some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD).

[113] According to some embodiments, the dose for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker of the angiotensin II receptor blocker, the diuretic (e.g., a thiazide diuretic or a thiazide-like diuretic), and the calcium channel blocker is independently from about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for the angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is from about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for the diuretic, the dose of the diuretic is from about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is independently from about 80% to about 120% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is from about 80% to about 120% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is from about 80% to about 120% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is from about 80% to about 120% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is about 100% of the lowest therapeutic dose for hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, a diuretic, or a calcium channel blocker, the dose of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is independently from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for a diuretic, the dose of the diuretic is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is from about 90% to about 110% of the lowest therapeutic dose for the treatment of hypertension (LHTD). According to some embodiments, for a calcium channel blocker, the dose of the calcium channel blocker is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[114] According to 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. According to some embodiments, the dose of telmisartan is from about 16 mg to about 30 mg, the dose of indapamide is from about 1 mg to about 1.875 mg, and the dose of amlodipine besylate is from about 2 mg to about 3.75 mg.

[115] According to some embodiments, 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.

[116] According to 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.

[117] According to 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.

[118] According to 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. According to some embodiments, the dose of telmisartan is from about 16 mg to about 30 mg, the dose of chlorthalidone is from about 20 mg to about 37.5 mg, and the dose of amlodipine besylate is from about 2 mg to about 3.75 mg.

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

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

[121] According to 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.

Compositions

[122] According to some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. According to some embodiments, each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is provided in a separate formulation. According to some embodiments, two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. According to some embodiments, the angiotensin II receptor and the diuretic are provided in a single formulation. According to some embodiments, the angiotensin II receptor blocker and the calcium channel blocker are provided in a single formulation. According to some embodiments, the diuretic and the calcium channel blocker are provided in a single formulation. According to some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in a single formulation. According to some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. According to some embodiments, the pharmaceutical composition is in the form of a pill. According to some embodiments, the pharmaceutical composition is in the form of a tablet. According to some embodiments, the pharmaceutical composition is in the form of a capsule. According to some embodiments, the pharmaceutical composition is suitable for oral administration.

[123] Other suitable formulations include, without limitation, those suitable for rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, or aerosol administration, although the most appropriate form of administration in any particular case will depend on the extent 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.

[124] Illustrative pharmaceutical compositions can be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, which contains one or more disclosed compounds as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for topical, enteral or parenteral administration. The active ingredient can be mixed, for example, with conventional non-toxic pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the disease process or condition.

[125] For the preparation of solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, for example, conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, water, to form a solid composition before shaping it into a dosage form containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to such compositions prior to shaping them into a dosage form as homogeneous, it is meant that the active ingredient is dispersed uniformly throughout the composition in such a way that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[126] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition in question is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: 1) fillers or diluents, such as starches, 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 glycerol; 4) agents for improving tablet disintegration, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; 5) dissolution retarders, such as paraffin; 6) absorption accelerators such as quaternary ammonium compounds; 7) wetting agents such as, for example, acetyl alcohol and glycerol monostearate; 8) absorbents such as kaolin and bentonite clay, 9) lubricating agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and 10) coloring agents. In the case of capsules, tablets and pills, the compositions can also contain buffering agents. Solid compositions of a similar type can optionally be employed as fillers in soft and hard gelatin capsules with the aid of such auxiliaries as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[127] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrating agent (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. According to some embodiments, capsules are prepared by encapsulating the tablets in hard gelatin capsules (e.g., superencapsulation). Tablets and other solid dosage forms such as dragees, capsules, pills and granules may optionally be scored or may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[128] According to some embodiments, the angiotensin II receptor blockers of the pharmaceutical compositions described herein may be replaced with angiotensin-converting enzyme inhibitors (ACE inhibitors). 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. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 80% to about 120% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 90% to about 110% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 100% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 40% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 40% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40% to about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 45% to about 55% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 50% to about 60% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 60% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 60% to about 70% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of the angiotensin-converting enzyme inhibitor is from about 70% to about 80% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin-converting enzyme inhibitor is about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for the treatment of hypertension. According to some embodiments, the dose of 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 lowest therapeutic dose for treating hypertension. According to some embodiments, the dose of angiotensin-converting enzyme inhibitor is about 66% of the lowest therapeutic dose for treating hypertension.

Treatment methods

[129] The pharmaceutical compositions described herein are useful for treating hypertension in a subject in need thereof. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 135 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by about 10 mmHg or more. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by about 10 mmHg to about 20 mmHg. In some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by about 10 mmHg to about 30 mmHg. According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by 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. According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) by 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. According to some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. According to some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 85 mmHg. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) by about 5 mmHg or more. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (D) by about 5 mmHg to about 10 mmHg. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (D) by about 5 mmHg to about 15 mmHg. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) by about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, or about 10 mmHg. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) by 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.

[130] According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of any of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition. According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of the angiotensin II receptor blocker in the pharmaceutical composition. According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of the diuretic in the pharmaceutical composition. According to some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction obtained with the full lowest therapeutic dose for the treatment of hypertension of the calcium channel blocker in the pharmaceutical composition.

[131] According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of any of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of the angiotensin II receptor blocker in the pharmaceutical composition. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) that is greater than the decrease obtained with the full lowest therapeutic dose for treating hypertension of the diuretic in the pharmaceutical composition. According to some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction obtained with the full lowest therapeutic dose for the treatment of hypertension of the calcium channel blocker in the pharmaceutical composition.

[132] According to some embodiments, the treatment results in longer tolerability and a reduced risk of adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of any of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition. According to some embodiments, the treatment results in longer tolerability and a reduced risk of adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of the angiotensin II receptor blocker in the pharmaceutical composition. According to some embodiments, the treatment results in longer tolerability and a reduced risk of adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of the diuretic in the pharmaceutical composition. According to some embodiments, the treatment results in longer tolerability and a reduced risk of adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of the calcium channel blocker in the pharmaceutical composition.

[133] According to some embodiments, the treatment results in a decrease in systolic blood pressure (SBP) that is greater than or equal to the decrease obtained with a combination of any two of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker in the pharmaceutical composition, wherein the dose of each angiotensin II receptor blocker, a diuretic, and a calcium channel blocker is about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) that is greater than or equal to the decrease obtained with a combination of any two of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker in the pharmaceutical composition, wherein the dose of each angiotensin II receptor blocker, a diuretic, and a calcium channel blocker is about 50% of the lowest therapeutic dose for treating hypertension. According to some embodiments, the treatment results in longer tolerability and a 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 angiotensin II receptor blocker, a diuretic, and a calcium channel blocker is about 50% of the lowest therapeutic dose for the treatment of hypertension.

[134] According to some embodiments, the treatment is an initial or first-line therapy for hypertension. According to some embodiments, the subject has a very moderate increase in blood pressure prior to the treatment. According to some embodiments, the subject does not receive any prior therapy for hypertension prior to the treatment. According to some embodiments, the subject has a very moderate increase in blood pressure prior to the treatment and does not receive any prior therapy for hypertension prior to the treatment.

[135] The present disclosure recognizes that the use of an angiotensin II receptor blocker in the pharmaceutical compositions disclosed herein in accordance with some embodiments provides beneficial therapeutic effects that include, but are not limited to, a significant reduction in blood pressure, a significant reduction in blood pressure in subjects with mild hypertension, higher long-term tolerability, and a reduced risk of adverse effects. The present disclosure recognizes that the exclusion of a platelet function-modifying agent, a serum homocysteine lowering agent, or a combination thereof in the pharmaceutical compositions disclosed herein in accordance with some embodiments provides beneficial therapeutic effects that include, but are not limited to, a significant reduction in blood pressure, a significant reduction in blood pressure in subjects with mild hypertension, higher long-term tolerability, and a reduced risk of adverse effects.

[136] It is also recognized herein that, in accordance with some embodiments, the triple combination described herein comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker with each component at about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) compared to a triple combination comprising an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) with each component at 100% of the lowest therapeutic dose for the treatment of hypertension. According to some embodiments, the triple combination described herein, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker with each component at about 40% to about 60% of the lowest therapeutic dose for the treatment of hypertension, provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) compared to a triple combination comprising an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) with each component at 100% of the lowest therapeutic dose for the treatment of hypertension.

[137] It is also recognized herein that, in accordance with some embodiments, the triple combination described herein comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker with each component at from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension, provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) compared to a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate). According to some embodiments, the triple combination described herein, comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker with each component at about 80% to about 120% of the lowest therapeutic dose for the treatment of hypertension, provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) compared to a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate).

[138] According to one aspect, there is provided a method of treating hypertension and/or dyslipidemia in a subject in need thereof, comprising administering to the subject:

(a) angiotensin II receptor blocker;

(b) diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD) and wherein the method further comprises at least one hypocholesterolemic active agent.

[139] According to some embodiments of the methods provided herein, the method does not comprise, contain, or consist 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. According to some embodiments of the methods provided herein, the method does not comprise, contain, or consist 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.

[140] According to 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.

[141] According to some embodiments of the methods provided herein, the angiotensin II receptor blocker is telmisartan.

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

[143] According to some embodiments of the methods provided herein, the diuretic is a thiazide-like diuretic, and for the thiazide-like diuretic, the dose of the thiazide-like diuretic is about 50% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

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

[145] According to some embodiments of the methods provided herein, for a calcium channel blocker, the dose of the calcium channel blocker is about 50% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[146] According to 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.

[147] According to some embodiments of the methods provided herein, for an angiotensin II receptor blocker, the dose of the angiotensin II receptor blocker is about 50% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

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

[149] According to 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.

[150] According to 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.

[151] According to 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.

[152] Provided herein is a method of treating hypertension and/or dyslipidemia in a subject in need thereof, comprising administering to the subject:

(a) telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD) and wherein the method further comprises at least one hypocholesterolemic active agent.

[153] According to some embodiments of the methods provided herein, the method does not substantially involve 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.

[154] According to some embodiments of the methods provided herein, the diuretic is a thiazide-like diuretic.

[155] According to some embodiments of the methods provided herein, the thiazide-like diuretic is quinetazone, clopamide, chlorthalidone, mefruside, clofenamid, metolazone, meticrane, xipamide, indapamide, clorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

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

[157] According to some embodiments of the methods provided herein, the thiazide-like diuretic is indapamide.

[158] According to 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

[160] According to some embodiments of the methods provided herein, the calcium channel blocker is amlodipine besylate.

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

[162] According to some embodiments of the methods provided herein, the dose of the thiazide-like diuretic is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD) for the thiazide-like diuretic.

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

[164] According to some embodiments of the methods provided herein, for a calcium channel blocker, the dose of the calcium channel blocker is about 100% of the lowest therapeutic dose for the treatment of hypertension (LHTD).

[165] According to 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.

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

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

[168] According to 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.

[169] According to 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.

[170] According to 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.

[171] According to some embodiments of the methods provided herein, at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

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

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

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

[175] According to some embodiments of the methods provided herein, the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

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

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

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

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

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

[181] According to some embodiments of the methods provided herein, (a), (b), (c) are provided in one formulation and the combination of ezetimibe and rosuvastatin are provided in another formulation.

Examples

Example 1: Measurement of cardiovascular parameters in spontaneously hypertensive rats treated with combinations of antihypertensive drugs

Summary

[182] The aim of this study was to evaluate the comparative effects on blood pressure of three different combinations of an angiotensin II receptor blocker, a calcium channel blocker, and a diuretic (a thiazide diuretic or a thiazide-like diuretic). The primary objectives were to assess whether there were differences in the effects of combinations using different drugs from the same class and differences between combinations using the same drugs at different doses, including very low doses (i.e., doses below the lowest approved and marketed doses, such as 50% of the lowest therapeutic dose for hypertension (LHTD).

[183] The specific combinations studied were:

• Combination 1: telmisartan, amlodipine besylate, and indapamide, all at 50% of the lowest therapeutic dose for hypertension (LHTD) or one-quarter of the usual FDA-recommended 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 therapeutic dose for hypertension (LHTD) or half of 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 therapeutic dose for hypertension (LHTD) or half of the usual FDA-recommended maintenance dose (equivalent to losartan 10 mg, amlodipine besylate 2.5 mg, and hydrochlorothiazide 12.5 mg).

[184] The study was performed in spontaneously hypertensive rats (SHR), which are the most commonly used animal model for studying hypertension (see: Pinto YM, Paul M, Ganten D. "Lessons from rat models of hypertension: from Goldblatt to genetic engineering". Cardiovascular Research. 39 (1): 77-88.). Drug doses were calculated using standard allometric scaling methods and published literature data on C _max and AUC for each of the six antihypertensive agents. Each animal was given a single dose of each drug combination in a Latin square pattern.

Methods

[185] The vehicle used for the following study was 0.5% methylcellulose (w/v) and 0.25% polysorbate 80 (v/v) in 25 mM phosphate buffer at pH 8±0.2.

[186] The animals used in the study were spontaneously hypertensive rats (strain: SHR/NCrl). Rats were obtained from Charles River Laboratories, Inc., Kingston, NY. The age at which drug administration began was approximately 12 weeks. Thirteen male rats were used for acclimatization. Eight male rats were used for the study. Animals were identified by a cell card and tattoo.

[187] Telemetry device implantation: Animals were implanted with Data Science International (HD-S10) transmitters to collect blood pressure and heart rate data. Animals were not administered medications until at least 10 days after surgery.

[188] Housing: Animals were housed individually in hard-bottomed cages supplied with water bottles.

[189] Diet: Teklad Global Diet - Rodent 2014 (Envigo RMS, Inc.) was provided ad libitum unless otherwise stated. In some cases, animals were maintained on this diet when indicated for health reasons.

[190] Water: Greenfield water was provided ad libitum.

[191] Contaminants: There were no known contaminants in the diet, water, or bedding (if applicable) at levels that would interfere with the conduct of this study.

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

[193] Acclimatization (pre-drug phase): The acclimatization phase lasted a maximum of 1 week.

[194] Environmental enhancements and dietary enrichment: Animals were provided with various cage enhancements and dietary enrichment devices (not requiring analysis).

[195] Randomization: Animals were randomly selected based on mean pre-drug blood pressure values.

[196] The following table shows the designation of the rats in the group used in the study.

[197] The following table shows the dose levels used in the study.

[198] Administration procedures: For combinations 1, 2, and 3, each study combination formulation was prepared fresh on each day of administration. A portion of the vehicle (approximately 80%) was added to the study combination formulation and mixed until homogeneous preparations were obtained. If a homogeneous suspension or solution was not obtained, 1 N NaOH and/or 1 N HCl was added to adjust the pH to 9 ± 0.2. The remainder of the vehicle was added and mixed with a stirrer. The study combination formulations were continuously stirred at room temperature and protected from light for approximately 30 minutes before and during administration. The study combination formulations were stored protected from light with stirring in a refrigerator set to maintain a temperature of 2 to 8°C.

[199] Administration Procedures: For pre-administration processing, study combination formulations were equilibrated to approximately room temperature for at least 30 minutes prior to administration. Animals were dosed at 10 mL/kg and the actual dose volume was based on the last measured body weight. Dosing was performed via gavage. The dosing interval was once daily on days 1, 8, 15, and 22. Following dosing, remaining study combination formulations were disposed of in accordance with standard operating procedures.

[200] Telemetry data collection: Animals were not disturbed or handled immediately before or during telemetry data collection without prior permission. Disturbances included, but were not limited to, cage changes, bedding changes, floor cleaning, sanitization, or anything that might disrupt the natural, quiet environment that was important for collecting cardiovascular telemetry data.

[201] Animal observation: Each rat was observed once daily in the morning. Any abnormalities were recorded. Rats were observed for mortality, abnormalities, and signs of pain or distress. Any abnormalities observed during unscheduled observation periods were also noted.

[202] Body weight: Body weight was obtained at least once during the pre-dose phase and prior to each scheduled dose. Additional body weights were recorded as needed to monitor the animals. Animals were equipped with a transmitter: An illustrative transmitter and leads were used to tare the scale prior to collecting body weight data for dose calculation.

[203] Telemetry data collection: Raw arterial pressure signals were digitized at a sampling rate of 500 Hz. The resulting parameters were identical during the pre- and intra-drug phases. For pre-drug data collection, all implanted telemetry devices were checked for signal consistency and to ensure the telemetry signal was acceptable for analysis. Signal checking consisted of at least one telemetry recording taken from each rat considered for the study. Telemetry data were recorded continuously for approximately 24 hours. Telemetry data were reviewed to determine if the rat was eligible for the study. Data were stored in study records and used to calculate a nominal 24-hour mean arterial pressure to support randomization of animals. For drug administration phase data collection, continuous telemetry data were collected during the drug administration phase beginning at least 90 minutes before administration and up to approximately 48 hours after administration.

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

[205] Telemetry data evaluation: Telemetry parameters including heart rate (beats per minute), systolic pressure (mmHg), diastolic pressure (mmHg), mean arterial pressure (mmHg), and arterial pulse pressure (mmHg) were analyzed and described. Telemetry data collected by Ponemah during drug administration phases were analyzed in 1-minute samples. Data were averaged over 15 minutes and made available for analysis. The 15-minute average data were further averaged by dividing into the following analysis periods:

• Period 1: 0.5 to 2 hours after dose administration;

• Period 2: 2 to 4 hours after dosing;

• Period 3: 4 to 8 hours after dosing;

• Period 4: 8 to 12 hours after dosing;

• Period 5: 12 to 12 hours after dosing;

• Period 6: 20 to 32 hours after dosing (second light cycle); and

• Period 7: 32 to 44 hours after dosing (second dark cycle).

Analysis

[206] Blood pressure was measured for 44 hours using an implanted telemetry device. The primary outcome was systolic blood pressure.

[207] Statistical analyses were performed using all available data points, with weighting to reflect heterogeneity in measurement timing. Estimates of treatment effects were calculated using estimated differences between treatments using a mixed model (SAS 9.4, SAS Institute, Cary, NC) with an autoregressive direct product correlation structure to account for repeated measurements within individuals over time.

Results

[208] Eight animals entered the study; however, the telemetry transmitter failed in one animal. As a result, complete data were available for seven animals.

[209] The following table shows the differences in systolic BP (mmHg) between treatments.

[210] Fig. 1 shows the average systolic blood pressure (mmHg) at different time periods during treatment. Fig. 2 shows the average diastolic blood pressure (mmHg) at different time periods during treatment. Fig. 3 shows the average heart rate at different time periods during treatment.

[211] In this non-limiting example, the results demonstrated that Combination 1 resulted in significantly greater reductions in systolic blood pressure than Combination 3, and Combination 2 resulted in significantly greater reductions in systolic blood pressure than Combination 3 or 1. These differences were maintained throughout the 44-hour observation period. The results demonstrated that both Combination 1 and Combination 2 resulted in significantly greater reductions in systolic blood pressure than Combination 3. These differences were maintained throughout the 44-hour observation period. There were similar differences between the three combinations in reduction of DPB and no differences between the combinations in heart rate.

[212] In this non-limiting example, these results demonstrate unexpected differences between the telmisartan, amlodipine besylate, indapamide combination and the losartan, amlodipine besylate, hydrochlorothiazide combination. Specifically, at equivalent or lower doses, the telmisartan, amlodipine besylate, and indapamide combination resulted in significantly greater reductions in blood pressure than the losartan, amlodipine besylate, and hydrochlorothiazide combination. Because the amlodipine besylate dose was the same in Combinations 2 and 3, the results demonstrate previously unknown differences in the efficacy of specific angiotensin II receptor blockers and specific diuretics (such as a thiazide diuretic versus a thiazide-like diuretic) when co-administered with amlodipine besylate.

Example 2: Triple combination therapy for hypertension

Methods

[213] The study was a randomised, placebo-controlled, double-blind, crossover study. The study was divided into three phases. During the first phase (4 weeks), participants were randomised (1:1) to receive either the triple combination therapy or placebo. This was followed by a two-week washout (placebo), and then participants crossed over to receive the other treatment for four weeks. Participants were recruited from the community, primarily through community GP practices in western Sydney, Australia.

Participants

[214] Participants were eligible if they met the following inclusion criteria: 1) adults aged 18 years or older, 2) SBP>140 mmHg and/or DBP>90 mmHg at the measurement site on 2 separate days; also baseline SBP>135 and/or DBP>85 in outpatient settings; 3) not receiving treatment for hypertension. Exclusion criteria included: no specific contraindications to the use of one or more components of the triple combination; the responsible clinician understanding that changing current therapy would put the patient at risk; severe or accelerated hypertension; pregnancy; inability to give informed consent; and medical illness with a life expectancy of less than 3 months.

Procedure

[215] For these studies, either a triple combination with each component at 50% of the lowest therapeutic dose for hypertension (LHTD) or a triple combination with each component at 100% of the lowest therapeutic dose for hypertension (LHTD) was tested.

[216] If the study tested a triple combination with each component at 50% of the lowest therapeutic dose for hypertension (LHTD), the study composition was as follows. The triple combination composition was a single encapsulated pill containing the following three components in the stated amounts: telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg. The placebo capsule was identical in appearance and contained placebo tablets of similar weight to those in the triple combination composition.

[217] If the study tested a triple combination with each component at 100% of the lowest therapeutic dose for hypertension (LHTD), the study composition was as follows. The triple combination composition was a single encapsulated pill containing the following three components in the stated amounts: telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg. The placebo capsule was identical in appearance and contained placebo tablets of similar weight to the tablets in the triple combination composition.

[218] Throughout the study, participants were given either a single pill, a triple combination formulation, or a placebo. Patients were instructed to take the pills at the same time each day, and were advised to take them in the morning, but the specific time (morning or evening) was up to the patient.

[219] All study drug products were manufactured in a Therapeutic Goods Australia (TGA-cGMP) licensed manufacturing facility. When required, low strength doses were prepared by halving half strength doses using a tablet splitter without crushing and weighed to ensure accuracy of halving. Low strength doses were then encapsulated using gelatin capsules (DBCaps-Capsugel). Capsules were stored in a cool, dry place and monitored with temperature loggers until dispensing.

[220] Treatment assignment was blinded to both study staff and participants. In addition to study medications, all participants were offered education on healthier lifestyles in accordance with hypertension control guidelines.

Randomization

[221] The randomization sequence was computer generated by a statistician and provided to the pharmaceutical packaging company. The research assistant, recruitment team, and investigators were blinded to the sequence. For each patient, i.e., assigned randomization number, pills were packaged in three child-resistant packages corresponding to the three phases of the study. All packages were identical in appearance, ensuring that the patient and study staff were not unaware of the contents. The medication packages were then dispensed in an ordered sequence.

Results and data collection

[222] The primary outcome was the reduction in mean 24-hour systolic blood pressure after 4 weeks using ambulatory blood pressure monitoring (ABPM). Secondary outcomes included:

a. reduction in mean 24-hour diastolic blood pressure, as well as daytime and nighttime SBP and DBP after 4 weeks,

b. reduction in SBP and DBP at the measurement point, measured with a standard automatic blood pressure cuff,

c. proportion with controlled blood pressure at 4 weeks, defined as 24-hour BP <135/85 mmHg and point BP <140/90 mmHg,

d. adverse reactions and pre-defined adverse events by laboratory parameters: increase in transaminase (ALT/AST) levels by more than 3 times the upper limit of normal or doubling if baseline levels are known to be elevated; decrease in estimated glomerular filtration rate by > 20%, as assessed by serum creatinine; sodium, potassium and uric acid levels,

e. assessment of acceptability and tolerability.

[223] Patients underwent 24-hour ABP monitoring at 4 times: baseline (no study drug), 4 weeks (Phase 1 drug), 6 weeks (placebo), and 10 weeks (Phase 3 drug). To minimize inconvenience, patients were referred to the laboratory for ABP determination. ABP units were calibrated at regular intervals in the laboratory according to the manufacturer's description. To minimize variability, subsequent measurements were repeated at a single collection center using the same brand of device. Participants were reimbursed for nominal travel and parking costs. Study drugs and tests were provided to participants at no charge. Point-of-care BP was recorded three times at each visit using an OMRON T9P (HEM-759-C1). The second and third readings were averaged for study analysis. In addition to blood tests at weeks 4 and 10 to assess biochemical side effects, patients were given a questionnaire to determine clinical side effects, and compliance was assessed by self-report and pill counting. Patients were blinded to their treatment assignment when completing the questionnaire.

[224] Acceptability and tolerability of the medications were also assessed at the end of the study. All adverse events were recorded. In addition, clinical adverse events that could be associated with blood pressure lowering medications were specifically asked about: dizziness, blurred vision, syncope/collapse, chest pain/angina, dyspnea, cough, wheezing, foot edema, skin rash, pruritus.

[225] The study had a simplified data safety and monitoring committee consisting of two core members with clinical, research and statistical expertise. One meeting was convened when 10 patients were randomized into the study to check safety and recommended continuation of the study.

Statistical aspects

[226] A sample size of 50 patients was planned to provide 90% power at p=0.05 to detect a 12 mmHg difference in SBP between procedure and control, assuming an SD of 12 mmHg for the between-patient difference, taking into account the possibility of a 10% loss to follow-up.

Statistical approach

[227] Analyses were performed on an intent-to-treat basis. All tests were two-sided and the nominal alpha level was 5%. All statistical analyses were unadjusted for prognostic covariates. Compliance with study drug was reported using pills taken (doses) and missed doses over time.

[228] A linear mixed model was used to estimate the treatment effect on change in blood pressure from baseline for each treatment period according to the approach of Kenward and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010; 11(1): 1-17.) To appropriately adjust for baseline levels collected at the beginning of each treatment period (week 0, week 6), this method used all measurements (baseline and follow-up, in both periods) as outcomes but accounted for 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). A linear contrast between the variables denoting period (first/second), type of measurement (baseline/final), and treatment received (placebo/triple combination) resulted in an unbiased estimate of the effect of the triple combination on blood pressure change compared with placebo. All available data were included in the model, missing data were not imputed. If a patient had missing data for one period, data for the available period were used. Sensitivity analysis was performed by including only patients with data for both periods to detect whether the treatment effect had changed. There was also an adjustment for the denominator of the degrees of freedom from Kenward and Roger (2009), which is optimal for smaller sample sizes (Kenward MG, Roger JH. An improved approximation to the precision of fixed effects from restricted maximum likelihood. Computational Statistics & Data Analysis 2009; 53(7): 2583-95).

[229] For the carryover study, an unpaired t-test of the primary outcome with ordering as the effect was used. The period effect was examined using a paired t-test comparing the primary outcome in period 1 with the primary outcome in period 2 in the same patient. Sensitivity analysis was also performed using a normal paired t-test comparing the primary outcomes across periods (different treatments) in the same patient, ignoring the baseline of each period.

[230] Continuous secondary endpoints with baseline values (eg, ambulatory SBP/DBP day/night) were analyzed similarly to the primary endpoint. Other continuous variables without a baseline value in each period were analyzed using paired t-tests. The number and percentage of all adverse events were reported. As a sensitivity analysis, the analysis was repeated for complete cases (ie, complete data for each measurement period).

[231] Interactions of treatment effect with age (≤60 vs. >60 years), gender, and BMI (≤30 vs. <30 kg/ ^m2 ) were examined. Subgroup analyses were also performed for each variable. All analyses were performed using SAS 9.4 software (Cary, NC, USA).

Example 3: Comparative study of low-dose combination formulation versus standard-dose monotherapy for the treatment of hypertension

Goals

[232] The primary objective of this study was to investigate in a double-blind, randomized, controlled trial whether initiating treatment with low-dose combination therapy would result in lower blood pressure more effectively and with fewer side effects than initiating standard-dose monotherapy according to current guidelines in patients with hypertension. A secondary objective was to evaluate whether this approach is safe and has fewer side effects than standard treatment.

Study design

[233] The study was a 12-week, double-blind, randomised controlled trial (1:1) in 650 patients with stage 1 and 2 essential hypertension. Subjects were randomised via a central computerised randomisation service to initial treatment with the triple combination formulation or an angiotensin receptor blocker (ARB) with the option to add a calcium channel blocker (CCB) as needed in line with current Australian hypertension guidelines. The primary outcome was reduction in mean systolic blood pressure using a standardised automated BP cuff at 12 weeks. Secondary outcomes included proportion with controlled blood pressure at 6 weeks, 12 weeks, ambulatory blood pressure (ABP) measurements and tolerability/occurrence of adverse events.

Eligibility Criteria

[234] The inclusion criteria were as follows:

- Adults (≥18 years).

- Previously untreated or currently untreated (no medication in the last 4 weeks) or taking one BP-lowering drug (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta-blocker, aldosterone antagonist, alpha-blocker).

- SBP 140-179 mmHg and/or DBP 90-109 mmHg, documented on two occasions more than a week apart.

- At least one of the measurements had to be documented by the study staff with an automated study

using a BP measuring device or measured as mean SBP ≥ 135 mmHg and/or DBP ≥ 85 mmHg during the day with 24-hour ambulatory BP monitoring.

- At least one of these measurements must be recent (within the last 12 weeks).

- 24-hour ambulatory BP monitoring mean SBP ≥ 135 mmHg and/or DBP ≥ 85 mmHg during the day - documented for 12 weeks after randomization.

The exclusion criteria were as follows:

- Contraindications to the use of telmisartan, amlodipine or indapamide.

- Evidence of a secondary cause of hypertension, such as renal artery stenosis; significant renal impairment (eGRF < 50), elevated serum potassium (above laboratory normal limit).

- Women who were pregnant, breastfeeding and/or of childbearing potential and did not use medically acceptable forms of contraception throughout the study (pharmacological or barrier methods).

- A concomitant disease, physical disorder or mental condition that, in the opinion of the research team/treating physician, could interfere with the conduct of the study, including the assessment of the results.

- Participation in a parallel interventional medical study or clinical trial. Patients participating in observational, natural history and/or epidemiological studies that did not involve intervention were eligible.

- The participant's primary care physician or other responsible physician considered that the participant was not eligible to change their current monotherapy.

- Inability or unwillingness to provide written informed consent.

- Inability to undergo investigation procedures, including 24-hour outpatient BP testing.

- Definite indication for combination therapy.

Treatment under investigation

[235] For these studies, either the triple combination with each component at 50% of the lowest therapeutic dose for hypertension (LHTD) or the triple combination with each component at 100% of the lowest therapeutic dose for hypertension (LHTD) was tested.

[236] If the study tested a triple combination with each component at 50% of the lowest therapeutic dose for hypertension (LHTD), the study composition was as follows. Eligible patients were 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.

[237] If the study tested a triple combination with each component at 100% of the lowest therapeutic dose for hypertension (LHTD), the study composition was as follows. Eligible patients were 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.

[238] Patients currently taking monotherapy were asked to stop treatment while they were taking study drug. After 6 weeks, if BP was above 140/90 mmHg in either group, study staff added amlodipine besylate (5 mg).

Results

[239] The primary outcome was the difference between groups in mean automated systolic blood pressure at the 12-week measurement point, adjusted for baseline values.

[240] Secondary outcomes included the following:

- 24-hour ambulatory blood pressure measurements.

Between-group difference in mean 24-hour SBP and DBP at 12 weeks.

Between-group difference in mean change in 24-hour SBP and DBP from weeks 0 to 12.

Between-group difference in mean daytime SBP and DBP after 12 weeks. Between-group difference in mean nighttime SBP and DBP after 12 weeks.

Between-group difference 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 2008 NHFA hypertension treatment guideline).

The difference between groups in the proportion of people with insufficient night-time blood pressure reduction (BP no more than 10% below average daytime BP according to the 2008 NHFA Guidelines for Hypertension Control) and the coefficient of BP variability (O'Brien, E., G. Parati, and G. Stergiou, Hypertension, 2013. 62(6): p. 988-94).

- Other blood pressure measurements in the triple group compared to the control group:

Change in mean diastolic blood pressure from baseline to 12 weeks.

Hypertension control (% with SBP < 140 mmHg and DBP < 90 mmHg) at 6 and 12 weeks.

Percentage requiring step-up dose escalation after 6 weeks. Percentage with both BP control (as defined above) and no adverse events.

Difference between groups in SBP and DBP variability.

- Tolerability

Difference between groups in potentially related adverse events (dizziness, blurred vision, syncope/collapse/fall, chest pain/angina, shortness of breath, cough, wheezing, foot swelling, skin rash, pruritus, gout, hyperkalemia, hypokalemia, hyponatremia, other).

Differences between groups in mean values of potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UACR (urine albumin to creatinine ratio) and creatinine levels.

Difference between groups in treatment discontinuation by participants.

Statistical methods

[241] All analyses of study outcomes were performed according to the intent-to-treat principle. The primary analysis of change in systolic blood pressure (SBP) at 12 weeks was performed using analysis of covariance (ANCOVA), including treatment group and baseline SBP as covariates. Continuous secondary outcomes were analyzed similarly. Additional analyses included both 6-week and 12-week measures in a longitudinal model, including interactions of treatment group, visit, and treatment by visit, as well as baseline measures. Between-patient correlations were modeled using generalized estimating equations. A similar approach was taken for binary endpoints (eg, hypertension control), using log-binomial regression instead of linear regression. Prespecified subgroup analyses also occurred, including those according to baseline pressure, sex, age, and history of hypertension treatment. A detailed analysis plan was developed prior to de-blinding.

Example 4: Pharmaceutical compositions 1

[242] The following pharmaceutical compositions were prepared using the specific components and dosages shown in the following table.

Example 5: Pharmaceutical compositions 2

[243] The following pharmaceutical compositions were prepared using the specific components and dosages shown in the following table.

Example 6: Pharmaceutical compositions 3

[244] The following pharmaceutical compositions were prepared using the specific components and dosages shown in the following table.

Example 7: Comparative study of low-dose combination formulation versus standard-dose monotherapy and placebo to evaluate effects on blood pressure and cholesterol levels in subjects with migraine

Goals

[245] To investigate in a double-blind, randomized factorial trial whether combination treatment with low-dose lipoproteins will lower BP and whether cholesterol-lowering therapy will lower BP and LDL levels, and to determine the safety of the interventions in participating subjects.

Study design: A 12-week, double-blind, randomized, controlled, 3x3 factorial trial in participants with migraine: participants were randomized to the BP group (low-dose telmisartan, amlodipine, indapamide versus standard-dose propranolol versus placebo) and the cholesterol-lowering group (low-dose rosuvastatin and ezetimibe versus simvastatin versus placebo). There was a 4-week screening period and a further 4-week post-study medication follow-up period.

Eligibility Criteria

[246] The inclusion criteria were as follows:

• Migraine-type headache (with or without typical aura) according to the diagnostic criteria of ICHD 3b according to IHS ICHD-3.

• 2-14 days per month with migraine headache on average over the past 3 months (90 days), based on self-reported by the subject.

• Migraine symptoms had to be present for ≥1 year prior to study entry.

• Migraine symptoms must have begun before age 50.

• Adults from 18 to 65 years old.

• SBP ≥ 120 mmHg and/or DBP ≥ 75 mmHg at the measurement point (average of the 2nd and 3rd readings).

• There were no specific contraindications to any of the study drugs at the doses used in this study. (Subjects could take other prophylactic or therapeutic drugs as long as they were not contraindicated for the study drug. Patients were eligible to participate if they were taking drugs from the same class as the study drugs.)

• Medically stable as determined by the investigator.

• When taking any concomitant medication(s) for migraine prophylaxis, a stabilized dose should be used at the discretion of the investigator.

• Desire to continue taking current medication(s) for migraine prophylaxis during the study.

• Ability to take oral medications, adhere to medication regimens, and perform study procedures throughout the study period.

[247] The exclusion criteria were as follows:

• Contraindications for any of telmisartan, amlodipine, indapamide, rosuvastatin, ezetimibe, simvastatin or propranolol.

• Concomitant use of an angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, calcium channel blocker, diuretic, or statin.

• A specific indication for any one or more investigational medicinal products.

• The subject had a history of cluster headaches.

• Subject who exclusively had migraine aura without headache, migraine with brainstem aura, hemiplegic migraine, or chronic migraine.

• Medication overuse headaches according to IHS criteria.

• Pregnant, lactating women or patients who are not using adequate contraception and who are capable of bearing children.

• Chronic medical conditions (eg, lupus) that could potentially influence headache frequency, as determined by the investigator.

• Alcohol or substance abuse within the past year.

• Any concomitant medical or psychiatric condition that, in the opinion of the investigator, could interfere with the conduct of the study or was a contraindication to participation.

• Abnormal creatinine or electrolytes on screening.

• Inability to provide informed consent.

• Treatment of migraines with botulinum toxin injections or nerve stimulation within the last three months.

• Participation in an interventional medical study or clinical trial currently or within the past 3 months. Subjects participating in observational, natural history, and/or epidemiological studies that did not involve intervention were eligible.

[248] Study design: 12-week, double-blind, randomized, controlled, 3×3 factorial trial: participants were randomized to the BP group (low-dose telmisartan, amlodipine, indapamide versus standard-dose propranolol versus placebo) and the cholesterol-lowering group (low-dose rosuvastatin and ezetimibe versus simvastatin versus placebo). There was a 4-week screening period and a further 4-week post-study drug follow-up period.

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

[250] Randomization allocation was blinded for all participants and study team members except for the primary study statisticians and the manufacturer of the study products. All individual drug products were double-coated and concealed with identical packaging, labeling, and administration schedule.

[251] Investigational treatment

[252] Low-dose combination for BP reduction = telmisartan 20 mg + amlodipine 2.5 mg + indapamide 1.25 mg once daily.

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

[254] Propranolol dose = 160 mg/day once daily.

[255] Simvastatin dose = 20 mg/day once daily.

Results

[256] Blood pressure and cholesterol results:

1. Change DBP and SBP.

2. Change in LDL.

[257] Secondary outcomes:

1. Tolerability:

a. Between-group differences in potentially related adverse events (dizziness, blurred vision, syncope/collapse/fall, foot edema, skin rash, pruritus, gout, hyperkalemia, hypokalemia, hyponatremia, myalgia, insomnia, nightmares, rebound hypertension).

b. Difference between groups in treatment discontinuation.

2. Safety: Percentage of any serious adverse event (SAE).

3. Treatment adherence: self-reported measures, number of pills.

BP measurement:

[258] Point-of-care BP was measured according to Australian National Heart Foundation recommendations. Participants rested in a seated position for 5 minutes, selected the appropriate cuff size, and recorded 3 BP measurements using an Omron HEM907 monitor or equivalent certified automated digital BP monitor. The principles of automated point-of-care BP measurement were used, with the patient left alone during BP recording.

Laboratory tests:

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

Safety:

[260] 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, as reported in the clinical record. AESIs included the following:

• Dizziness

• Hypotension

• Swelling of the foot

• Headache

• Muscle cramps

• Bradycardia

• Tides

• Hypersensitivity reactions (skin rash, itching of the skin)

• Gastrointestinal complaints

• Myalgia

• Fainting/collapse/fall

• Gout

• Insomnia

• Nightmares

• Rebound hypertension

• Chest tightness/pain

• Tremors/shaking

• Irregular heartbeat/tachycardia.

Statistical methods

[261] Statistical and analytical plans

[262] All analyses of study outcomes were performed according to the intent-to-treat principle. Continuous outcomes such as SBP and LDL-cholesterol at 12 weeks were analyzed using ANCOVA, including treatment group and baseline values as covariates. Additional analyses included between-measures in a longitudinal model, including the interaction of treatment group, visit, and treatment by visit, as well as baseline measurements. Between-patient correlations were modeled using generalized estimating equations. A similar approach was applied to binary endpoints, using log-binomial regression instead of linear regression. Subgroup analyses of baseline BP, baseline LDL, sex, and age were also prespecified.

[263] Determining sample size

[264] With 60 participants randomized to each BP-lowering group and 60 participants to each LDL-lowering group, the study had 80% power at p=0.05 to detect a 7 mmHg difference in SBP between each group, assuming an SD of 13; and 80% power at p=0.05 to detect a 0.5 mmol/L difference in LDL, assuming an SD of 0.7 mmol/L. Given recruitment issues, the full sample size was not reached.

Results

[265]

[266] Additional embodiments

[267] Embodiments include the following embodiments 1 to 161.

[268] Embodiment 1. A pharmaceutical composition comprising:

(a) angiotensin II receptor blocker;

(b) a diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD) for each of (a), (b) and (c), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

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

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

[271] Embodiment 4. The pharmaceutical composition according to any one of embodiments 1-3, wherein the pharmaceutical composition substantially does not comprise a beta blocker or a pharmaceutically acceptable salt thereof.

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

[273] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is substantially free of a platelet function altering agent.

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

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

[276] Embodiment 12. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition substantially does not comprise a serum homocysteine lowering agent.

[277] 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.

[278] Embodiment 14. The pharmaceutical composition according to embodiment 12 or 13, wherein the serum homocysteine lowering agent is folic acid.

[279] Embodiment 15. The pharmaceutical composition according to any one of embodiments 1-14, wherein the diuretic is a thiazide diuretic.

[280] 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.

[281] Embodiment 17. The pharmaceutical composition of embodiment 15, wherein the thiazide diuretic is hydrochlorothiazide.

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

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

[284] Embodiment 20. The pharmaceutical composition of embodiment 15, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

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

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

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

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

[289] Embodiment 25. The pharmaceutical composition according to 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.

[290] 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

[293] Embodiment 29. The pharmaceutical composition according to 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.

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

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

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

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

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

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

[300] 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.

[301] 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.

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

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

[304] 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.

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

[306] 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.

[307] 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.

[308] 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.

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

[310] 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.

[311] 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.

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

[313] 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.

[314] 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.

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

[316] 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.

[317] 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.

[318] Embodiment 54. The pharmaceutical composition of embodiment 53, wherein 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.

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

[320] 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.

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

[322] 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.

[323] 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.

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

[325] 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.

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

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

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

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

[330] 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.

[331] 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.

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

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

[334] 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.

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

[336] 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.

[337] 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.

[338] 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.

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

[340] 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.

[341] 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.

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

[343] 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.

[344] 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.

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

[346] 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.

[347] 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.

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

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

[350] 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.

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

[352] 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.

[353] 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.

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

[355] 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.

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

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

[358] Embodiment 94. The pharmaceutical composition of embodiment 92, wherein for the diuretic, the dose of the diuretic is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

[359] Embodiment 95. The pharmaceutical composition of embodiment 92, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

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

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

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

[363] Embodiment 99. The pharmaceutical composition of embodiment 98, wherein for the diuretic, the dose of the diuretic is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD).

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

[365] Embodiment 101. The pharmaceutical composition of embodiment 96, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD).

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

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

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

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

[370] Embodiment 106. The pharmaceutical composition of embodiment 103, wherein for the diuretic, the dose of the diuretic is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

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

[372] Embodiment 108. The pharmaceutical composition of embodiment 103, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

[373] Embodiment 109. The pharmaceutical composition of embodiment 108, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD).

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

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

[376] Embodiment 112. The pharmaceutical composition of embodiment 110, wherein for the diuretic, the dose of the diuretic is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

[377] Embodiment 113. The pharmaceutical composition of embodiment 110, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

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

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

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

[381] Embodiment 117. The pharmaceutical composition of embodiment 114, wherein for the diuretic, the dose of the diuretic is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD).

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

[383] Embodiment 119. The pharmaceutical composition of embodiment 114, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest therapeutic dose for hypertension (LHTD).

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

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

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

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

[388] Embodiment 124. The pharmaceutical composition of embodiment 121, wherein for the diuretic, the dose of the diuretic is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

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

[390] Embodiment 126. The pharmaceutical composition of embodiment 121, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest therapeutic dose for hypertension (LHTD).

[391] Embodiment 127. The pharmaceutical composition of embodiment 126, wherein for the calcium channel blocker, the dose of the calcium channel blocker is replaced by about 200% of the lowest therapeutic dose for hypertension (LHTD).

[392] Embodiment 128 A pharmaceutical composition comprising:

(a) telmisartan;

(b) thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), and wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[393] Embodiment 129. The pharmaceutical composition of embodiment 128, wherein the pharmaceutical composition is substantially 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.

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

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

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

[397] 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

[400] Embodiment 136. The pharmaceutical composition of any one of embodiments 128-135, wherein the dose of each of (a), (b), and (c) is from about 80% to about 120% of the lowest therapeutic dose for hypertension (LHTD).

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

[402] 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.

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

[404] 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.

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

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

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

[408] 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.

[409] Embodiment 145 The pharmaceutical composition of embodiment 144, 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.

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

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

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

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

[414] 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.

[415] Embodiment 151. The pharmaceutical composition of any one of embodiments 1-150, wherein the pharmaceutical composition is suitable for oral administration.

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

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

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

[419] 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.

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

[421] 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 obtained with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition.

[422] 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 obtained with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition.

[423] Embodiment 159. The method according to any one of embodiments 151-158, wherein the treatment results in longer tolerability and a reduced risk of side effects or adverse effects compared to treatment with the full lowest therapeutic dose for the treatment of hypertension of any of (a), (b), and (c) in the pharmaceutical composition.

[424] Embodiment 160. The method of any one of embodiments 151-159, wherein the treatment is initial or first-line hypertension therapy.

[425] Embodiment 161. The method of any one of embodiments 151-160, wherein the subject does not receive any prior therapy for hypertension prior to treatment.

[426] According to some embodiments above or any of them, at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[427] According to some embodiments above or any of them, at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[428] According to some embodiments above or any of them, at least one hypocholesterolemic active agent is a combination of an NPC1L1 inhibitor and a statin.

[429] According to some embodiments above or any of them, at least one hypocholesterolemic active agent is selected from ezetimibe, rosuvastatin, or a combination thereof.

[430] According to some embodiments above or any of them, the at least one hypocholesterolemic active agent is a combination of ezetimibe and rosuvastatin.

[431] According to some embodiments above or any of them, the dose of ezetimibe is about 10 mg and the dose of rosuvastatin is about 10 mg.

[432] According to some embodiments of the above, or any of them, (a), (b), and (c) are provided in a single composition.

[433] According to some embodiments of the above or any of them, (a), (b), (c) and at least one hypocholesterolemic active agent are provided in a single formulation.

[434] According to some embodiments of the above or any of them, (a), (b), (c) and the at least one hypocholesterolemic active agent are provided in a separate formulation.

[435] Embodiments include the following embodiments P1 to P99.

[436] Embodiment P1. A pharmaceutical composition comprising:

(a) angiotensin II receptor blocker;

(b) a diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD), and wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[437] Embodiment P2. The pharmaceutical composition of embodiment P1, wherein the pharmaceutical composition is substantially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, an agent that modifies platelet function, an agent that lowers serum homocysteine levels, or a combination thereof.

[438] Embodiment P3. The pharmaceutical composition according to embodiment P1 or P2, wherein the diuretic is a thiazide-like diuretic.

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

[440] Embodiment P5. The pharmaceutical composition according to embodiment P4, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[441] Embodiment P6. The pharmaceutical composition of embodiment P5, wherein the thiazide-like diuretic is indapamide.

[442] 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

[444] Embodiment P9. The pharmaceutical composition of any one of embodiments P1-P8, wherein the calcium channel blocker is amlodipine besylate.

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

[446] Embodiment P11. The pharmaceutical composition of any one of embodiments P1-P10, wherein the angiotensin II receptor blocker is telmisartan.

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

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

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

[450] Embodiment P15. The pharmaceutical composition of any one of embodiments PI-P14, wherein for the calcium channel blocker, the dose of the calcium channel blocker is about 50% of the lowest therapeutic dose for hypertension (LHTD).

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

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

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

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

[455] Embodiment P20. The pharmaceutical composition of embodiment P19, wherein 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.

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

[457] Embodiment P22. A pharmaceutical composition comprising:

(a) telmisartan;

(b) thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), and wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[458] Embodiment P23. The pharmaceutical composition of embodiment P22, wherein the pharmaceutical composition is substantially free of an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, an agent that alters platelet function, an agent that lowers serum homocysteine levels, or a combination thereof.

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

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

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

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

[463] Embodiment P28. The pharmaceutical composition of any one of embodiments P22-P27, 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

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

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

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

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

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

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

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

[474] Embodiment P39. The pharmaceutical composition of embodiment P38, 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.

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

[476] Embodiment P41: The pharmaceutical composition of any of the preceding embodiments, wherein the at least one hypocholesterolemic active agent is selected from an NPC1L1 inhibitor, a statin, or a combination thereof.

[477] Embodiment P42. The pharmaceutical composition of any one of the preceding embodiments, wherein the at least one cholesterol-lowering active agent is a combination of an NPC1L1 inhibitor and a statin.

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

[479] Embodiment P44: The pharmaceutical composition of any one of the preceding embodiments, wherein the at least one cholesterol-lowering active agent is a combination of ezetimibe and rosuvastatin.

[480] 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.

[481] Embodiment P46: A method of treating at least one of hypertension and dyslipidemia in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of any of the preceding embodiments.

[482] Embodiment P47: A method of treating a combination of hypertension and dyslipidemia in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of any of the preceding embodiments.

[483] Embodiment P48: The method of embodiment 46 or 47, wherein the method is first-line therapy.

[484] Embodiment P49. A method of treating hypertension and/or dyslipidemia in a subject in need thereof, comprising administering to the subject:

(a) angiotensin II receptor blocker;

(b) diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD) and wherein the method further comprises at least one hypocholesterolemic active agent.

[485] Embodiment P50. The method of embodiment P1, wherein the method does not substantially involve 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.

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

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

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

[489] Embodiment P54: The method of embodiment P53, wherein the thiazide-like diuretic is indapamide.

[490] Embodiment P55. The method of any one of embodiments P49-P54, 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

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

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

[496] Embodiment P61. The method of any one of embodiments P49-P60, wherein the diuretic is a thiazide-like diuretic, and for the thiazide-like diuretic, the dose of the thiazide-like diuretic is about 50% of the lowest therapeutic dose for hypertension (LHTD).

[497] Embodiment P62. The method of any one of embodiments P49 through P61, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.625 mg.

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

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

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

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

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

[503] Embodiment P68. The method of embodiment P67, wherein 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.

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

[505] Embodiment P70. A method of treating hypertension and/or dyslipidemia in a subject in need thereof, comprising administering to the subject:

(a) telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD) and wherein the method further comprises at least one hypocholesterolemic active agent.

[506] Embodiment P71. The method of embodiment P70, wherein the method does not substantially involve an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, an agent that alters platelet function, an agent that lowers serum homocysteine levels, or combinations thereof.

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

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

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

[510] Embodiment P75: The method of embodiment P74, wherein the thiazide-like diuretic is indapamide.

[511] Embodiment P76. The method of any one of Embodiments P70-P75, 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, dotarizin, diproterene, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

[515] Embodiment P80. The method of any one of embodiments P70-P79, wherein for a thiazide-like diuretic, the dose of the thiazide-like diuretic is about 100% of the lowest therapeutic dose for hypertension (LHTD).

[516] Embodiment P81: The method of any one of embodiments P70-P80, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg.

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

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

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

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

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

[522] 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.

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

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

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

[526] Embodiment P91: The method of any of the preceding embodiments, wherein the at least one cholesterol-lowering active agent is ezetimibe, rosuvastatin, or a combination thereof.

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

[528] 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.

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

[530] Embodiment P95: The method 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.

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

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

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

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

[535] According to one aspect, there is provided a pharmaceutical composition comprising at least two of:

(a) angiotensin II receptor blocker;

(b) diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[536] According to another aspect, there is provided a pharmaceutical composition comprising at least three of:

(a) angiotensin II receptor blocker;

(b) diuretic; and

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 40% to about 80% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent. According to another aspect, there is provided a pharmaceutical composition comprising at least two of:

(a) telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[537] According to another aspect, there is provided a pharmaceutical composition comprising at least two of:

(a) telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[538] According to another aspect, there is provided a pharmaceutical composition comprising at least three of:

(a) telmisartan;

(b) a thiazide-like diuretic; And

(c) calcium channel blocker,

wherein the dose of each of (a), (b) and (c) is from about 80% to about 150% of the lowest therapeutic dose for the treatment of hypertension (LHTD), wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent.

[539] According to some embodiments, (a), (b), (c) are provided in one formulation, and the combination of ezetimibe and rosuvastatin is provided in another formulation.

[540] Also provided herein in accordance with another aspect is a method of treating at least one of hypertension and dyslipidemia in a subject in need thereof, comprising administering a pharmaceutical composition disclosed in accordance with some or any of the embodiments above. In a clarification, the method is a first-line therapy.

[541] Also provided herein in accordance with another aspect is a method of treating a combination of hypertension and dyslipidemia in a subject in need thereof, comprising administering a pharmaceutical composition disclosed in accordance with some or any of the embodiments above. In a clarification, the method is a first-line therapy.

[542] Although 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 for exemplary purposes only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be used in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of the present claims and their equivalents will be encompassed therein.

Claims (19)

1. A pharmaceutical composition for the treatment of hypertension, containing: (a) telmisartan; (b) indapamide; and (c) amlodipine besylate, wherein the amount of telmisartan is from 8 mg to 12 mg, the amount of indapamide is from 0.5 mg to 0.75 mg and the amount of amlodipine besylate is from 1 mg to 1.5 mg, and wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent comprising a combination of ezetimibe and rosuvastatin, wherein the amount of ezetimibe is 10 mg and the amount of rosuvastatin is 10 mg. 2. The pharmaceutical composition according to claim 1, wherein the amount of indapamide is 0.625 mg. 3. The pharmaceutical composition according to claim 1 or 2, wherein the amount of amlodipine besylate is 1.25 mg. 4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of telmisartan is 10 mg. 5. A pharmaceutical composition for the treatment of hypertension, containing: (a) telmisartan; (b) indapamide; and (c) amlodipine besylate, wherein the amount of telmisartan is from 16 mg to 24 mg, the amount of indapamide is from 1 mg to 1.5 mg and the amount of amlodipine besylate is from 2 mg to 3 mg, and wherein the pharmaceutical composition further comprises at least one hypocholesterolemic active agent comprising a combination of ezetimibe and rosuvastatin, wherein the amount of ezetimibe is 10 mg and the amount of rosuvastatin is 10 mg. 6. The pharmaceutical composition according to claim 5, wherein the amount of indapamide is 1.25 mg. 7. The pharmaceutical composition according to claim 5 or 6, wherein the amount of amlodipine besylate is 2.5 mg. 8. A pharmaceutical composition according to any one of claims 5-7, wherein the amount of telmisartan is 20 mg. 9. A method for treating hypertension in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition according to any one of claims 1-8.

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