Compositions for treatment of hypertension

Abstract

To provide an effective and tolerable pharmaceutical composition for reducing hypertension.SOLUTION: Provided is a pharmaceutical composition for use in treating hypertension, containing (a) telmisartan, (b) indapamide, and (c) amlodipine besylate, the dosage of the telmisartan being about 16 mg to about 24 mg, the dosage of the indapamide being about 1 mg to about 1.5 mg, and the dosage of the amlodipine besylate being about 2 mg to about 3 mg, as well as the pharmaceutical composition not including an angiotensin-converting enzyme inhibitor or a pharmaceutical acceptable salt thereof, a β-blocker or a pharmaceutical acceptable salt thereof, a lipid regulating agent, a platelet function modifying agent, a serum homocysteine lowering agent, or a combination thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 62 / 450,324, filed Jan. 25, 2017, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] High blood pressure, also known as hypertension, is a major cause of preventable morbidity and mortality, and it is well established that treatments that lower blood pressure (BP) are beneficial. However, despite the availability of drugs that reduce excessive blood pressure, many patients continue to have poorly controlled blood pressure as evidenced by many large population studies. Contributing factors to poor blood pressure control include poor adherence, complex guidelines that recommend multiple up-titration steps, and treatment inertia. Furthermore, the majority of treated patients only receive monotherapy, which has limited efficacy even at high doses, increased side effects, and reduced tolerability. Therefore, new treatments for reducing high blood pressure that are effective and tolerable are needed. Summary of the Invention

[0003] In one aspect, a pharmaceutical composition is provided herein, the pharmaceutical composition comprising: (a) Angiotensin II receptor blockers; (b) diuretics; and (c) Calcium channel blockers Including, Here, the dosage of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0004] In some embodiments, the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharma- ceutically acceptable salt thereof, a beta-blocker or a pharma- ceutically acceptable salt thereof, a lipid-modulating agent, a platelet function-altering agent, a serum homocysteine-lowering agent, or a combination thereof.

[0005] In some embodiments, the diuretic is a thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

[0006] In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate.

[0007] In some embodiments, the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is telmisartan.

[0008] In some embodiments, the dosage of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the diuretic is a thiazide-like diuretic, and the dosage of the thiazide-like diuretic is about 50% of the minimum hypertension therapeutic dose (LHTD) for the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dosage of the indapamide is about 0.625 mg. In some embodiments, the dosage of the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dosage of the amlodipine besylate is about 1.25 mg. In some embodiments, the dosage of the angiotensin II receptor blocker is about 50% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the angiotensin II receptor blocker is telmisartan, and the dosage of telmisartan is about 10 mg. In some embodiments, the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate. In some embodiments, the dosage of telmisartan is about 8 mg to about 12 mg, the dosage of indapamide is about 0.5 mg to about 0.75 mg, and the dosage of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of indapamide is about 0.625 mg, and the dosage of amlodipine besylate is about 1.25 mg.

[0009] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) Telmisartan; (b) thiazide-like diuretics; and (c) Calcium channel blockers Including, Here, the dosage of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0010] In some embodiments, the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharma- ceutically acceptable salt thereof, a beta-blocker or a pharma- ceutically acceptable salt thereof, a lipid-regulating agent, a platelet function-modifying agent, a serum homocysteine-lowering agent, or a combination thereof.

[0011] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

[0012] In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate.

[0013] In some embodiments, the dosage of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of the thiazide-like diuretic is about 100% of the minimum hypertension therapeutic dose (LHTD) for the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dosage of the indapamide is about 1.25 mg. In some embodiments, the dosage of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dosage of the amlodipine besylate is about 2.5 mg. In some embodiments, the dosage of the telmisartan is about 100% of the minimum hypertension therapeutic dose (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 about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg. In some embodiments, the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0014] In some embodiments of the pharmaceutical compositions disclosed herein, (a), (b), and (c) are provided in one formulation. In some embodiments, (a), (b), and (c) are each provided in a separate formulation. In some embodiments, two of (a), (b), and (c) are provided in one formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0015] Also provided herein is a method of treating hypertension in a subject in need thereof, comprising administering any one 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 reduction in systolic blood pressure (SBP) of 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 reduction in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) of the pharmaceutical composition. In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) of the pharmaceutical composition. In some embodiments, the treatment results in greater long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject does not undergo the aforementioned hypertension treatment prior to the treatment.

[0016] In another aspect, there is provided herein a pharmaceutical composition, the pharmaceutical composition comprising: (a) Angiotensin II receptor blockers; (b) diuretics; and (c) Calcium channel blockers consisting essentially of Here, the dosage of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0017] In another aspect, the present specification provides a pharmaceutical composition, the pharmaceutical composition 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 dosage of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0018] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0019] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings in which: [Figure 1] Mean systolic blood pressure (mmHg) over the time period by treatment is shown. [Diagram 2] Mean diastolic blood pressure (mmHg) over the time period by treatment is shown. [Diagram 3] Average heart rate over the time period by treatment is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Provided herein is a pharmaceutical composition for the treatment of hypertension, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. In some embodiments, the dosage of each component is less than the minimum dosage approved for the treatment of hypertension. The present disclosure recognizes the technical advantages of the low-dose combination therapy described herein, including, but not limited to, the use of low dosages to avoid or improve side effects while maintaining or improving benefits, synergistic therapeutic effects of certain drug combinations, early introduction of combination therapy to improve therapeutic effects, and the like. Described herein, in one aspect, is a low-dose combination composition for the treatment of hypertension, including early or primary treatment of hypertension.

[0021] Specific Terms As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "composition" includes a reference to one or more compositions (or compositions), and equivalents thereof known to those of skill in the art. When ranges are used herein for a physical property, such as a molecular weight, or a chemical property, such as a chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be encompassed. The term "about," when referring to a numerical value or numerical range, means that the numerical value or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus, in some embodiments, the numerical value or numerical range varies between 1% and 10% of the stated numerical value or numerical range. The term "comprising" (and related words such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, embodiments such as, for example, any composition, method, or process described herein may "consist of" or "consist essentially of" the recited features.

[0022] definition As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0023] "Pharmaceutically acceptable salts" as used herein includes both acid and base addition salts. In some embodiments, the pharmaceutically acceptable salt of any one 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.

[0024] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanediol (alkanediol) acids, aromatic acids, and aliphatic and aromatic sulfonic acids, including, 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, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19(1997), incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those of ordinary skill in the art.

[0025] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts may also be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0026] As used herein, a "hydrate" is a compound that contains a stoichiometric or non-stoichiometric amount of water, and in some embodiments, is formed during the process of crystallization with water. Hydrate is meant to include any hydrate of the compounds described herein that is approved for use by the U.S. Food and Drug Administration.

[0027] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the general health of the subject receiving the treatment.

[0028] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0029] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, and the like; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0030] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, including, but not limited to, therapeutic and / or prophylactic effects. A "therapeutic effect" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic effect is achieved by the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that the patient is observed to improve, even though the patient may still be affected by the underlying disease. With regard to a prophylactic effect, the composition may be administered to a patient at risk of developing a particular disease or to a patient who reports one or more of the physiological symptoms of the disease, even if no diagnosis of the disease has been made.

[0031] Triple Compositions Described herein is a pharmaceutical composition, the pharmaceutical composition comprising: (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 60% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 66% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0032] In some embodiments, the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active ingredients, where the blood pressure lowering active ingredients consist of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

[0033] In another aspect, a pharmaceutical composition is described, the pharmaceutical composition comprising: (a) an angiotensin II receptor blocker, such as telmisartan; (b) a thiazide-like diuretic; and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 95% to about 105% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 100% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0034] In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of angiotensin-converting enzyme inhibitors (ACE inhibitors) or pharma- ceutically acceptable salts thereof. In some embodiments, angiotensin-converting enzyme inhibitors include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or pharma- ceutically acceptable salts or hydrates thereof.

[0035] Also described herein is a pharmaceutical composition, the pharmaceutical composition consisting essentially of (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 60% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 66% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0036] Also described herein is a pharmaceutical composition, the pharmaceutical composition 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 dosage of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 95% to about 105% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 100% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0037] In some embodiments, the pharmaceutical compositions disclosed herein achieve a significant reduction in blood pressure in subjects with moderately elevated blood pressure. In some embodiments, the pharmaceutical compositions disclosed herein achieve a significant reduction in blood pressure in subjects with moderately elevated blood pressure with minimal, minor, or no side effects.

[0038] Beta-blockers In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of beta-blockers or pharma- ceutically acceptable salts thereof. In some embodiments, beta-blockers are compounds that inhibit the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on the adrenergic agonist beta-receptors of the sympathetic nervous system. In some embodiments, beta-blockers include, but are not limited to, beta-adrenergic blockers, beta antagonists, beta-adrenergic antagonists, beta-adrenergic receptor antagonists, or beta-adrenergic receptor blockers. In some embodiments, beta-blockers inhibit activation of all types of beta-adrenergic receptors. In some embodiments, beta-blockers inhibit both beta-adrenergic receptors and alpha-adrenergic receptors. In some embodiments, beta-blockers are selective for one of the following beta-receptors: beta1, beta2, and beta3 receptors.

[0039] In some embodiments, the beta blocker is a non-selective beta adrenergic receptor antagonist. Examples of non-selective beta adrenergic receptor antagonists include, but are not limited to, pindolol, propranolol, oxprenolol, sotalol, timolol, carteolol, penbutolol, and nadolol. In some embodiments, the beta blocker is a compound that has a combination of beta and alpha adrenergic receptor blocking actions. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the beta blocker is a beta 1 selective adrenergic receptor antagonist. Examples of beta 1 selective adrenergic receptor antagonists include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nebivolol, and acebutolol. In some embodiments, the beta blocker is a beta2 selective adrenoceptor antagonist, such as butoxamine.

[0040] In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, practolol, metipranolol, landiolol, bopindolol, pronethalol, butoxamine, bevantolol, tertatolol, arotinolol, levobetaxolol, befunolol, amosulalol, tilisolol, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, oxprenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, carvedilol, labetalol, timolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is atenolol. In some embodiments, the beta blocker is bisoprolol or a pharmaceutically acceptable salt thereof.

[0041] Lipid Regulatory Agents In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of lipid regulating agents, platelet function modifying agents, serum homocysteine ​​lowering agents, or combinations thereof.

[0042] In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of lipid regulating drugs. In some embodiments, the lipid regulating drug is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, also known as a statin. In some embodiments, the lipid regulating drug is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin. In some embodiments, the lipid regulating drug is atorvastatin or simvastatin. In some embodiments, the lipid regulating drug is atorvastatin. In some embodiments, the lipid regulating drug is simvastatin.

[0043] Platelet function modifying drugs In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of platelet function modifying drugs. In some embodiments, the platelet function modifying drug is aspirin, ticlopidine, dipyridamole, clopidogrel. In some embodiments, the platelet function modifying drug is a glycoprotein IIb / IIIa receptor inhibitor, such as abciximab. In some embodiments, the platelet function modifying drug is a nonsteroidal anti-inflammatory drug, such as ibuprofen. In some embodiments, the platelet function modifying drug is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen. In some embodiments, the platelet function modifying drug is aspirin.

[0044] Serum homocysteine-lowering drugs In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of serum homocysteine ​​lowering drugs. In some embodiments, the serum homocysteine ​​lowering drug is folic acid, vitamin B6, or vitamin B12, or a combination thereof. In some embodiments, the serum homocysteine ​​lowering drug is folic acid.

[0045] Angiotensin II receptor blockers / blockers As used herein, angiotensin II receptor blockers 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 losartan, valsartan, candesartan, eprosartan, irbesartan, telmisartan, or a pharma- ceutically 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.

[0046] Diuretics As used herein, a diuretic refers to a compound that increases urine flow. Diuretics are classified by chemical structure (thiazide and thiazide-like diuretics), by site of action (e.g., loop diuretics), or by pharmacological effect (e.g., osmotic diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics).

[0047] In some embodiments, the pharmaceutical compositions disclosed herein include a thiazide diuretic. In some embodiments, the pharmaceutical compositions disclosed herein include a thiazide-like diuretic. In some embodiments, the pharmaceutical compositions disclosed herein include a loop diuretic. In some embodiments, the pharmaceutical compositions disclosed herein include an osmotic diuretic. In some embodiments, the pharmaceutical compositions disclosed herein include a carbonic anhydrase inhibitor. In some embodiments, the pharmaceutical compositions disclosed herein include a potassium-sparing diuretic.

[0048] Thiazide diuretics As used herein, thiazide diuretics refer to compounds that contain a benzothiadiazine molecular structure. In some embodiments, thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubules of the kidney, resulting in increased urinary excretion of sodium and water. Examples of thiazide diuretics include, but are not limited to, altizide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, and trichlormethiazide. In some embodiments, the thiazide diuretic is altizide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, methyclothiazide, polythiazide, trichlormethiazide, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is altizide. In some embodiments, the thiazide diuretic is bendroflumethiazide. In some embodiments, the thiazide diuretic is chlorothiazide. In some embodiments, the thiazide diuretic is cyclopenthiazide. In some embodiments, the thiazide diuretic is cyclothiazide. In some embodiments, the thiazide diuretic is epitizide. In some embodiments, the thiazide diuretic is hydrochlorothiazide. In some embodiments, the thiazide diuretic is hydroflumethiazide. In some embodiments, the thiazide diuretic is mebutizide. In some embodiments, the thiazide diuretic is methyclothiazide. In some embodiments, the thiazide diuretic is polythiazide. In some embodiments, the thiazide diuretic is trichlormethiazide.

[0049] Thiazide-like diuretics As used herein, a thiazide-like diuretic is a sulfonamide diuretic that has similar physiological properties as a thiazide diuretic, but does not have the chemical properties of a thiazide compound (i.e., does not have a benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, and fenquizone.

[0050] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharma- ceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is quinethazone. In some embodiments, the thiazide-like diuretic is clopamide. In some embodiments, the thiazide-like diuretic is chlorthalidone. In some embodiments, the thiazide-like diuretic is mefruside. In some embodiments, the thiazide-like diuretic is clofenamide. In some embodiments, the thiazide-like diuretic is metolazone. In some embodiments, the thiazide-like diuretic is meticrane. In some embodiments, the thiazide-like diuretic is xipamide. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide. In some embodiments, the thiazide-like diuretic is chlorexolone. In some embodiments, the thiazide-like diuretic is fenquizone.

[0051] Loop diuretics As used herein, a loop diuretic is a compound that acts on the Na+ / K+ / 2Cl- cotransporter in the thick ascending loop of Henle to inhibit reabsorption of sodium, chloride, and potassium. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, etozolin, muzolimine, ozolinone, piretanide, tienilic acid, torasemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0052] Other diuretics Osmotic diuretics are compounds that retain water in the proximal tubule and the descending limb of the loop of Henle. In some embodiments, osmotic diuretics expand fluid and plasma volume, increasing blood flow to the kidney. Examples include, but are not limited to, mannitol and glycerol.

[0053] Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors, as used herein, are compounds that are inhibitors of carbonic anhydrase. In some embodiments, carbonic anhydrase inhibitors increase the excretion of bicarbonate with accompanying sodium, potassium, and water, resulting in increased alkaline urinary flow. In some embodiments, carbonic anhydrase inhibitors inhibit the transport of bicarbonate from the proximal tubule convolution to the interstitium, resulting in less sodium reabsorption and more sodium, bicarbonate, and water loss in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorphenamide, and methazolamide.

[0054] Potassium-sparing diuretics Potassium-sparing diuretics are compounds that compete with aldosterone for cytoplasmic receptor sites within cells or that directly block sodium channels, specifically the epithelial sodium channel (ENaC). Examples of potassium-sparing diuretics include, but are not limited to, amiloride, spironolactone, eplerenone, triamterene, and potassium canrenoate.

[0055] Other diuretics contemplated for use include, but are not limited to, caffeine, theophylline, theobromine, tolvaptan, conivaptan, dopamine, and pamabrom.

[0056] In some embodiments, the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharma- ceutically 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.

[0057] Calcium channel blockers As used herein, a calcium channel blocker is a compound that promotes vasodilatory activity by reducing calcium influx into vascular smooth muscle cells. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, 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 pharma- ceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine sylate. 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.

[0058] Minimum hypertension treatment dose As used herein, the lowest hypertension therapeutic dose (LHTD) refers to the lowest strength dose of a single drug approved for hypertension by the U.S. Food and Drug Administration and not marked as "discontinued" by the Orange Book database (http: / / www.accessdata.fda.gov / scripts / cder / ob / ) as of the filing date of this application. The lowest hypertension therapeutic dose does not include the lowest manufactured dose for cases where the lowest hypertension therapeutic dose is not the same as the lowest manufactured dose. Furthermore, the lowest hypertension therapeutic dose does not include the dose as recommended by a physician for cases where the lowest hypertension therapeutic dose is not the same dose as recommended by a physician. Furthermore, the lowest hypertension dose of an angiotensin II receptor blocker, diuretic, or calcium channel blocker described herein refers to the dose of the form of an angiotensin II receptor blocker, diuretic, or calcium channel blocker approved for use by the U.S. Food and Drug Administration, including the free base, pharma- ceutically acceptable salts, or hydrates thereof.

[0059] In some embodiments, the dosage of the angiotensin II receptor blocker is about 40% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 40% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 40% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 40% to about 50% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 45% to about 55% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 50% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 50% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 50% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 60% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 60% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 70% to about 80% of the minimum therapeutic dose for hypertension.

[0060] In some embodiments, the dosage of the angiotensin II receptor blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dosage. In some embodiments, the dosage of the angiotensin II receptor blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin II receptor blocker is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin II receptor blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin II receptor blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin II receptor blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin II receptor blocker is about 66% of the minimum hypertension therapeutic dose.

[0061] In some embodiments, the diuretic dosage is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0062] In some embodiments, the dosage of the diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dosage. In some embodiments, the diuretic dosage is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the diuretic dosage is about 66% of the minimum hypertension therapeutic dose.

[0063] In some embodiments, the dosage of the thiazide diuretic is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0064] In some embodiments, the dose of the thiazide diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide diuretic is about 66% of the minimum hypertension therapeutic dose.

[0065] In some embodiments, the dosage of the thiazide-like diuretic is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0066] In some embodiments, the dosage of the thiazide-like diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 66% of the minimum hypertension therapeutic dose.

[0067] In some embodiments, the loop diuretic is administered at a dose of about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic is administered at a dose of about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dosage is about 60% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dosage is about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dosage is about 70% to about 80% of the minimum hypertension therapeutic dose.

[0068] In some embodiments, the dosage of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the loop diuretic is about 66% of the minimum hypertension therapeutic dose.

[0069] In some embodiments, the dosage of the calcium channel blocker is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 50% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 60% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the calcium channel blocker is about 60% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the calcium channel blocker is about 70% to about 80% of the minimum therapeutic dose for hypertension.

[0070] In some embodiments, the dosage of the calcium channel blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dosage. In some embodiments, the dosage of the calcium channel blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 66% of the minimum hypertension therapeutic dose.

[0071] In some embodiments, the minimum hypertension therapeutic doses (LHTD) and corresponding suggested doses and dose ranges for the following compounds are as set forth in the table below:

[0072] [Table 1]

[0073] In some embodiments, the pharmaceutical composition comprises (a) irbesartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 30 mg to about 45 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of irbesartan is about 37.5 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0074] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of hydrochlorothiazide is about 6.25 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0075] In some embodiments, the pharmaceutical composition comprises (a) irbesartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 30 mg to about 45 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of irbesartan is about 37.5 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0076] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0077] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of chlorthalidone is about 12.5 mg, and the dose of amlodipine besylate is about 1.25 mg.

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

[0079] In some embodiments, the pharmaceutical composition comprises (a) irbesartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0080] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) hydrochlorothiazide as a thiazide diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of hydrochlorothiazide is about 8.25 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0081] In some embodiments, the pharmaceutical composition comprises (a) irbesartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0082] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) indapamide as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0083] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 12 mg to about 16 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of telmisartan is about 13.2 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0084] In some embodiments, the pharmaceutical composition comprises (a) irbesartan as an angiotensin II receptor blocker; (b) chlorthalidone as a thiazide-like diuretic; and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of irbesartan is about 45 mg to about 60 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg. In some embodiments, the dose of irbesartan is about 49.5 mg, the dose of chlorthalidone is about 16.5 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0085] In some embodiments, the dosage of the angiotensin II receptor blocker, such as telmisartan, is about 80% to about 150% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 80% to about 140% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 80% to about 130% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 80% to about 120% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 80% to about 110% of the minimum therapeutic dose for hypertension.

[0086] In some embodiments, the dosage of the angiotensin II receptor blocker, such as telmisartan, is about 85% to about 145% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 85% to about 135% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 85% to about 125% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 85% to about 115% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 85% to about 105% of the minimum therapeutic dose for hypertension.

[0087] In some embodiments, the dosage of the angiotensin II receptor blocker, such as telmisartan, is about 90% to about 140% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 90% to about 130% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 90% to about 120% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 90% to about 110% of the minimum therapeutic dose for hypertension.

[0088] In some embodiments, the dosage of the angiotensin II receptor blocker, such as telmisartan, is about 95% to about 135% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 95% to about 125% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 95% to about 115% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 95% to about 105% of the minimum therapeutic dose for hypertension.

[0089] In some embodiments, the dose of the angiotensin II receptor blocker is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, 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%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141%, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 16 %, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120%. In some embodiments, the dosage of the angiotensin II receptor blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose.

[0090] In some embodiments, the dosage of the thiazide-like diuretic is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 80% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 80% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 80% to about 110% of the minimum hypertension therapeutic dose.

[0091] In some embodiments, the dosage of the thiazide-like diuretic is about 85% to about 145% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 85% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 85% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 85% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 85% to about 105% of the minimum hypertension therapeutic dose.

[0092] In some embodiments, the dosage of the thiazide-like diuretic is about 90% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 90% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 90% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 90% to about 110% of the minimum hypertension therapeutic dose.

[0093] In some embodiments, the dosage of the thiazide-like diuretic is about 95% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 95% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 95% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 95% to about 105% of the minimum hypertension therapeutic dose.

[0094] In some embodiments, the dose of the thiazide-like diuretic is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, 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%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141%, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 9%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120%. In some embodiments, the dosage of the thiazide-like diuretic is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the thiazide-like diuretic is about 100% of the minimum hypertension therapeutic dose.

[0095] In some embodiments, the dosage of the calcium channel blocker is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 80% to about 140% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 80% to about 130% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 80% to about 110% of the minimum hypertension therapeutic dose.

[0096] In some embodiments, the dosage of the calcium channel blocker is about 85% to about 145% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 85% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 85% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 85% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 85% to about 105% of the minimum hypertension therapeutic dose.

[0097] In some embodiments, the dosage of the calcium channel blocker is about 90% to about 140% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the calcium channel blocker is about 90% to about 130% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the calcium channel blocker is about 90% to about 120% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the calcium channel blocker is about 90% to about 110% of the minimum therapeutic dose for hypertension.

[0098] In some embodiments, the dosage of the calcium channel blocker is about 95% to about 135% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 95% to about 125% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 95% to about 115% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 95% to about 105% of the minimum hypertension therapeutic dose.

[0099] In some embodiments, the dosage of the calcium channel blocker is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120% of the minimum hypertension therapeutic dosage. In some embodiments, the dosage of the calcium channel blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose.

[0100] In some embodiments, the minimum hypertension therapeutic doses (LHTD) and corresponding suggested doses and dose ranges for the following compounds are as set forth in the table below:

[0101] [Table 2-1]

[0102] [Table 2-2]

[0103] In some embodiments, the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker, hi some embodiments, the dosage of the calcium channel blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.In some embodiments, the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosage of the calcium channel blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.

[0104] In some embodiments, the dosage 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 minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosage 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 minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker, hi some embodiments, the dosage of the calcium channel blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.In some embodiments, the dosage 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 minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosage of the calcium channel blocker is replaced by about 200% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.

[0105] In some embodiments, the dosages of the angiotensin II receptor blocker, the diuretic (e.g., a thiazide diuretic or a thiazide-like diuretic), and the calcium channel blocker are each independently replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose for the diuretic. In some embodiments, the dosage of the calcium channel blocker is replaced by about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosages of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each independently replaced by about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 80% to about 120% of the minimum hypertension therapeutic dose for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose for the diuretic. In some embodiments, the dosage of the calcium channel blocker is substituted at about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker, hi some embodiments, the dosage of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.In some embodiments, the dosages of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each independently replaced by about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is replaced by about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the diuretic is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the diuretic. In some embodiments, the dosage of the calcium channel blocker is substituted at about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker, hi some embodiments, the dosage of the calcium channel blocker is about 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.

[0106] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker, (b) indapamide as a thiazide-like diuretic, and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 16 mg to about 30 mg, the dose of indapamide is about 1 mg to about 1.875 mg, and the dose of amlodipine besylate is about 2 mg to about 3.75 mg.

[0107] In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0108] In some embodiments, the dose of telmisartan is about 18 mg to about 22 mg, the dose of indapamide is about 1.125 mg to about 1.375 mg, and the dose of amlodipine besylate is about 2.25 mg to about 2.75 mg.

[0109] In some embodiments, the dosage amount of telmisartan is about 20 mg, the dosage amount of indapamide is about 1.25 mg, and the dosage amount of amlodipine besylate is about 2.5 mg.

[0110] In some embodiments, the pharmaceutical composition comprises (a) telmisartan as an angiotensin II receptor blocker, (b) chlorthalidone as a thiazide-like diuretic, and (c) amlodipine besylate as a calcium channel blocker. In some embodiments, the dose of telmisartan is about 16 mg to about 30 mg, the dose of chlorthalidone is about 20 mg to about 37.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3.75 mg.

[0111] In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of chlorthalidone is about 20 mg to about 30 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0112] In some embodiments, the dose of telmisartan is about 18 mg to about 22 mg, the dose of chlorthalidone is about 22.5 mg to about 27.5 mg, and the dose of amlodipine besylate is about 2.25 mg to about 2.75 mg.

[0113] In some embodiments, the dosage of telmisartan is about 20 mg, the dosage of chlorthalidone is about 25 mg, and the dosage of amlodipine besylate is about 2.5 mg.

[0114] formulation In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in one formulation. In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each provided in a separate formulation. In some embodiments, two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in one formulation. In some embodiments, the angiotensin II receptor and the diuretic are provided in one formulation. In some embodiments, the angiotensin II receptor blocker and the calcium channel blocker are provided in one formulation. In some embodiments, the diuretic and the calcium channel blocker are provided in one formulation. In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in one formulation. In some embodiments, the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are provided in one formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is in the form of a pill. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical compositions are suitable for oral administration.

[0115] Other suitable formulations include, but are not limited to, those suitable for rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the level and severity of the disease being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as a unit dosage.

[0116] A typical pharmaceutical composition may be used in the form of a pharmaceutical preparation, e.g., solid, semi-solid, or liquid form, which contains one or more of the disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient may be compounded with a normally non-toxic pharma- ceutically acceptable carrier, e.g., as tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the disease process or condition.

[0117] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with conventional tableting ingredients such as pharmaceutical carriers, e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogenous mixture of the disclosed compound or a non-toxic pharma- ceutically acceptable salt thereof. When such a preformulation composition is referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0118] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, 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) diluents, such as glycerin; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) kaolin and bentonite clays. (9) lubricants 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 may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0119] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, capsules are prepared by encapsulating a tablet in a hard gelatin capsule (e.g., overencapsulation). Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0120] In some embodiments, the angiotensin II receptor blocker of the pharmaceutical compositions described herein may be replaced with an angiotensin converting enzyme inhibitor (ACE inhibitor). Examples of suitable angiotensin converting enzyme inhibitors include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or pharma- ceutically acceptable salts or hydrates thereof. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 80% to about 150% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 80% to about 120% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 90% to about 110% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 100% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40% to about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 45% to about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 50% to about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 50% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 50% to about 60% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 60% to about 80% of the minimum therapeutic dose for hypertension.In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 60% to about 70% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin-converting enzyme inhibitor is about 70% to about 80% of the minimum therapeutic dose for hypertension. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the minimum hypertension therapeutic dose. In some embodiments, the dosage of the angiotensin converting enzyme inhibitor is about 66% of the minimum hypertension therapeutic dose.

[0121] Treatment Method The pharmaceutical compositions described herein are useful for treating hypertension in a subject in need thereof. In some embodiments, treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, treatment results in a systolic blood pressure (SBP) of less than about 135 mmHg. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg to about 20 mmHg. In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg to about 30 mmHg. In some embodiments, treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, or about 20 mmHg. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 21 mmHg, about 22 mmHg, about 23 mmHg, about 24 mmHg, about 25 mmHg, about 26 mmHg, about 27 mmHg, about 28 mmHg, about 29 mmHg, or about 30 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 85 mmHg. In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 10 mmHg. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 15 mmHg. In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, or about 10 mmHg.In some embodiments, treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, or about 15 mmHg.

[0122] In some embodiments, the treatment results in a greater reduction in systolic blood pressure (SBP) than that obtained with a full minimum hypertension therapeutic dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in systolic blood pressure (SBP) than that obtained with a full minimum hypertension therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in systolic blood pressure (SBP) than that obtained with a full minimum hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in systolic blood pressure (SBP) than that obtained with a full minimum hypertension therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

[0123] In some embodiments, the treatment results in a greater reduction in diastolic blood pressure (DBP) than that obtained with a full minimum hypertension therapeutic dose of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in diastolic blood pressure (DBP) than that obtained with a full minimum hypertension therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in diastolic blood pressure (DBP) than that obtained with a full minimum hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a greater reduction in diastolic blood pressure (DBP) than that obtained with a full minimum hypertension therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

[0124] In some embodiments, treatment results in more long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of any one of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker in a pharmaceutical composition. In some embodiments, treatment results in more long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of an angiotensin II receptor blocker in a pharmaceutical composition. In some embodiments, treatment results in more long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of a diuretic in a pharmaceutical composition. In some embodiments, treatment results in more long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of a calcium channel blocker in a pharmaceutical composition.

[0125] In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than or equal to the reduction achieved by a combination of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in a pharmaceutical composition, where the dosage of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than or equal to the reduction achieved by a combination of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in a pharmaceutical composition, where the dosage of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose. In some embodiments, treatment results in greater long-term tolerance and reduced risk of side effects compared to treatment with a combination of any two of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker in a pharmaceutical composition, where the dosage of each of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is about 50% of the minimum hypertension therapeutic dose.

[0126] In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject's blood pressure is very mildly elevated prior to the treatment. In some embodiments, the subject has not received a prior hypertension treatment prior to the treatment. In some embodiments, the subject's blood pressure is very mildly elevated prior to the treatment and the subject has not received a prior hypertension treatment prior to the treatment.

[0127] The present disclosure recognizes that the use of an angiotensin II receptor blocker in the pharmaceutical compositions disclosed herein, in some embodiments, provides beneficial therapeutic effects, including, but not limited to, a substantial reduction in blood pressure, a substantial reduction in blood pressure among subjects with mildly elevated blood pressure, more long-term tolerability, and a reduced risk of side effects. The present disclosure recognizes that the omission of a lipid regulating agent, a platelet function modifying agent, a serum homocysteine ​​lowering agent, or a combination thereof, in the pharmaceutical compositions disclosed herein, in some embodiments, provides beneficial therapeutic effects, including, but not limited to, a substantial reduction in blood pressure, a substantial reduction in blood pressure among subjects with mildly elevated blood pressure, more long-term tolerability, and a reduced risk of side effects.

[0128] It is also recognized herein that, in some embodiments, the triple combinations described herein that include an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each of which is about 40% to about 80% of the minimum hypertension therapeutic dose, provide a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination that includes an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (e.g., amlodipine besylate), each of which is 100% of the minimum hypertension therapeutic dose. In some embodiments, the triple combinations described herein, including an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each of which is about 40% to about 60% of the minimum hypertension therapeutic dose, provide a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination including an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (e.g., amlodipine besylate), each of which is 100% of the minimum hypertension therapeutic dose.

[0129] It is also recognized herein that, in some embodiments, the triple combination described herein, including telmisartan, a thiazide-like diuretic, and a calcium channel blocker, each of which is about 80% to about 150% of the minimum therapeutic dose, provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination including losartan, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) as an angiotensin II receptor blocker. In some embodiments, the triple combination described herein, including telmisartan, a thiazide-like diuretic, and a calcium channel blocker, each of which is about 80% to about 120% of the minimum therapeutic dose, provides a significantly greater reduction in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination including losartan, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) as an angiotensin II receptor blocker. EXAMPLES

[0130] Example 1: Cardiovascular measurements in spontaneously hypertensive rats receiving a combination of antihypertensive drugs

[0131] overview The objective of this study was to evaluate the relative effects on blood pressure of three different combinations of angiotensin II receptor blockers, calcium channel blockers, and diuretics (thiazide or thiazide-like diuretics). The primary objective was to evaluate whether there were differences in the effects of combinations utilizing different drugs from the same class, and between combinations utilizing the same drug at different doses, including very low doses (i.e., doses below the lowest approved and manufactured dose, such as 50% of the lowest hypertension therapeutic dose (LHTD)).

[0132] The specific combinations studied were: Combination 1: telmisartan, amlodipine besylate, and indapamide, all at 50% of the lowest hypertension therapeutic dose (LHTD) or one-quarter of the usual maintenance dose recommended by the FDA (equivalent to 10 mg telmisartan, 1.25 mg amlodipine besylate, and 0.625 mg indapamide); Combination 2: telmisartan, amlodipine, and indapamide, all at 100% of the minimum hypertension therapeutic dose (LHTD) or half the usual maintenance dose recommended by the FDA (equivalent to 20 mg telmisartan, 2.5 mg amlodipine besylate, and 1.25 mg indapamide); and Combination 3: Losartan, amlodipine besylate, and hydrochlorothiazide, all at 100% of the minimum hypertension therapeutic dose (LHTD) or half the usual maintenance dose recommended by the FDA (equivalent to 25 mg losartan, 2.5 mg amlodipine besylate, and 12.5 mg hydrochlorothiazide);

[0133] The study was performed in spontaneously hypertensive rats (SHR), the animal model most commonly used to study 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 and data from the published literature for Cmax and AUC for each of the six antihypertensive drugs. Each animal was exposed to a single dose of all compound drugs in a Latin square configuration.

[0134] method The following was used as the vehicle for the following studies: 0.5% methylcellulose (w / v) and 0.25% polysorbate 80 (v / v) in 25 mM phosphate buffer at pH 8+ / -0.2.

[0135] The following animals were used in the study: Spontaneously Hypertensive Rats (strain: SHR / NCrl). Rats were obtained from Charles River Laboratories, Inc., Kingston, New York. Age at initiation of dosing was approximately 12 weeks. Thirteen male rats were used for acclimation. Eight male rats were used in the study. Animals were identified by cage cards and tattoos.

[0136] Telemetry Implantation: Animals were implanted with Data Science International transmitters (HD-S10) for collection of blood pressure and heart rate data. Animals were not administered any formulations until at least 10 days post-surgery.

[0137] Housing: Animals were individually housed in solid bottom cages equipped with a water bottle.

[0138] Diet: Unless otherwise specified, animals were fed Teklad Global Diet-Rodent 2014 (Envigo RMS, Inc.) ad libitum. In some cases, animals were fed this diet in chow form when indicated by health status.

[0139] Water: Frontier tap water was provided ad libitum.

[0140] Impurities: No known impurities were present in the diet, water, or bedding (where applicable) at levels that would interfere with this study.

[0141] Environment: Environmental controls for the animal room were set up to maintain the following room conditions: temperature range of 20-26°C, relative humidity of 30-70%, and a 12-hour light / 12-hour dark cycle.

[0142] Acclimatization (pre-treatment phase): The acclimation phase lasted up to 1 week.

[0143] Environmental and dietary enrichment: Animals were exposed to various cage enrichment devices and dietary enrichment (no statistical analysis required).

[0144] Randomization: Animals were selected arbitrarily based on mean arterial pressure values ​​from the pre-dosing phase.

[0145] The following table shows the group designations of the rats used in the study:

[0146] [Table 3]

[0147] The following table shows the dosage levels administered in the study:

[0148] [Table 4]

[0149] Dosing Procedure: For Combinations 1, 2, and 3, each test combination formulation was prepared fresh on each dosing day. A portion of the vehicle (approximately 80%) was added to the test combination formulation and mixed until the preparation was homogenous. If a homogenous suspension or solution was not obtained, 1N NaOH and / or 1N HCl was added to adjust the pH to 9+0.2. The remainder of the vehicle was added and mixed with a stir bar. The test combination formulations were stirred continuously at room temperature and protected from light for approximately 30 minutes prior to dosing and throughout administration. The test combination formulations were stored protected from light and stirred in a refrigerator set and maintained at 2-8°C.

[0150] Dosing Procedures: For pre-dosing handling, test combination formulations were allowed to equilibrate to approximately room temperature for at least 30 minutes prior to dosing. Animals were dosed at a volume of 10 mL / kg, with actual dose volume based on most recent body weight. Doses were administered using oral gavage. Dosing intervals were once daily on days 1, 8, 15, and 22. After dosing, remaining test combination formulations were disposed of according to standard handling procedures.

[0151] Telemetry Collection: Animals were not disturbed or handled in any way immediately prior to and during telemetry data collection without prior approval. Such disturbances included, but were not limited to, cage changes, bedding changes, swabbing, sanitation, or anything that disrupted the natural, quiet environment that was important for the collection of cardiovascular telemetry data.

[0152] Animal Observations: Each rat was observed once daily, every morning. Any abnormal findings were recorded. Rats were observed for mortality, abnormalities, and signs of pain or distress. Any abnormal findings observed during unscheduled observation periods were also noted.

[0153] Body weight: Body weights were taken at least once during the pre-dosing phase and before each scheduled dose. Additional body weights were recorded, if appropriate, to monitor animal health. Animals were instrumented with transmitters and tare using representative transmitters and leads prior to collection of body weights for dose calculations.

[0154] Telemetry Data Collection: Raw arterial pressure signals were digitized at a sampling rate of 500 Hz. Parameters derived during the pre-dose and dosing phases were the same. For pre-dose data collection, all implanted telemetry devices were checked for signal consistency and to verify that the telemetry signal was acceptable for analysis. Signal validation consisted of at least one telemetry recording obtained from each rat considered for the study. Telemetry data was recorded continuously for approximately 24 hours. Telemetry data was examined to determine whether the rat was study eligible. Data was stored in the study record and used to calculate nominal 24-hour mean arterial pressure and to aid in randomized animal selection. For dosing phase data collection, continuous telemetry data was collected during the dosing phase, beginning at least 90 minutes prior to dosing and continuing for approximately 48 hours post-dose.

[0155] Nominal dosing times: Telemetry collection time points were based on a single nominal dosing time for all animals. The nominal dosing time for each dosing phase day was the end of dosing for the first half of the animals dosed on that day as recorded on each computer for all animals based on calculations.

[0156] Telemetry Data Evaluation: Telemetry parameters were analyzed and reported, including heart rate (beats / min), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), mean arterial pressure (mmHg), and arterial pressure (mmHg). Telemetry data generated by Ponemah during the dosing phase was analyzed in 1-minute samples. Data was processed in 15-minute averages and submitted for data review. The 15-minute average data was further averaged by binning into the following analysis periods: Period 1: 0.5 to 2 hours after administration; Period 2: 2 to 4 hours after administration; Period 3: 4 to 8 hours after administration; · Period 4: 8 to 12 hours after administration; Period 5: 12 to 20 hours after administration; Period 6: 20:00 to 32:00 post-dose (second light cycle); and Period 7: 32-44 hours after dosing (second dark cycle).

[0157] analysis Blood pressure was measured over a 44-h period using an implanted telemetry device. The primary outcome was systolic blood pressure.

[0158] Statistical analyses were performed using all available data points, and body weight was measured to reflect the heterogeneous timing of measurements. Treatment effect estimates were calculated using estimated differences between treatments using a model (SAS 9.4, SAS Institute, Cary, NC) combined with a direct product autoregressive correlation structure to account for repeated measurements over time within individuals.

[0159] result Eight animals were started in the study; however, the telemetry transmitter did not function in one animal, and as a result, complete data were available from seven animals.

[0160] The table below shows the difference in systolic BP (mmHg) between treatments:

[0161] [Table 5]

[0162] Figure 1 shows the average systolic blood pressure (mmHg) over the time period by treatment. Figure 2 shows the average diastolic blood pressure (mmHg) over the time period by treatment. Figure 3 shows the average heart rate over the time period by treatment.

[0163] In this non-limiting example, the results demonstrated that combination 1 provided a significantly greater reduction in systolic blood pressure than combination 3, and combination 2 provided a significantly greater reduction in systolic blood pressure than combinations 3 or 1. These differences persisted over the full 44 hour period of observation. The results demonstrated that both combination 1 and combination 2 provided a significantly greater reduction in systolic blood pressure than combination 3. These differences persisted over the full 44 hour period of observation. There were similar differences between the three combinations in the reduction of DPB, and no differences between the combinations in heart rate.

[0164] In this non-limiting example, the results demonstrate an unexpected difference between the combination of telmisartan, amlodipine besylate, and indapamide and the combination of losartan, amlodipine besylate, and hydrochlorothiazide. Specifically, at equivalent or lower doses, the combination of telmisartan, amlodipine besylate, and indapamide produced a significantly greater reduction in blood pressure than the combination of losartan, amlodipine besylate, and hydrochlorothiazide. Because the dose of amlodipine besylate was the same in combinations 2 and 3, the results demonstrate a previously unknown difference in the efficacy of certain angiotensin II receptor blockers and certain diuretics (such as thiazide diuretics vs. thiazide-like diuretics) when provided in parallel with amlodipine besylate.

[0165] Example 2: Treatment with a triple combination composition for the treatment of hypertension method The study is a randomized, placebo-controlled, double-blind, crossover study. The study is divided into three phases. During the first phase (4 weeks), participants are randomized (1:1) to receive treatment with the triple combination composition or placebo. This is followed by a 2-week washout (placebo), after which participants are crossed over to the opposite group and receive the alternative treatment for 4 weeks. Participants are recruited through general practice in the community, primarily in Western Sydney, Australia.

[0166] participants Participants were eligible if they met the following inclusion criteria: 1) adults aged 18 years or older, 2) office SBP>140mmHg and / or DBP>90mmHg for two readings on separate days; and baseline ambulatory SBP>135 and / or DBP>85; 3) not receiving medical treatment for hypertension. Exclusion criteria included: no clear contraindication to one or more of the component drugs in the triple combination composition; a responsible clinician felt that a change in current treatment would put the patient at risk; severe or advanced hypertension; pregnancy; inability to provide informed consent; and medical illness with an expected life expectancy of less than 3 months.

[0167] intervention For these studies, either triple combinations with each component at 50% of their minimum hypertension therapeutic dose (LHTD) or triple combinations with each component at 100% of their minimum hypertension therapeutic dose (LHTD) are tested.

[0168] If the study tests a triple combination with each component at 50% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: The triple combination composition is a single encapsulated pill containing the following three components in specific amounts: telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg. The placebo capsules appear identical and contain placebo tablets of similar weight to those in the triple combination composition.

[0169] If the study tests a triple combination with each component at 100% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: The triple combination composition is a single encapsulated pill containing the following three components in specific amounts: telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg. The placebo capsule appears identical and contains a placebo tablet of similar weight to those in the triple combination composition.

[0170] Participants will receive a single pill, the triple combination composition, or a placebo throughout the study. Patients will be instructed to take the tablets at the same time each day and will be encouraged to take them in the morning, although the time of day (morning or evening) is subject to patient preference.

[0171] All study medications are prepared by a manufacturing facility licensed by TGA-cGMP (Therapeutic Goods Australia-certificate of Good Manufacturing Practice). Where appropriate, low strength doses are obtained by halving the half strength doses using a pill splitter without grinding, which is weighed to ensure accuracy of the dose halving. The low strength doses are then encapsulated using gelatin capsules (DBCaps-Capsugel). Capsules are stored in a cool, dry place until dispensed and monitored using a temperature logger.

[0172] Treatment assignment will be blinded to both study staff and participants. In addition to study drug, all participants will be provided with education regarding healthy lifestyle options as recommended by guidelines for the management of hypertension.

[0173] Randomization A computer-assisted randomization sequence is created by a statistician and provided to the drug packaging company. Research assistants, refill teams and investigators are blinded to this sequence. For each patient, i.e. the randomized number of patients assigned, pills are packaged into three child-resistant packs, corresponding to the three phases of the study. All packs are of identical appearance ensuring blinding of patients and study staff. Drug packs are then dispensed in the organized sequence.

[0174] Results and Data Collection The primary endpoint was reduction in mean 24-hour systolic blood pressure using ambulatory blood pressure monitoring (ABP) over 4 weeks. Secondary endpoints included: a. Reduction in mean 24-hour diastolic blood pressure, and daytime and nighttime SBP and DBP over 4 weeks b. Reduction in office SBP and DBP as measured by standardized automated blood cuffs c. Proportion of controlled blood pressure over 4 weeks, defined as 24-hour BP <135 / 85 mmHg and office BP <140 / 90 mmHg d. Adverse events and adverse events prespecified by laboratory parameters: elevation of transaminases (ALT / AST) more than 3 times the upper limit of normal or 2-fold when baseline levels are known to be elevated; decrease in estimated glomerular filtration rate >20% as assessed by serum creatinine; sodium, potassium, and uric acid levels. e. Acceptability and tolerability assessment

[0175] Patients undergo 24-hour ABP monitoring four times - at baseline (study drug off), 4 weeks (phase 1 drug), 6 weeks (placebo), and 10 weeks (phase 3 drug). To minimize inconvenience, patients will have their ABP referred to the laboratory. ABP units will be calibrated at equal intervals by the laboratory according to manufacturer specifications. To minimize variability, follow-up readings will be repeated from the same collection center using the same brand of equipment. Participants will be reimbursed for nominal value, including transportation and parking costs. Study drug and surveys will be provided to participants at no cost. Office BP will be recorded in triplicate at each visit using an OMRON T9P (HEM-759-C1). The second and third readings will be averaged for study analysis. In addition, at weeks 4 and 10, patients will have blood tests to assess biochemical side effects, will receive questionnaires for clinical side effects, and compliance will be assessed by self-report and pill counts. Patients will remain blinded to their treatment assignment once they complete this questionnaire.

[0176] Drug acceptability and tolerability will also be evaluated at the end of the study. All adverse events will be recorded. In addition, clinical adverse events possibly related to the blood pressure lowering drug will be specifically asked: dizziness, blurred vision, loss of consciousness / collapse, chest pain / angina, shortness of breath, cough, wheeze, pedal edema, rash, pruritus.

[0177] The trial has a simplified data safety and management of two core members with expertise in clinical medicine, trials, and statistics. Once 10 patients are randomized into the trial to check the safety, a meeting will be convened to advise continuing the study.

[0178] Statistical Considerations A sample size of 50 patients is planned to obtain 90% power at p=0.05 to detect an SBP difference of 12 mmHg between intervention and control, assuming a SD within patient difference of 12 mmHg, and allowing for a possible 10% loss to follow-up.

[0179] Statistical methods Statistical analyses were performed on an intention to treat basis. All tests were two-sided, with a nominal level of alpha of 5%. All statistical analyses were unadjusted for prognostic covariates. Data on pills taken (doses) and doses lost over time were used to report adherence to study medication.

[0180] Following the method of Kenward and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010;11(1):1-17), linear mixed models are used to assess the effect of treatment on change in blood pressure from baseline in each treatment period. This method uses all measurements (baseline and follow-up in both periods) as outcomes, but accounts for covariance between measurements within individuals, to appropriately adjust for baseline levels collected at the beginning of each treatment period (weeks 0 and 6) (Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analysis of change from baseline in clinical trials? Stat Med 2009;28(20):2509-30). Linear contrasts between variables that mean time period (first / second), type of measurement (baseline / final), and treatment received (placebo / triple combination composition) provide unbiased estimates of the effect of the triple combination composition on change in blood pressure compared to placebo. All available data are included in the model and missing data are not imputed. If patients are missing data for some time periods, data from the efficacy period are used. A sensitivity analysis is performed including only patients with available data from both periods to see if the effect of treatment was modified. There is also an adjustment of the denominator degrees of freedom from Kenward and Roger (2009) that 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).

[0181] Tests for carryover will use unpaired t-tests of the primary outcome with order as the effect. Period effects will be tested by using paired t-tests comparing the primary outcome in period 1 with the primary outcome in period 2 from the same patient. Sensitivity analyses will also be performed using standard paired t-tests to compare primary endpoints between different periods (different treatments) from the same patient, ignoring baseline levels in each period.

[0182] Continuous secondary endpoints at baseline values ​​(e.g., daytime / nighttime ambulatory SBP / DBP) will be analyzed similarly against the primary endpoint. Other continuous variables without baseline values ​​at each time period will be analyzed with paired t-tests. Numbers and percentages of all adverse events will be reported. As a sensitivity analysis, the analysis will be repeated for complete cases (i.e., complete data for each measurement period).

[0183] Age (<=60 vs. >60 years), sex, and BMI (<=30 vs. <30 kg / m 2 ) for interactions of treatment effects. Subgroup analyses will also be performed for each variable. All analyses will be performed using the software SAS 9.4 (Cary, NC, USA).

[0184] Example 3: Comparative study of triple combination versus standard dose monotherapy for the treatment of hypertension the purpose The primary objective of this study is to investigate in a double-blind, randomized controlled trial whether initiating treatment with the triple combination therapy reduces blood pressure more effectively and causes fewer side effects compared to initiating standard-dose monotherapy according to current guidelines in patients with hypertension. A secondary objective is to assess whether this approach is safe and causes fewer side effects compared to standard of care.

[0185] research design This is a 12-week, double-blind, randomized controlled trial (1:1) of 650 patients with grade 1 and 2 essential hypertension. Subjects were randomized via a central computer-based randomization service according to current Australian hypertension guidelines to receive initial treatment with the triple combination composition or to begin treatment with an angiotensin receptor blocker (ARB), with options including adding a calcium channel blocker (CCB) if needed. The primary endpoint was reduction in mean systolic blood pressure using a standardized automated BP cuff at 12 weeks. Secondary endpoints included ratios to controlled blood pressure at 6 and 12 weeks, ambulatory blood pressure (ABP) measurements, and tolerability / occurrence of adverse events.

[0186] Eligibility Criteria Inclusion criteria were as follows: -Adults (≥18 years old) - Treatment naive or currently not receiving treatment (i.e., not within the last 4 weeks) or taking one BP-lowering medication (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta-blocker, aldosterone antagonist, alpha-blocker) - SBP 140-179mmHg and / or DBP 90-109mmHg documented on two separate occasions for more than one week At least one of the measurements must be documented by study staff and the study's automated BP device OR recorded as daytime mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg during 24-hour ambulatory BP monitoring -At least one of these measurements must be recent (within the last 12 weeks) - Daytime mean SBP ≥ 135mmHg and / or DBP ≥ 85mmHg documented on 24-hour ambulatory BP monitoring within 12 weeks prior to randomization

[0187] Exclusion criteria were as follows: - Contraindications to telmisartan, amlodipine, or indapamide - Hypertension, e.g. renal artery stenosis; evidence of secondary causes of significant renal dysfunction (eGRF<50), elevated serum potassium (above lab normal limit) - Women who are pregnant, lactating, and / or of childbearing potential and who do not use a medically acceptable form of contraception (pharmaceutical or barrier method) throughout the study - Concomitant illness, physical impairment, or psychiatric condition that, in the opinion of the study team / primary care physician, may interfere with the conduct of the study, including the evaluation of the results. - Participation in a concurrent interventional medical investigation or clinical trial. Patients in non-interventional observational naturalistic and / or epidemiological studies are eligible. - The participant's trusted primary care or other trusted physician does not believe that switching their current monotherapy is appropriate for the participant. - Unable or unwilling to provide written informed consent - Failure to complete study procedures including 24-hour ambulatory BP -Clear indication for combination therapy

[0188] Study Procedures For these studies, either triple combinations with each component at 50% of their minimum hypertension therapeutic dose (LHTD) or triple combinations with each component at 100% of their minimum hypertension therapeutic dose (LHTD) are tested.

[0189] If the study is testing a triple combination with each component at 50% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients who meet the inclusion criteria will be randomized to: 1) a combination pill containing the following three components - telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg; or 2) telmisartan 40 mg.

[0190] If the study is testing a triple combination with each component at 100% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients who meet the inclusion criteria will be randomized to: 1) a combination pill containing the following three components - telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg; or 2) telmisartan 40 mg.

[0191] Patients currently receiving monotherapy will be asked to discontinue treatment while receiving study treatment. At 6 weeks, if BP is greater than 140 / 90 mmHg in either group, amlodipine besylate (5 mg) will be added by study staff.

[0192] result The primary outcome measure was the between-group difference in mean automated office systolic blood pressure at 12 weeks, adjusted for baseline values.

[0193] Secondary endpoints included: -24-hour ambulatory blood pressure monitoring Between-group differences in mean 24-h SBP and DBP over 12 weeks b. Between-group differences in mean changes in 24-h SBP and DBP from 0 to 12 weeks c. Between-group differences in mean daytime SBP and DBP over 12 weeks; between-group differences in mean nighttime SBP and DBP over 12 weeks d. Between-group differences in daytime, nighttime, and 24-hour BP stress (percentage of area under the blood pressure curve above normal daytime, nighttime, and 24-hour values ​​according to the NHFA Guide to management of hypertension 2008) e. Between-group differences in the proportion of patients with no nocturnal BP decline (nocturnal BP at most 10% lower than mean daytime BP according to the NHFA Guide to management of hypertension 2008) 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 vs. control group: a. Change in mean diastolic blood pressure from baseline to 12 weeks b. Hypertension control at 6 and 12 weeks (% with SBP < 140mmHg and DBP < 90mmHg) c. Percentage requiring step-up of treatment at 6 weeks d. Percentage of BP control (as defined above) and free of adverse events e. Between-group differences in variability of SBP and DBP -Durability a. Differences between groups in possible associated side effects (dizziness, blurred vision, loss of consciousness / fading / decreased consciousness, chest pain / angina, shortness of breath, cough, wheezing, ankle edema, rash, pruritus, gout, hyperkalaemia, hypokalaemia, hyponatremia, etc.) b. Differences between groups in mean potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UACR (urinary albumin-creatinine ratio), and creatinine levels c. Group differences in participants who discontinued treatment

[0194] statistical methods All statistical analyses of study results will be performed according to the intent-to-treat principle. The primary analysis of change in systolic blood pressure (SBP) at 12 weeks will be performed using analysis of covariance (ANCOVA) including treatment group and baseline SBP as covariates. Continuous secondary endpoints will be analyzed similarly. Additional analyses will include measurements at 6 and 12 weeks in a longitudinal model including treatment group, visit, and visit interactions, as well as baseline measurements. Within-patient correlations will be modeled using a generalized assessment equation. A similar approach will be applied to binary endpoints (e.g., hypertensive controls) with log-binomial regression used instead of linear regression. There will also be predefined subgroup analyses including baseline blood pressure, sex, age, and history of hypertension treatment. A detailed analysis plan will be developed prior to unblinding.

[0195] Example 4: Pharmaceutical Composition 1 The following pharmaceutical compositions are prepared with the specific ingredients and dosage amounts as shown in the table below.

[0196] [Table 6]

[0197] Example 5: Pharmaceutical Composition 2 The following pharmaceutical compositions are prepared with the specific ingredients and dosage amounts as shown in the table below.

[0198] [Table 7]

[0199] Example 6: Pharmaceutical Composition 3 The following pharmaceutical compositions are prepared with the specific ingredients and dosage amounts as shown in the table below.

[0200] [Table 8]

[0201] Embodiment Embodiment 1. A pharmaceutical composition comprising: (a) Angiotensin II receptor blockers; (b) diuretics; and (c) Calcium channel blockers Including, wherein the dosage of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c), in the pharmaceutical composition.

[0202] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active ingredients, wherein the blood pressure lowering active ingredients consist of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

[0203] Embodiment 3. The pharmaceutical composition of embodiment 1 or 2, wherein the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharma- ceutically acceptable salt thereof.

[0204] Embodiment 4. The pharmaceutical composition of any one of embodiments 1 to 3, wherein the pharmaceutical composition is essentially free of a beta-blocker or a pharma- ceutically acceptable salt thereof.

[0205] Embodiment 5. The pharmaceutical composition of any one of embodiments 1 to 4, wherein the pharmaceutical composition is essentially free of a lipid regulating agent, a platelet function modifying agent, a serum homocysteine ​​lowering agent, or a combination thereof.

[0206] Embodiment 6. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is essentially free of a lipid regulating drug.

[0207] Embodiment 7. The pharmaceutical composition of embodiment 6, wherein the lipid-regulating agent is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin.

[0208] Embodiment 8. The pharmaceutical composition of embodiment 6 or 7, wherein the lipid-regulating drug is atorvastatin or simvastatin.

[0209] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is essentially free of a platelet function modifying drug.

[0210] Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the platelet function modifying drug is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen.

[0211] Embodiment 11. The pharmaceutical composition of embodiment 9 or 10, wherein the platelet function modifying drug is aspirin.

[0212] Embodiment 12. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is essentially free of a serum homocysteine ​​lowering drug.

[0213] Embodiment 13. The pharmaceutical composition of embodiment 12, wherein the serum homocysteine-lowering drug is folic acid, vitamin B6, vitamin B12, or a combination thereof.

[0214] Embodiment 14. The pharmaceutical composition of embodiment 12 or 13, wherein the serum homocysteine ​​lowering drug is folic acid.

[0215] Embodiment 15. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the diuretic is a thiazide diuretic.

[0216] 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 pharma- ceutically acceptable salt or hydrate thereof.

[0217] Embodiment 17. The pharmaceutical composition of embodiment 16, wherein the thiazide diuretic is hydrochlorothiazide.

[0218] Embodiment 18. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the diuretic is a thiazide-like diuretic.

[0219] Embodiment 19. The pharmaceutical composition of embodiment 18, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharma- ceutically acceptable salt or hydrate thereof.

[0220] Embodiment 20. The pharmaceutical composition of embodiment 19, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0221] Embodiment 21. The pharmaceutical composition of embodiment 20, wherein the thiazide-like diuretic is indapamide.

[0222] Embodiment 22. The pharmaceutical composition of embodiment 19, wherein the thiazide-like diuretic is chlorthalidone.

[0223] Embodiment 23. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the diuretic is a loop diuretic.

[0224] Embodiment 24. The pharmaceutical composition of embodiment 23, wherein the loop diuretic is furosemide, bumetanide, ethacrynic acid, etozolin, muzolimine, ozolinone, piretanide, tienilic acid, torasemide, or a pharma- ceutically acceptable salt or hydrate thereof.

[0225] Embodiment 25. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharma- ceutically acceptable salt or hydrate thereof.

[0226] Embodiment 26. A pharmaceutical composition according to any one of embodiments 1 to 25, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibefradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dotalidine, diproteverine, or a pharma- ceutically acceptable salt or hydrate thereof.

[0227] Embodiment 27. The pharmaceutical composition of embodiment 26, wherein the calcium channel blocker is amlodipine or a pharma- ceutically acceptable salt thereof.

[0228] Embodiment 28. The pharmaceutical composition of embodiment 27, wherein the calcium channel blocker is amlodipine besylate.

[0229] Embodiment 29. A pharmaceutical composition according to any one of embodiments 1 to 28, wherein the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharma- ceutically acceptable salt or hydrate thereof.

[0230] Embodiment 30. The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is irbesartan.

[0231] Embodiment 31 The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is telmisartan.

[0232] Embodiment 32. The pharmaceutical composition of any one of embodiments 1 to 31, wherein the dosage of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0233] Embodiment 33. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide diuretic and the dosage of the thiazide diuretic is about 50% of the lowest hypertensive therapeutic dose (LHTD) for the thiazide diuretic.

[0234] Embodiment 34. The pharmaceutical composition of embodiment 33, wherein the thiazide diuretic is hydrochlorothiazide and the dosage of hydrochlorothiazide is about 6.25 mg.

[0235] Embodiment 35. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide-like diuretic and the dosage of the thiazide-like diuretic is about 50% of the minimum hypertensive therapeutic dose (LHTD) for the thiazide-like diuretic.

[0236] Embodiment 36. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is indapamide and the dosage of indapamide is about 0.625 mg.

[0237] Embodiment 37. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is chlorthalidone and the dosage of chlorthalidone is about 12.5 mg.

[0238] Embodiment 38. The pharmaceutical composition of embodiment 32, wherein the diuretic is a loop diuretic and the dosage of the loop diuretic is about 50% of the minimum hypertensive therapeutic dose (LHTD) for the loop diuretic.

[0239] Embodiment 39. The pharmaceutical composition of any one of embodiments 32 to 38, wherein the dosage of the calcium channel blocker is about 50% of the lowest hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0240] Embodiment 40. The pharmaceutical composition of embodiment 39, wherein the calcium channel blocker is amlodipine besylate and the dosage of amlodipine besylate is about 1.25 mg.

[0241] Embodiment 41. The pharmaceutical composition of any one of embodiments 32 to 40, wherein the dosage of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0242] Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is irbesartan and the dosage of irbesartan is about 37.5 mg.

[0243] Embodiment 43. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is telmisartan and the dosage of telmisartan is about 10 mg.

[0244] 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.

[0245] Embodiment 45. The pharmaceutical composition of embodiment 44, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0246] 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.

[0247] 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.

[0248] Embodiment 48. The pharmaceutical composition of embodiment 47, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of hydrochlorothiazide is about 5 mg to about 7.5 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0249] 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.

[0250] 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.

[0251] Embodiment 51. The pharmaceutical composition of embodiment 50, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0252] 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.

[0253] 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.

[0254] Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0255] Embodiment 55. The pharmaceutical composition of embodiment 54, wherein the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0256] 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.

[0257] Embodiment 57. The pharmaceutical composition of embodiment 56, wherein the dose of telmisartan is about 8 mg to about 12 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0258] 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.

[0259] 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.

[0260] Embodiment 60. The pharmaceutical composition of embodiment 59, wherein the dose of irbesartan is about 30 mg to about 45 mg, the dose of chlorthalidone is about 10 mg to about 15 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg.

[0261] 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.

[0262] Embodiment 62. The pharmaceutical composition of any one of embodiments 1 to 31, wherein the dosage of each of (a), (b), and (c) is about 60% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0263] Embodiment 63. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide diuretic and the dosage of the thiazide diuretic is about 66% of the minimum hypertensive therapeutic dose (LHTD) for the thiazide diuretic.

[0264] Embodiment 64. The pharmaceutical composition of embodiment 63, wherein the thiazide diuretic is hydrochlorothiazide and the dosage of hydrochlorothiazide is about 8.25 mg.

[0265] Embodiment 65. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide-like diuretic and the dosage of the thiazide-like diuretic is about 66% of the minimum hypertensive therapeutic dose (LHTD) for the thiazide-like diuretic.

[0266] Embodiment 66. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is indapamide and the dosage of indapamide is about 0.825 mg.

[0267] Embodiment 67. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is chlorthalidone and the dosage of chlorthalidone is about 16.5 mg.

[0268] Embodiment 68. The pharmaceutical composition of embodiment 62, wherein the diuretic is a loop diuretic and the dosage of the loop diuretic is about 66% of the minimum hypertensive therapeutic dose (LHTD) for the loop diuretic.

[0269] Embodiment 69. The pharmaceutical composition of any one of embodiments 62 to 68, wherein the dosage of the calcium channel blocker is about 66% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0270] Embodiment 70. The pharmaceutical composition of embodiment 69, wherein the calcium channel blocker is amlodipine besylate and the dosage of amlodipine besylate is about 1.65 mg.

[0271] Embodiment 71. The pharmaceutical composition of any one of embodiments 62 to 70, wherein the dosage of the angiotensin II receptor blocker is about 66% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0272] Embodiment 72. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is irbesartan and the dosage of irbesartan is about 49.5 mg.

[0273] Embodiment 73. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is telmisartan and the dosage of telmisartan is about 13.2 mg.

[0274] 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.

[0275] Embodiment 75. The pharmaceutical composition of embodiment 74, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0276] 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.

[0277] 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.

[0278] Embodiment 78. The pharmaceutical composition of embodiment 77, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of hydrochlorothiazide is about 7.5 mg to about 10 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0279] 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.

[0280] 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.

[0281] Embodiment 81. The pharmaceutical composition of embodiment 80, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0282] 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.

[0283] 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.

[0284] Embodiment 84. The pharmaceutical composition described in embodiment 83, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0285] Embodiment 85. The pharmaceutical composition of embodiment 84, wherein the dose of telmisartan is about 13.2 mg, the dose of indapamide is about 0.825 mg, and the dose of amlodipine besylate is about 1.65 mg.

[0286] 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.

[0287] Embodiment 87. The pharmaceutical composition of embodiment 86, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0288] 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.

[0289] 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.

[0290] Embodiment 90. The pharmaceutical composition of embodiment 89, wherein the dose of irbesartan is about 45 mg to about 60 mg, the dose of chlorthalidone is about 15 mg to about 20 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0291] 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.

[0292] Embodiment 92. A pharmaceutical composition described in any one of embodiments 1 to 91, wherein the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is substituted with about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0293] Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the dosage of the angiotensin II receptor blocker is substituted at about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0294] Embodiment 94. The pharmaceutical composition of embodiment 92, wherein the dose of the diuretic is substituted at about 80% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0295] Embodiment 95. The pharmaceutical composition of embodiment 92, wherein the dosage of the calcium channel blocker is substituted at about 80% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0296] Embodiment 96. A pharmaceutical composition described in any one of embodiments 92 to 95, wherein the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced with about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0297] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the dosage of the angiotensin II receptor blocker is substituted at about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0298] Embodiment 98. The pharmaceutical composition of embodiment 97, wherein the dosage of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0299] Embodiment 99. The pharmaceutical composition of embodiment 96, wherein the dose of the diuretic is substituted at about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0300] Embodiment 100. The pharmaceutical composition of embodiment 99, wherein the dose of the diuretic is replaced by about 100% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0301] Embodiment 101. The pharmaceutical composition of embodiment 96, wherein the dosage of the calcium channel blocker is substituted at about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0302] Embodiment 102. The pharmaceutical composition of embodiment 101, wherein the dosage of the calcium channel blocker is replaced with about 100% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0303] Embodiment 103. A pharmaceutical composition described in any one of embodiments 92 to 95, wherein the dosage of any one of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced with about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0304] Embodiment 104. The pharmaceutical composition of embodiment 103, wherein the dosage of the angiotensin II receptor blocker is substituted at about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0305] Embodiment 105. The pharmaceutical composition of embodiment 104, wherein the dosage of the angiotensin II receptor blocker is substituted with about 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0306] Embodiment 106. The pharmaceutical composition of embodiment 103, wherein the dose of the diuretic is substituted at about 150% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0307] Embodiment 107. The pharmaceutical composition of embodiment 106, wherein the dose of the diuretic is replaced by about 200% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0308] Embodiment 108. The pharmaceutical composition of embodiment 103, wherein the dosage of the calcium channel blocker is substituted at about 150% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0309] Embodiment 109. The pharmaceutical composition of embodiment 108, wherein the dosage of the calcium channel blocker is substituted with about 200% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0310] Embodiment 110. A pharmaceutical composition described in any one of embodiments 1 to 91, wherein the dosages of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are replaced by about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0311] Embodiment 111. The pharmaceutical composition of embodiment 110, wherein the dosage of the angiotensin II receptor blocker is substituted at about 80% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0312] Embodiment 112. The pharmaceutical composition of embodiment 110, wherein the dose of the diuretic is substituted at about 80% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0313] Embodiment 113. The pharmaceutical composition of embodiment 110, wherein the dosage of the calcium channel blocker is substituted at about 80% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0314] Embodiment 114. A pharmaceutical composition described in any one of embodiments 110 to 113, wherein the dosage of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker is replaced with about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0315] Embodiment 115. The pharmaceutical composition of embodiment 114, wherein the dosage of the angiotensin II receptor blocker is substituted at about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0316] Embodiment 116. The pharmaceutical composition of embodiment 115, wherein the dosage of the angiotensin II receptor blocker is replaced by about 100% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0317] Embodiment 117. The pharmaceutical composition of embodiment 114, wherein the dose of the diuretic is substituted at about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0318] Embodiment 118. The pharmaceutical composition of embodiment 117, wherein the dose of the diuretic is replaced by about 100% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0319] Embodiment 119. The pharmaceutical composition of embodiment 114, wherein the dosage of the calcium channel blocker is substituted at about 80% to about 150% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0320] Embodiment 120. The pharmaceutical composition of embodiment 119, wherein the dosage of the calcium channel blocker is substituted with about 100% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0321] Embodiment 121. A pharmaceutical composition described in any one of embodiments 110 to 113, wherein the dosages of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are replaced with about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker.

[0322] Embodiment 122. The pharmaceutical composition of embodiment 121, wherein the dosage of the angiotensin II receptor blocker is substituted at about 150% to about 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0323] Embodiment 123. The pharmaceutical composition of embodiment 122, wherein the dosage of the angiotensin II receptor blocker is substituted with about 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0324] Embodiment 124. The pharmaceutical composition of embodiment 121, wherein the dose of the diuretic is substituted at about 150% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0325] Embodiment 125. The pharmaceutical composition of embodiment 124, wherein the dose of the diuretic is replaced by about 200% of the minimum hypertensive therapeutic dose (LHTD) for the diuretic.

[0326] Embodiment 126. The pharmaceutical composition of embodiment 121, wherein the dosage of the calcium channel blocker is substituted at about 150% to about 250% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0327] Embodiment 127. The pharmaceutical composition of embodiment 126, wherein the dosage of the calcium channel blocker is substituted with about 200% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0328] Embodiment 128: A pharmaceutical composition comprising: (a) Telmisartan; (b) thiazide-like diuretics; and (c) Calcium channel blockers Including, wherein the dosage of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0329] Embodiment 129: The pharmaceutical composition of embodiment 128, wherein the pharmaceutical composition is essentially free of an angiotensin-converting enzyme inhibitor or a pharma- ceutically acceptable salt thereof, a beta-blocker or a pharma- ceutically acceptable salt thereof, a lipid regulating agent, a platelet function modifying agent, a serum homocysteine-lowering agent, or a combination thereof.

[0330] Embodiment 130: The pharmaceutical composition of embodiment 128 or 129, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, chlorexolone, fenquizone, or a pharma- ceutically acceptable salt or hydrate thereof.

[0331] Embodiment 131: The pharmaceutical composition of embodiment 130, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0332] Embodiment 132: The pharmaceutical composition of embodiment 131, wherein the thiazide-like diuretic is indapamide.

[0333] Embodiment 133: A pharmaceutical composition according to any one of embodiments 128 to 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, dotalizine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0334] Embodiment 134: The pharmaceutical composition of embodiment 133, wherein the calcium channel blocker is amlodipine or a pharma- ceutical acceptable salt thereof.

[0335] Embodiment 135: The pharmaceutical composition of embodiment 134, wherein the calcium channel blocker is amlodipine besylate.

[0336] Embodiment 136: The pharmaceutical composition of any one of embodiments 128 to 135, wherein the dosage of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0337] Embodiment 137: The pharmaceutical composition of embodiment 136, wherein the dosage of the thiazide-like diuretic is about 100% of the minimum hypertensive therapeutic dose (LHTD) for the thiazide-like diuretic.

[0338] Embodiment 138: The pharmaceutical composition of embodiment 137, wherein the thiazide-like diuretic is indapamide and the dosage of indapamide is about 1.25 mg.

[0339] Embodiment 139: The pharmaceutical composition of any one of embodiments 136 to 138, wherein the dosage of the calcium channel blocker is about 100% of the minimum hypertensive therapeutic dose (LHTD) for the calcium channel blocker.

[0340] Embodiment 140: The pharmaceutical composition of embodiment 139, wherein the calcium channel blocker is amlodipine besylate and the dosage of amlodipine besylate is about 2.5 mg.

[0341] Embodiment 141: The pharmaceutical composition according to any one of embodiments 136 to 140, wherein the dosage of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) for telmisartan.

[0342] Embodiment 142: The pharmaceutical composition of embodiment 141, wherein the dose of telmisartan is about 20 mg.

[0343] Embodiment 143: The pharmaceutical composition of embodiment 136, wherein the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate.

[0344] Embodiment 144: The pharmaceutical composition of embodiment 143, wherein the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg.

[0345] Embodiment 145: The pharmaceutical composition of embodiment 143, wherein the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0346] Embodiment 146. A pharmaceutical composition according to any one of embodiments 1 to 145, wherein (a), (b), and (c) are provided in a single formulation.

[0347] Embodiment 147. The pharmaceutical composition of any one of embodiments 1 to 145, wherein (a), (b), and (c) are each provided in a separate formulation.

[0348] Embodiment 148. A pharmaceutical composition according to any one of embodiments 1 to 145, wherein two of (a), (b), and (c) are provided in a single formulation.

[0349] Embodiment 149. The pharmaceutical composition of any one of embodiments 1 to 148, wherein the pharmaceutical composition is in the form of a pill, tablet, or capsule.

[0350] Embodiment 150. A pharmaceutical composition according to any one of embodiments 1 to 149, wherein the pharmaceutical composition is suitable for oral administration.

[0351] Embodiment 151: A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of any one of embodiments 1 to 150.

[0352] Embodiment 152. The method of embodiment 151, wherein the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg.

[0353] Embodiment 153. The method according to embodiment 150 or 151, wherein the treatment results in a decrease in systolic blood pressure (SBP) of about 10 mmHg or more.

[0354] Embodiment 154. The method of any one of embodiments 150 to 153, wherein the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg.

[0355] Embodiment 155. The method according to any one of embodiments 150 to 154, wherein the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg or more.

[0356] Embodiment 156. The method of any one of embodiments 150 to 155, wherein the treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction obtained with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0357] Embodiment 157. The method of any one of embodiments 150 to 156, wherein the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0358] Embodiment 158. The method of any one of embodiments 150 to 157, wherein the treatment results in greater long-term tolerance and reduced risk of side effects compared to treatment with a full minimum hypertension therapeutic dose of any one of (a), (b), and (c) in a pharmaceutical composition.

[0359] Embodiment 159. The method of any one of embodiments 150 to 158, wherein the treatment is an initial or primary treatment of hypertension.

[0360] Embodiment 160. The method of any one of embodiments 150 to 159, wherein the subject does not undergo any of the aforementioned hypertension treatments prior to treatment.

[0361] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the disclosure described herein may be utilized in the practice of the present disclosure. The following claims define the scope of the present disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. (a) Telmisartan, (b) Indapamide, and (c) Amlodipine besylate comprising a pharmaceutical composition, wherein the dosage of the telmisartan is about 8 mg to about 12 mg, the dosage of the indapamide is about 0.5 mg to about 0.75 mg, and the dosage of the amlodipine besylate is about 1 - 1.5 mg or about 1.5 - 2 mg, wherein the pharmaceutical composition does not contain a β-blocker.

2. The pharmaceutical composition according to Claim 1, wherein the dosage of the indapamide is about 0.625 mg.

3. The pharmaceutical composition according to Claim 1, wherein the dosage of the amlodipine besylate is about 1 - 1.5 mg.

4. The pharmaceutical composition according to Claim 1, wherein the dosage of the amlodipine besylate is about 1.5 - 2 mg.

5. The pharmaceutical composition according to Claim 1, wherein the dosage of the telmisartan is about 10 mg.

6. The pharmaceutical composition according to Claim 1, wherein the dosage of the indapamide is about 0.625 mg, the dosage of the amlodipine besylate is about 1.5 - 2 mg, and the dosage of the telmisartan is about 10 mg.

7. (a) Telmisartan, (b) Indapamide, and (c) Amlodipine besylate comprising a pharmaceutical composition, wherein the dosage of the telmisartan is about 16 mg to about 24 mg, the dosage of the indapamide is about 1 mg to about 1.5 mg, and the dosage of the amlodipine besylate is about 2 - 3.75 mg, about 2 - 3 mg, about 2.25 - 2.75 mg, or about 3.75 - 6.25 mg, wherein the pharmaceutical composition does not contain a β-blocker.

8. The pharmaceutical composition according to Claim 7, wherein the dosage of the amlodipine besylate is about 2 - 3.75 mg.

9. The pharmaceutical composition according to Claim 7, wherein the dosage of the amlodipine besylate is about 2 - 3 mg.

10. The pharmaceutical composition according to Claim 7, wherein the dosage of the amlodipine besylate is about 2.25 - 2.75 mg.

11. The pharmaceutical composition according to Claim 7, wherein the dosage of the amlodipine besylate is about 3.75 - 6.25 mg.

12. The pharmaceutical composition according to Claim 7, wherein the dosage of the indapamide is about 1.25 mg.

13. The pharmaceutical composition according to Claim 7, wherein the dosage of the telmisartan is about 20 mg. The pharmaceutical composition according to claim 7, wherein the dosage of indapamide is about 1.25 mg, the dosage of amlodipine besylate is about 2 mg to 3.75 mg, and the dosage of telmisartan is about 20 mg. The pharmaceutical composition according to claim 1 or claim 7, wherein the pharmaceutical composition is suitable for oral administration. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is in the form of pills, tablets, or capsules.

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