Composition for treating hypertension

Abstract

Provided herein are pharmaceutical compositions useful for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic and a calcium channel blocker. These compositions are administered at a dose of 40-80% of the lowest hypertensive therapeutic dose (LHTD) per agent. The present application also relates to a composition comprising telmisartan, a thiazine-like diuretic and a calcium channel blocker, administered at a dose of from 80 to 150% of the LHTD of each agent.

Description

[0001] This application is a divisional application of the Chinese patent application with application date of January 23, 2018, application number 201880021071.6, and invention name “Composition for treating hypertension” (the application date of its corresponding PCT application is January 23, 2018, and application number PCT / IB2018 / 000083).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 450,324, filed January 25, 2017, which is incorporated herein by reference in its entirety. Background Art

[0004] Hypertension (high blood pressure), also referred to as hypertension (hypertension), is the leading cause of preventable morbidity and mortality, and it has been determined that treatment to reduce blood pressure (BP) is beneficial. However, despite the availability of a large number of antihypertensive drugs, as demonstrated by multiple large-scale cohort studies, the blood pressure control of many patients remains poor. The influencing factors for poor blood pressure control include poor compliance, the complexity of the guidelines for advising multiple upward titration steps, and treatment inertia. In addition, most patients receiving treatment only receive monotherapy, which is still limited in effectiveness even at high doses with increased side effects and reduced tolerance. Therefore, there is a need for effective and tolerable new treatments for reducing hypertension. Summary of the Invention

[0005] In one aspect, a pharmaceutical composition is provided herein comprising

[0006] (a) Angiotensin II receptor blockers;

[0007] (b) diuretics; and

[0008] (c) Calcium channel blockers

[0009] wherein the dosage of each of (a), (b) and (c) is from about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0010] In some embodiments, the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitors or pharmaceutically acceptable salts thereof, beta-blockers or pharmaceutically acceptable salts thereof, lipid modulators, platelet function altering agents, serum homocysteine ​​lowering agents, or combinations thereof.

[0011] In some embodiments, the diuretic is a thiazide diuretic. In some embodiments, the thiazide diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clophenamide, metolazone, meticol, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide 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, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalipine, diprofenicline, 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 angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is telmisartan.

[0014] In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the diuretic is a thiazide diuretic, and the dose of the thiazide diuretic is about 50% of the lowest hypertension therapeutic dose (LHTD) of the thiazide diuretic. In some embodiments, the thiazide diuretic is indapamide, and the dose of indapamide is about 0.625 mg. In some embodiments, the dose of the calcium channel blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is about 1.25 mg. In some embodiments, the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 10 mg. In some embodiments, the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate. In some embodiments, the dose of telmisartan is about 8 mg to about 12 mg, the dose of indapamide is about 0.5 mg to about 0.75 mg, and the dose of amlodipine besylate is about 1 mg to about 1.5 mg. In some embodiments, the dose of telmisartan is about 10 mg, the dose of indapamide is about 0.625 mg, and the dose of amlodipine besylate is about 1.25 mg.

[0015] In another aspect, a pharmaceutical composition is provided, comprising

[0016] (a) Telmisartan;

[0017] (b) thiazide-like diuretics; and

[0018] (c) Calcium channel blockers

[0019] wherein the dosage of each of (a), (b) and (c) is from about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0020] In some embodiments, the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitors or pharmaceutically acceptable salts thereof, beta-blockers or pharmaceutically acceptable salts thereof, lipid modulators, platelet function altering agents, serum homocysteine ​​lowering agents, or combinations thereof.

[0021] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, clophenamide, metolazone, meticol, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

[0022] In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalipine, diprofenicol, 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.

[0023] In some embodiments, the dose of each of (a), (b) and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c). In some embodiments, the dose of the thiazide-like diuretic is about 100% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is about 2.5 mg. In some embodiments, the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan. In some embodiments, the dose of telmisartan is about 20 mg. In some embodiments, the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate. In some embodiments, the dose of telmisartan is about 16 mg to about 24 mg, the dose of indapamide is about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is about 2 mg to about 3 mg. In some embodiments, the dose of telmisartan is about 20 mg, the dose of indapamide is about 1.25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0024] 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.

[0025] Also provided herein is a method for 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 systolic blood pressure (SBP) being lower than about 140 mmHg. In some embodiments, the treatment results in systolic blood pressure (SBP) being reduced by about 10 mmHg or more. In some embodiments, the treatment results in diastolic blood pressure (DBP) being lower than about 90 mmHg. In some embodiments, the treatment results in diastolic blood pressure (DBP) being reduced by about 5 mmHg or more. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) greater than the reduction obtained by the complete minimum hypertension treatment dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) greater than the reduction obtained by the complete minimum hypertension treatment dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) greater than the reduction obtained by the complete minimum hypertension treatment dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in a higher long-term tolerance and a reduced risk of side effects compared to the treatment using the complete minimum hypertension treatment dose of any one of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment is an initial or first-line treatment for hypertension.In some embodiments, the subject has not received any previous hypertension therapy prior to treatment.

[0026] In another aspect, there is provided a pharmaceutical composition consisting essentially of the following ingredients

[0027] (a) Angiotensin II receptor blockers;

[0028] (b) diuretics; and

[0029] (c) Calcium channel blockers

[0030] wherein the dosage of each of (a), (b) and (c) is from about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0031] In another aspect, there is provided herein a pharmaceutical composition consisting essentially of the following ingredients

[0032] (a) Angiotensin II receptor blockers, such as telmisartan;

[0033] (b) thiazide-like diuretics; and

[0034] (c) Calcium channel blockers

[0035] wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0036] Incorporation by reference

[0037] 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

[0038] The novel features of the present disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by referring to the following detailed description and accompanying drawings which illustrate illustrative embodiments utilizing the principles of the invention, in which:

[0039] Figure 1 The mean systolic blood pressure (mmHg) over the period is shown by treatment.

[0040] Figure 2 The mean diastolic blood pressure (mmHg) over the period is shown by treatment.

[0041] Figure 3 Shows the average heart rate during the session by treatment. DETAILED DESCRIPTION

[0042] 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 lower than the minimum dose approved for the treatment of hypertension. The present disclosure recognizes the technical effects of low-dose combination therapies described herein, including but not limited to using low doses to avoid or alleviate side effects while maintaining or improving benefits, synergistic therapeutic benefits of certain drug combinations, early introduction of combination therapies to improve therapeutic effects, etc. On the one hand, described herein is a low-dose combination composition for the treatment of hypertension, including initial or first-line treatment of hypertension.

[0043] Certain terms

[0044] Unless the context clearly dictates otherwise, as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the composition" includes reference to one or more compositions (or multiple compositions) and equivalents thereof known to those skilled in the art, and so on. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulae, all combinations and subcombinations of the ranges and specific embodiments herein are intended to be included. When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximate value within experimental variability (or within statistical experimental error), and thus in some embodiments, the number or numerical range varies from 1% to 10% above and below the number or numerical range. The term "comprising" (and related terms such as "including" or "having") is not intended to exclude the fact that in certain other embodiments, for example, embodiments of any composition of matter, composition, method or process described herein may be "consisting of" or "essentially consisting of" the features.

[0045] As used in the specification and appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0046] As used herein, "pharmaceutically acceptable salts" include acid addition salts and base addition salts. In some embodiments, the pharmaceutically acceptable salts of any of the compounds described herein are forms 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.

[0047] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free bases, are biologically or otherwise desirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is incorporated herein by reference in its entirety). The acid addition salts of basic compounds can be prepared according to methods and techniques familiar to those skilled in the art by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0048] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids and are biologically or otherwise desirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0049] 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 crystallization with water. Hydrates are intended to include hydrates of any of the compounds described herein that are approved for use by the U.S. Food and Drug Administration.

[0050] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0051] As used herein, the terms "administer," "administer," and the like refer to methods that can be used to deliver a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with 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.

[0052] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates, such as chimpanzees, and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0053] As used herein, "treat," "treat," "treating," "alleviate," or "relieve" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" means eradication or alleviation of the underlying condition being treated. Additionally, therapeutic benefit can be achieved by eradication or alleviation of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, notwithstanding that the patient may still be suffering from the underlying condition. For prophylactic benefit, the composition can be administered to a patient at risk for developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

[0054] Triple Composition

[0055] Described herein are pharmaceutical compositions 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 lowest hypertension therapeutic dose (LHTD) of 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 lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 50% of the lowest hypertension therapeutic dose (LHTD) of 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 lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 66% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0056] In some embodiments, the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active agents, wherein the blood pressure lowering active agents consist of an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

[0057] In another aspect, described herein are pharmaceutical compositions comprising (a) an angiotensin II receptor blocker such as telmisartan, (b) a thiazide-like diuretic, and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 95% to about 105% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0058] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of angiotensin converting enzyme inhibitors (ACE inhibitors) or pharmaceutically acceptable salts thereof. In some embodiments, the angiotensin converting enzyme inhibitors include but are not limited to benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or pharmaceutically acceptable salts or hydrates thereof.

[0059] In addition, described herein are pharmaceutical compositions consisting essentially of (a) an angiotensin II receptor blocker, (b) a diuretic, and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is from about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 50% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 60% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 66% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0060] In addition, described herein are pharmaceutical compositions consisting essentially of (a) an angiotensin II receptor blocker such as telmisartan, (b) a thiazide-like diuretic, and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of 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 lowest hypertension therapeutic dose (LHTD) of 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 lowest hypertension therapeutic dose (LHTD) of 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 lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 100% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0061] In some embodiments, the pharmaceutical compositions disclosed herein achieve significant blood pressure reduction in subjects with moderately elevated blood pressure. In some embodiments, the pharmaceutical compositions disclosed herein achieve significant blood pressure reduction in subjects with moderately elevated blood pressure with minimal, insignificant, or no side effects.

[0062] beta-blockers

[0063] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of beta-blockers or pharmaceutically acceptable salts thereof. In some embodiments, beta-blockers are compounds that inhibit the receptor sites for the endogenous catecholamines adrenaline (epinephrine) and norepinephrine (norepinephrine) on the adrenergic beta receptors of the sympathetic nervous system. In some embodiments, beta-blockers include but are not limited to beta-adrenergic blockers, beta-adrenergic antagonists, beta-adrenergic antagonists, beta-adrenergic receptor antagonists or beta-adrenergic receptor antagonists. In some embodiments, beta-blockers inhibit the activation of all types of beta-adrenergic receptors. In some embodiments, beta-blockers inhibit both beta-adrenergic receptors and alpha-adrenergic receptors. In some embodiments, beta-blockers are selective for one of the following beta receptors: beta 1 receptors, beta 2 receptors, and beta 3 receptors.

[0064] 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 with combined beta-adrenergic receptor and alpha-adrenergic receptor blocking effects. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the beta-blocker is a beta1-selective adrenergic receptor antagonist. Examples of beta1-selective adrenergic receptor antagonists include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nebivolol, and acebutolol. In some embodiments, the beta-blocker is a beta2-selective adrenergic receptor antagonist, such as butaxamine.

[0065] 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, pralolol, metipranolol, landiolol, bopindolol, propanolol, butaxamine, bevantolol, tertalol, arotinolol, levobetaxolol, befunolol, amosulalol, tilesolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, oxprenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, carvedilol, labetalol, timolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is atenolol. In some embodiments, the beta blocker is bisoprolol or a pharmaceutically acceptable salt thereof.

[0066] Lipid regulators

[0067] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of lipid regulating agents, platelet function altering agents, serum homocysteine ​​lowering agents, or a combination thereof.

[0068] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of lipid modulators. In some embodiments, the lipid modulator is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, also known as a statin. In some embodiments, the lipid modulator is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin. In some embodiments, the lipid modulator is atorvastatin or simvastatin. In some embodiments, the lipid modulator is atorvastatin. In some embodiments, the lipid modulator is simvastatin.

[0069] Platelet function altering agents

[0070] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of platelet function-altering agents. In some embodiments, the platelet function-altering agent is aspirin, ticlopidine, dipyridamole, or clopidogrel. In some embodiments, the platelet function-altering agent is a glycoprotein IIb / IIIa receptor inhibitor, such as abciximab. In some embodiments, the platelet function-altering agent is a nonsteroidal anti-inflammatory drug, such as ibuprofen. In some embodiments, the platelet function-altering agent is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen. In some embodiments, the platelet function-altering agent is aspirin.

[0071] serum homocysteine ​​lowering agents

[0072] In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of a serum homocysteine ​​lowering agent. In some embodiments, the serum homocysteine ​​lowering agent is folic acid, vitamin B6, or vitamin B12, or a combination thereof. In some embodiments, the serum homocysteine ​​lowering agent is folic acid.

[0073] Angiotensin II receptor antagonists / blockers

[0074] As used herein, angiotensin II receptor antagonists or blockers (ARBs) are compounds that modulate the effects 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 pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is losartan. In some embodiments, the angiotensin II receptor blocker is valsartan. In some embodiments, the angiotensin II receptor blocker is candesartan. In some embodiments, the angiotensin II receptor blocker is eprosartan. In some embodiments, the angiotensin II receptor blocker is irbesartan. In some embodiments, the angiotensin II receptor blocker is telmisartan.

[0075] diuretics

[0076] As used herein, a diuretic refers to a compound that increases urine flow. Diuretics are classified by chemical structure (thiazide diuretics and thiazide-like diuretics), site of action (such as loop diuretics), or pharmacological action (such as osmotic diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics).

[0077] In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide-like diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a loop diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise an osmotic diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a carbonic anhydrase inhibitor. In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium-sparing diuretic.

[0078] Thiazide diuretics

[0079] As used herein, thiazide diuretics refer to compounds containing a benzothiadiazine molecular structure. In some embodiments, thiazide diuretics inhibit the reabsorption of sodium and chloride in the distal tubules of the kidney, which results in increased urinary excretion of sodium and water. Examples of thiazide diuretics include, but are not limited to, althiazide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutiazide, methylclothiazide, polythiazide, and trichloromethiazide.

[0080] In some embodiments, the thiazide diuretic is althiazide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutiazide, methylclothiazide, polythiazide, trichlorothiazide, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is althiazide. In some embodiments, the thiazide diuretic is bendroflumethiazide. In some embodiments, the thiazide diuretic is chlorothiazide. In some embodiments, the thiazide diuretic is cyclopenthiazide. In some embodiments, the thiazide diuretic is cyclothiazide. In some embodiments, the thiazide diuretic is epithiazide. In some embodiments, the thiazide diuretic is hydrochlorothiazide. In some embodiments, the thiazide diuretic is hydroflumethiazide. In some embodiments, the thiazide diuretic is mebutiazide. In some embodiments, the thiazide diuretic is methylclothiazide. In some embodiments, the thiazide diuretic is polythiazide. In some embodiments, the thiazide diuretic is trichlorothiazide.

[0081] Thiazide-like diuretics

[0082] As used herein, thiazide diuretics are sulfonamide diuretics that have similar physiological properties to thiazide diuretics but do not have the chemical properties of thiazides (i.e., do not have a benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticolene, xipamide, indapamide, cloxolone, and fenquinazole.

[0083] In some embodiments, the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticoren, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is quinethazone. In some embodiments, the thiazide-like diuretic is clopamide. In some embodiments, the thiazide-like diuretic is chlorthalidone. In some embodiments, the thiazide-like diuretic is mefruside. In some embodiments, the thiazide-like diuretic is chlorphenamide. In some embodiments, the thiazide-like diuretic is metolazone. In some embodiments, the thiazide-like diuretic is meticoren. 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 cloxolone. In some embodiments, the thiazide-like diuretic is fenquinazole.

[0084] loop diuretics

[0085] As used herein, loop diuretics are compounds that act on the Na+ / K+ / 2Cl- cotransporter in the thick ascending limb of the loop of Henle to inhibit the reabsorption of sodium, chloride, and potassium. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, etazolin, mozolomide, oxazolinone, piretanide, tinic acid, and torsemide. In some embodiments, the loop diuretic is furosemide, bumetanide, ethacrynic acid, etazolin, mozolomide, oxazolinone, piretanide, tinic acid, torsemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0086] Other diuretics

[0087] Osmotic diuretics are compounds that cause water to be retained in the proximal tubule and descending limb of the loop of Henle. In some embodiments, osmotic diuretics expand fluid and plasma volume and increase blood flow to the kidneys. Examples include, but are not limited to, mannitol and glycerol.

[0088] Carbonic anhydrase inhibitors

[0089] Carbonic anhydrase inhibitors as used herein are compounds as inhibitors of carbonic anhydrase. In some embodiments, carbonic anhydrase inhibitors increase the excretion of bicarbonate accompanied by sodium, potassium and water, which causes alkaline urine flow to increase. In some embodiments, carbonic anhydrase inhibitors suppress the transport of bicarbonate from the proximal convoluted tubule to the interstitial space, which causes the sodium that is reabsorbed to decrease and provide greater sodium, bicarbonate and water loss in urine. The example of such compound includes but is not limited to acetazolamide, dichlorphenamide and methazolamide.

[0090] Potassium-sparing diuretics

[0091] Potassium-sparing diuretics are compounds that compete with aldosterone for intracellular cytoplasmic receptor sites or directly block sodium channels, particularly the epithelial sodium channel (ENaC). Examples of potassium-sparing diuretics include, but are not limited to, amiloride, spironolactone, eplerenone, triamterene, and potassium canrenoate.

[0092] Other diuretics contemplated include, but are not limited to, caffeine, theophylline, theobromine, tolvaptan, conivaptan, dopamine, and pamabrom.

[0093] In some embodiments, the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the diuretic is dichlorphenamide. In some embodiments, the diuretic is amiloride. In some embodiments, the diuretic is pamabrom. In some embodiments, the diuretic is mannitol. In some embodiments, the diuretic is acetazolamide. In some embodiments, the diuretic is methazolamide. In some embodiments, the diuretic is spironolactone. In some embodiments, the diuretic is triamterene.

[0094] calcium channel blockers

[0095] 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, a dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalipine, diprofenicline, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate. In some embodiments, the calcium channel blocker is nifedipine. In some embodiments, the calcium channel blocker is diltiazem. In some embodiments, the calcium channel blocker is nimodipine. In some embodiments, the calcium channel blocker is verapamil. In some embodiments, the calcium channel blocker is isradipine. In some embodiments, the calcium channel blocker is felodipine. In some embodiments, the calcium channel blocker is nicardipine. In some embodiments, the calcium channel blocker is nisoldipine. In some embodiments, the calcium channel blocker is clevidipine.

[0096] Minimum dose for treating hypertension

[0097] As used herein, the lowest hypertension therapeutic dose (LHTD) refers to the lowest strength dose of a single hypertension medication that is approved by the U.S. Food and Drug Administration and that has not been included in the Orange Book database ( http: / / www.accessdata.fda.gov / scripts / cder / ob / ) is marked as "Discontinue use." In cases where the minimum hypertension treatment dose is different from the minimum manufacturing dose, the minimum hypertension treatment dose does not include the minimum manufacturing dose. In addition, in cases where the minimum hypertension treatment dose is different from the dose recommended by the physician, the minimum hypertension treatment dose does not include the dose recommended by the physician. In addition, the minimum hypertension treatment dose of angiotensin II receptor blockers, diuretics, or calcium channel blockers described herein refers to the dose of angiotensin II receptor blockers, diuretics, or calcium channel blockers approved for use by the U.S. Food and Drug Administration, including their free base, pharmaceutically acceptable salts, or hydrates.

[0098] In some embodiments, the dose of angiotensin II receptor blocker is about 40% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 40% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 40% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 40% to about 50% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 45% to about 55% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 50% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 50% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 50% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 60% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 60% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 70% to about 80% of the minimum dose for treating hypertension.

[0099] In some embodiments, the dose of the angiotensin II receptor blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of angiotensin II receptor blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 50% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 66% of the lowest dose for treating hypertension.

[0100] In some embodiments, the dose of the diuretic is about 40% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 40% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 40% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 40% to about 50% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 45% to about 55% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 50% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 50% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 50% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 60% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 60% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 70% to about 80% of the minimum hypertension treatment dose.

[0101] In some embodiments, the dose of the diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest hypertension treatment dose. In some embodiments, the dose of the diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest hypertension treatment dose. In some embodiments, the dose of the diuretic is about 50% of the lowest hypertension treatment dose. In some embodiments, the dose of the diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest hypertension treatment dose. In some embodiments, the dose of the diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest hypertension treatment dose. In some embodiments, the dose of the diuretic is about 66% of the lowest hypertension treatment dose.

[0102] In some embodiments, the dose of the thiazide diuretic is about 40% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 40% to about 50% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 45% to about 55% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 60% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 60% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide diuretic is about 70% to about 80% of the minimum hypertension treatment dose.

[0103] 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 treatment dose. In some embodiments, the dose of the thiazide diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide diuretic is about 66% of the lowest dose for treating hypertension.

[0104] In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 80% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 70% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 60% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 40% to about 50% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 45% to about 55% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 80% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 70% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 50% to about 60% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 60% to about 80% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 60% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 70% to about 80% of the minimum hypertension treatment dose.

[0105] In some embodiments, the dose of the thiazide-like diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 66% of the lowest dose for treating hypertension.

[0106] In some embodiments, the dose of the loop diuretic is about 40% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 40% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 40% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 40% to about 50% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 45% to about 55% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 50% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 50% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 50% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 60% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of loop diuretic is about 60% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of loop diuretic is about 70% to about 80% of the minimum hypertension treatment dose.

[0107] In some embodiments, the dose of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the loop diuretic is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the loop diuretic is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the loop diuretic is about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the loop diuretic is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the loop diuretic is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of the loop diuretic is about 66% of the lowest dose for treating hypertension.

[0108] In some embodiments, the dose of the calcium channel blocker is about 40% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 40% to about 50% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 45% to about 55% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 50% to about 60% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 60% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 60% to about 70% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 70% to about 80% of the minimum hypertension treatment dose.

[0109] In some embodiments, the dose of the calcium channel blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 66% of the lowest dose for treating hypertension.

[0110] In some embodiments, the lowest hypertension therapeutic dose (LHTD) of the following compounds and the corresponding suggested doses and suggested dose ranges are described in the following table:

[0111] Table 1.

[0112]

[0113]

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

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

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] In some embodiments, the dose of angiotensin II receptor blocker, such as telmisartan, is about 80% to about 150% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 80% to about 140% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 80% to about 130% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 80% to about 120% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 80% to about 110% of the minimum dose for treating hypertension.

[0127] In some embodiments, the dose of angiotensin II receptor blocker, such as telmisartan, is about 85% to about 145% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 85% to about 135% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 85% to about 125% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 85% to about 115% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 85% to about 105% of the minimum dose for treating hypertension.

[0128] In some embodiments, the dose of angiotensin II receptor blocker, such as telmisartan, is about 90% to about 140% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 90% to about 130% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 90% to about 120% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 90% to about 110% of the minimum dose for treating hypertension.

[0129] In some embodiments, the dose of angiotensin II receptor blocker, such as telmisartan, is about 95% to about 135% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 95% to about 125% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 95% to about 115% of the minimum dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 95% to about 105% of the minimum dose for treating hypertension.

[0130] 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%, or about 120% of the minimum hypertension treatment dose. In some embodiments, the dose of angiotensin II receptor blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the lowest dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the lowest dose for treating hypertension. In some embodiments, the dose of angiotensin II receptor blocker is about 100% of the lowest dose for treating hypertension.

[0131] In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 150% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 140% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 130% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 120% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 80% to about 110% of the lowest hypertension treatment dose.

[0132] In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 145% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 135% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 125% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 115% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 85% to about 105% of the lowest hypertension treatment dose.

[0133] In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 140% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 130% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 120% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 90% to about 110% of the lowest hypertension treatment dose.

[0134] In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 135% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 125% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 115% of the lowest hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 95% to about 105% of the lowest hypertension treatment dose.

[0135] 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%, or about 120% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the lowest dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic blocker is about 100% of the lowest dose for treating hypertension.

[0136] In some embodiments, the dose of the calcium channel blocker is about 80% to about 150% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 140% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 130% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 120% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 80% to about 110% of the lowest hypertension treatment dose.

[0137] In some embodiments, the dose of the calcium channel blocker is about 85% to about 145% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 135% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 125% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 115% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 85% to about 105% of the lowest hypertension treatment dose.

[0138] In some embodiments, the dose of the calcium channel blocker is about 90% to about 140% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 130% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 120% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 90% to about 110% of the lowest hypertension treatment dose.

[0139] In some embodiments, the dose of the calcium channel blocker is about 95% to about 135% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 125% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 115% of the lowest hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 95% to about 105% of the lowest hypertension treatment dose.

[0140] In some embodiments, the dose of the calcium channel blocker is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, or about 120% of the minimum hypertension treatment dose. In some embodiments, the dose of the calcium channel blocker is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, or about 110% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, or about 105% of the lowest dose for treating hypertension. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest dose for treating hypertension.

[0141] In some embodiments, the lowest hypertension therapeutic dose (LHTD) of the following compounds and the corresponding suggested doses and suggested dose ranges are described in the following table:

[0142] Table 2.

[0143]

[0144]

[0145] In some embodiments, the dose of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of a diuretic is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of a diuretic. In some embodiments, the dose of a calcium channel blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of a calcium channel blocker. In some embodiments, the dose of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of a diuretic is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of a diuretic. In some embodiments, the dose of a diuretic is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of a diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.In some embodiments, the dose of the diuretic is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0146] In some embodiments, the dose of any two of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blockers, diuretics, or calcium channel blockers. In some embodiments, the dose of angiotensin II receptor blockers is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blockers. In some embodiments, the dose of diuretics is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of diuretics. In some embodiments, the dose of calcium channel blockers is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of calcium channel blockers. In some embodiments, the dose of any two of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blockers, diuretics, or calcium channel blockers. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blockers. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of angiotensin II receptor blockers. In some embodiments, the dose of a diuretic is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of a diuretic. In some embodiments, the dose of a diuretic is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of a diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.In some embodiments, the dose of the diuretic is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0147] In some embodiments, the dose 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 about 80% to about 150% of the lowest therapeutic dose (LHTD) of the angiotensin II receptor blocker, the diuretic, or the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 80% to about 150% of the lowest therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is about 80% to about 150% of the lowest therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is about 80% to about 150% of the lowest therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is each independently about 80% to about 120% of the lowest therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is about 80% to about 120% of the lowest therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is about 100% of the lowest therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dosage of the diuretic is about 80% to about 120% of the lowest therapeutic dose (LHTD) of the diuretic. In some embodiments, the dosage of the diuretic is about 100% of the lowest therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the calcium channel blocker is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is each independently about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the diuretic is about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of the diuretic. In some embodiments, the dose of the diuretic is about 100% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.In some embodiments, the dose of the calcium channel blocker is about 90% to about 110% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0148] 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 dosage of telmisartan is about 16 mg to about 30 mg, the dosage of indapamide is about 1 mg to about 1.875 mg, and the dosage of amlodipine besylate is about 2 mg to about 3.75 mg.

[0149] In some embodiments, the dose of telmisartan is from about 16 mg to about 24 mg, the dose of indapamide is from about 1 mg to about 1.5 mg, and the dose of amlodipine besylate is from about 2 mg to about 3 mg.

[0150] 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.

[0151] 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.

[0152] 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 dosage of telmisartan is about 16 mg to about 30 mg, the dosage of chlorthalidone is about 20 mg to about 37.5 mg, and the dosage of amlodipine besylate is about 2 mg to about 3.75 mg.

[0153] 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.

[0154] 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.

[0155] In some embodiments, the dose of telmisartan is about 20 mg, the dose of chlorthalidone is about 25 mg, and the dose of amlodipine besylate is about 2.5 mg.

[0156] preparation

[0157] In some embodiments, the angiotensin II receptor blocker, diuretic, and calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker, diuretic, and calcium channel blocker are each provided in separate formulations. In some embodiments, two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor and diuretic are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker and calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker and calcium channel blocker are provided in a single formulation. In some embodiments, the diuretic and calcium channel blocker are provided in a single formulation. In some embodiments, the angiotensin II receptor blocker, diuretic, and calcium channel blocker are provided in a single formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is in the form of a pill. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0158] 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 appropriate form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound being used. For example, the disclosed compositions can be formulated as a unit dosage.

[0159] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations (e.g., in solid, semisolid, or liquid form) comprising one or more disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. For example, the active ingredient can be mixed with a generally nontoxic pharmaceutically acceptable carrier for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0160] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0161] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents. agents) such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents, for example, acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the composition may also contain a buffering agent. Similar types of solid compositions may also use excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc. as fillers in soft and hard-filled gelatin capsules.

[0162] Tablet can be prepared by compression or molding, optionally adopting one or more auxiliary ingredients.Binding agent (for example, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant can be used to prepare compressed tablet.Molded tablets can be prepared by molding the mixture of the subject composition moistened with an inert liquid diluent in a suitable machine.In some embodiments, capsule is prepared by being enclosed in a hard gelatin capsule (for example encapsulation).Tablet and other solid dosage forms, such as dragee, capsule, pill and granule, can optionally be scored or prepared with coating and shell, such as other coatings known to enteric coating and pharmaceutical formulations.

[0163] In some embodiments, the angiotensin II receptor blocker of the pharmaceutical composition described herein can be replaced with an angiotensin converting enzyme inhibitor (ACE inhibitor). Examples of suitable angiotensin converting enzyme inhibitors include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 80% to about 150% of the minimum hypertension treatment dose. In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 80% to about 120% of the minimum hypertension treatment dose. In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 90% to about 110% of the minimum hypertension treatment dose. In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 100% of the minimum hypertension treatment dose. In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 40% to about 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the ACE inhibitor is about 40% to about 70% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 40% to about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 40% to about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 45% to about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 50% to about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 50% to about 70% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 50% to about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 60% to about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the ACE inhibitor is about 60% to about 70% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 70% to about 80% of the minimum hypertension treatment dose.In some embodiments, the dose of the angiotensin converting enzyme inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, 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 treatment dose. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 50% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71% of the lowest dose for treating hypertension. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is about 66% of the lowest dose for treating hypertension.

[0164] Treatment

[0165] Pharmaceutical compositions as described herein can be used to treat hypertension in a subject in need thereof. In some embodiments, the treatment causes systolic blood pressure (SBP) to be lower than about 140 mmHg. In some embodiments, the treatment causes systolic blood pressure (SBP) to be lower than about 135 mmHg. In some embodiments, the treatment causes systolic blood pressure (SBP) to be reduced by about 10 mmHg or more. In some embodiments, the treatment causes systolic blood pressure (SBP) to be reduced by about 10 mmHg to about 20 mmHg. In some embodiments, the treatment causes systolic blood pressure (SBP) to be reduced by about 10 mmHg to about 30 mmHg. In some embodiments, the treatment causes systolic blood pressure (SBP) to be reduced by about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg or about 20 mmHg. In some embodiments, the treatment results in a systolic blood pressure (SBP) reduction 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) reduction of less than about 90 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) reduction of less than about 85 mmHg. In some embodiments, the treatment results in a diastolic blood pressure (DBP) reduction of about 5 mmHg or more. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 10 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg to about 15 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, or about 10 mmHg. In some embodiments, the treatment results in a decrease in diastolic blood pressure (DBP) of about 5 mmHg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, or about 15 mmHg.

[0166] In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than that achieved with a full minimal hypertension treatment dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than that achieved with a full minimal hypertension treatment dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than that achieved with a full minimal hypertension treatment dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in systolic blood pressure (SBP) that is greater than that achieved with a full minimal hypertension treatment dose of the calcium channel blocker in the pharmaceutical composition.

[0167] In some embodiments, the treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with a full minimal hypertension treatment dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in 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 minimal hypertension treatment dose of the angiotensin II receptor blocker in 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 minimal hypertension treatment dose of the diuretic in 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 minimal hypertension treatment dose of the calcium channel blocker in the pharmaceutical composition.

[0168] In some embodiments, the treatment results in improved long-term tolerability and reduced risk of side effects compared to treatment with the full minimal hypertension treatment dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in improved long-term tolerability and reduced risk of side effects compared to treatment with the full minimal hypertension treatment dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in improved long-term tolerability and reduced risk of side effects compared to treatment with the full minimal hypertension treatment dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in improved long-term tolerability and reduced risk of side effects compared to treatment with the full minimal hypertension treatment dose of the calcium channel blocker in the pharmaceutical composition.

[0169] In some embodiments, treatment results in a reduction in systolic blood pressure (SBP) that is greater than or equal to the reduction achieved with the combination of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition, wherein the dose of each of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is about 50% of the lowest dose for treating hypertension. In some embodiments, treatment results in a reduction in diastolic blood pressure (DBP) that is greater than or equal to the reduction achieved with the combination of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition, wherein the dose of each of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is about 50% of the lowest dose for treating hypertension. In some embodiments, the treatment results in greater long-term tolerability and reduced risk of side effects compared to treatment with the combination of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition, wherein the dose of each of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is about 50% of the lowest dose for treating hypertension.

[0170] In some embodiments, the treatment is an initial or first-line treatment for hypertension. In some embodiments, the subject has very mildly elevated blood pressure prior to treatment. In some embodiments, the subject has not received any prior treatment for hypertension prior to treatment. In some embodiments, the subject has very mildly elevated blood pressure prior to treatment and has not received any prior treatment for hypertension prior to treatment.

[0171] The present disclosure recognizes that, in some embodiments, the use of angiotensin II receptor blockers in the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects, including but not limited to a significant reduction in blood pressure, a significant reduction in blood pressure in subjects with mildly elevated blood pressure, greater long-term tolerability, and a reduced risk of side effects. The present disclosure recognizes that, in some embodiments, the exclusion of lipid modifiers, platelet function altering agents, serum homocysteine ​​lowering agents, or a combination thereof from the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects, including but not limited to a significant reduction in blood pressure, a significant reduction in blood pressure in subjects with mildly elevated blood pressure, greater long-term tolerability, and a reduced risk of side effects.

[0172] It is also recognized herein that, in some embodiments, the triple combination described herein comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker (each component at about 40% to about 80% of the minimum therapeutic dose for hypertension) provides significantly greater lowering of blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) as compared to a triple combination comprising an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) (each component at 100% of the minimum therapeutic dose for hypertension). In some embodiments, the triple combination described herein comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker (each component at about 40% to about 60% of the minimum therapeutic dose for hypertension) provides significantly greater lowering of blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) as compared to a triple combination comprising an angiotensin II receptor blocker (e.g., losartan), a diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate) (each component at 100% of the minimum therapeutic dose for hypertension).

[0173] It is also recognized herein that, in some embodiments, the triple combination described herein comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker (each component at about 80% to about 150% of the lowest therapeutic dose for hypertension) provides significantly greater reductions in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate). In some embodiments, the triple combination described herein comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker (each component at about 80% to about 120% of the lowest therapeutic dose for hypertension) provides significantly greater reductions in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, or both) than a triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide-like diuretic (e.g., hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate).

[0174] The present invention provides embodiments including but not limited to the following:

[0175] 1. A pharmaceutical composition comprising

[0176] (a) Angiotensin II receptor blockers;

[0177] (b) diuretics; and

[0178] (c) Calcium channel blockers

[0179] wherein the dosage of each of (a), (b) and (c) is from about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0180] 2. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a lipid regulator, a platelet function altering agent, a serum homocysteine ​​lowering agent, or a combination thereof.

[0181] 3. The pharmaceutical composition according to embodiment 1, wherein the diuretic is a thiazide-like diuretic.

[0182] 4. The pharmaceutical composition according to embodiment 3, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticol, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof.

[0183] 5. The pharmaceutical composition according to embodiment 4, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0184] 6. The pharmaceutical composition according to embodiment 5, wherein the thiazide-like diuretic is indapamide.

[0185] 7. The pharmaceutical composition of embodiment 1, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, a dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalidomide, diprofenicline, or a pharmaceutically acceptable salt or hydrate thereof.

[0186] 8. The pharmaceutical composition according to embodiment 7, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0187] 9. The pharmaceutical composition according to embodiment 8, wherein the calcium channel blocker is amlodipine besylate.

[0188] 10. The pharmaceutical composition according to embodiment 1, wherein the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0189] 11. The pharmaceutical composition according to embodiment 10, wherein the angiotensin II receptor blocker is telmisartan.

[0190] 12. The pharmaceutical composition of embodiment 1, wherein the dose of each of (a), (b) and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0191] 13. The pharmaceutical composition of embodiment 12, wherein the diuretic is a thiazide-like diuretic, and the dose of the thiazide-like diuretic is about 50% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic.

[0192] 14. The pharmaceutical composition of embodiment 13, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 0.625 mg.

[0193] 15. The pharmaceutical composition of embodiment 12, wherein the dose of the calcium channel blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0194] 16. The pharmaceutical composition of embodiment 15, wherein the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is about 1.25 mg.

[0195] 17. The pharmaceutical composition of embodiment 12, wherein the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0196] 18. The pharmaceutical composition according to embodiment 17, wherein the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 10 mg.

[0197] 19. The pharmaceutical composition of embodiment 12, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

[0198] 20. The pharmaceutical composition of embodiment 19, 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.

[0199] 21. The pharmaceutical composition of embodiment 19, 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.

[0200] 22. A pharmaceutical composition comprising

[0201] (a) Telmisartan;

[0202] (b) thiazide-like diuretics; and

[0203] (c) Calcium channel blockers

[0204] wherein the dosage of each of (a), (b) and (c) is from about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0205] 23. A pharmaceutical composition according to embodiment 22, wherein the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a lipid regulator, a platelet function altering agent, a serum homocysteine ​​lowering agent, or a combination thereof.

[0206] 24. The pharmaceutical composition according to embodiment 22, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticol, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof.

[0207] 25. The pharmaceutical composition according to embodiment 24, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0208] 26. The pharmaceutical composition of embodiment 25, wherein the thiazide-like diuretic is indapamide.

[0209] 27. The pharmaceutical composition of embodiment 22, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, a dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalidomide, diprofenicline, or a pharmaceutically acceptable salt or hydrate thereof.

[0210] 28. The pharmaceutical composition of embodiment 27, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0211] 29. The pharmaceutical composition of embodiment 28, wherein the calcium channel blocker is amlodipine besylate.

[0212] 30. The pharmaceutical composition of embodiment 22, wherein the dose of each of (a), (b) and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0213] 31. The pharmaceutical composition of embodiment 30, wherein the dose of the thiazide-like diuretic is about 100% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic.

[0214] 32. The pharmaceutical composition of embodiment 31, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg.

[0215] 33. The pharmaceutical composition of embodiment 30, wherein the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0216] 34. The pharmaceutical composition of embodiment 33, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg.

[0217] 35. The pharmaceutical composition according to embodiment 30, wherein the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan.

[0218] 36. The pharmaceutical composition according to embodiment 35, wherein the dose of telmisartan is about 20 mg.

[0219] 37. The pharmaceutical composition of embodiment 30, wherein the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate.

[0220] 38. The pharmaceutical composition of embodiment 37, 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.

[0221] 39. The pharmaceutical composition of embodiment 37, 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.

[0222] 40. A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of embodiment 1.

[0223] 41. A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of embodiment 22.

[0224] Example

[0225] Example 1: Overview of Cardiovascular Measurements in Spontaneously Hypertensive Rats Received an Antihypertensive Drug Combination

[0226] The aim of this study was to assess the comparative effects of three different combinations of angiotensin II receptor blockers, calcium channel blockers, and diuretics (thiazide diuretics or thiazide-like diuretics) on blood pressure. The primary objectives were to assess whether there were differences in effects between combinations using different drugs from the same class, and between combinations using different doses of the same drug, including very low doses (i.e., doses less than the lowest approved and manufactured dose, such as 50% of the lowest hypertension therapeutic dose (LHTD)).

[0227] The specific combinations studied were:

[0228] Combination 1: telmisartan, amlodipine besylate, and indapamide, each at 50% of the lowest hypertension therapeutic dose (LHTD) or one-quarter of the FDA-recommended usual maintenance dose (corresponding to telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg);

[0229] Combination 2: telmisartan, amlodipine, and indapamide, each at 100% of the lowest hypertension therapeutic dose (LHTD) or half the FDA-recommended usual maintenance dose (corresponding to telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg); and

[0230] Combination 3: losartan, amlodipine besylate, and hydrochlorothiazide, each at 100% of the lowest hypertension therapeutic dose (LHTD) or half the FDA-recommended usual maintenance dose (corresponding to losartan 25 mg, amlodipine besylate 2.5 mg, and hydrochlorothiazide 12.5 mg).

[0231] The study was conducted in spontaneously hypertensive rats (SHR), the most commonly used animal model for studying hypertension (see: Pinto YM, Paul M, Ganten D. "Lessons from rat models of hypertension: from Goldblatt to genetic engineering". Cardiovascular Research. 39(1): 77–88). Standard allometric scaling methods and C values ​​from each of the six antihypertensive drugs were used. max Drug doses were calculated based on published literature data on AUC and AUC. Each animal was exposed to a single dose of each drug combination in a Latin square design.

[0232] method

[0233] The following studies used the following as vehicles: 0.5% methylcellulose (w / v) and 0.25% polysorbate 80 (v / v) in 25 mM phosphate buffer (pH 8 + / - 0.2).

[0234] The following animals were used in the study: spontaneously hypertensive rats (strain: SHR / NCrl). These rats were obtained from Charles River Laboratories, Inc., Kingston, New York. Dosing was initiated at approximately 12 weeks of age. Thirteen male rats were used for acclimation. Eight male rats were used for the study. Animals were identified by cage cards and tattoos.

[0235] Telemetry Implantation: Animals were implanted with a Data Science International transmitter (HD-S10) for the collection of blood pressure and heart rate data. Animals were not dosed until at least 10 days after surgery.

[0236] Housing: Animals were housed individually in fixed-bottom cages equipped with water bottles.

[0237] Diet: Unless otherwise stated, Teklad Global Diet-Rodent 2014 (Envigo RMS, Inc.) was provided ad libitum. In some cases, animals were fed a dietary form of this diet if health conditions indicated.

[0238] Water: Greenfield city water is provided ad libitum.

[0239] Contaminants: There were no known contaminants in the diet, water, or bedding (if any) at levels that would interfere with this study.

[0240] Environment: The environmental controls of the animal room were set to maintain the following room conditions: temperature range of 20 to 26°C, relative humidity of 30% to 70%, and a 12 h light / 12 h dark cycle.

[0241] Acclimation (pre-dose phase): The acclimation phase is a maximum of 1 week.

[0242] Environmental and dietary enrichment: Animals were provided with various cage enrichment devices and dietary enrichment (not required for analysis).

[0243] Randomization: Animals were randomly selected based on mean arterial pressure values ​​during the pre-dose period.

[0244] The following table shows the grouping of rats used in this study:

[0245] Table 3.

[0246]

[0247]

[0248] The following table shows the dose levels administered in this study:

[0249] Table 4.

[0250]

[0251] Dosing procedure: For combinations 1, 2 and 3, each test combination formulation was freshly prepared on each day of administration. A portion of the vehicle (approximately 80%) was added to the test combination formulation and mixed until the formulation was uniform. If a uniform suspension or solution was not obtained, 1N NaOH and / or 1N HCl was added to adjust to pH 9 ± 0.2. The remaining vehicle was added and mixed with a stirring rod. The test combination formulation was stirred continuously at room temperature and protected from light for approximately 30 minutes before administration and throughout the administration process. The test combination formulation was stored in the dark and stirred in a refrigerator set to maintain 2 to 8 ° C.

[0252] Dosing Procedure: For pre-dose treatment, the test combination formulation was 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, and the actual dose volume was based on the most recent body weight. Doses were administered by oral gavage. Dosing intervals were once daily on days 1, 8, 15, and 22. Following dosing, the remaining test combination formulation was disposed of according to standard operating procedures.

[0253] Telemetry Collection: Animals will not be disturbed or handled immediately prior to or during telemetry data collection without prior approval. Such disturbances include, but are not limited to, cage changes, bedding changes, mopping, cleaning, or any other manipulation that disrupts the natural, quiet environment essential for the collection of cardiovascular telemetry data.

[0254] Animal Observation: Each rat should be observed once daily in the morning. Any abnormal findings should be recorded. Rats should be observed for death, abnormalities, and signs of pain or distress. Any abnormal findings observed during unscheduled observation periods should also be noted.

[0255] Body Weight: Obtain body weights at least once during the pre-dose period and before each scheduled dose. Record additional body weights, if appropriate, to monitor animal health. Fitting Animals with Transmitters: Prior to collecting body weights, tarre using a representative transmitter and lead wire for dose calculations.

[0256] Telemetry Data Acquisition: Arterial pressure raw signals are digitized at a sampling rate of 500 Hz. The derivation parameters are the same for the pre-dose and dosing phases. For pre-dose data acquisition, all implanted telemetry devices are checked for signal consistency and the telemetry signal is verified to be acceptable for analysis. Signal checking includes collecting at least one telemetry recording from each rat considered for this study. Telemetry data is recorded continuously for approximately 24 hours. Telemetry data is reviewed to determine whether the rat meets the study criteria. The data is retained in the study records and used to calculate the nominal 24-hour mean arterial pressure average to support randomized animal selection. For dosing phase data acquisition, continuous telemetry data is collected during the dosing phase, starting at least 90 minutes before dosing and until approximately 48 hours after dosing.

[0257] Nominal Dosing Time: Telemetry acquisition time points are based on a single nominal dosing time for all animals. The nominal dosing time for each day of the dosing phase is the end of dosing time recorded on each computer for the first half of the animals dosed that day for all animals on that computer.

[0258] Telemetry Data Evaluation: Telemetry parameters including heart rate (beats / minute), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), mean arterial pressure (mmHg), and arterial pulse pressure (mmHg) were analyzed and reported. Telemetry data generated by Ponemah during the dosing phase were analyzed in 1-minute samples. Data were processed as 15-minute averages and provided to data review. The 15-minute average data were further averaged by dividing into the following analysis periods:

[0259] Phase 1: 0.5 to 2 hours after administration;

[0260] Phase 2: 2 to 4 hours after dosing;

[0261] Phase 3: 4-8 hours after dosing;

[0262] Phase 4: 8-12 hours after dosing;

[0263] Phase 5: 12-20 hours after dosing;

[0264] Phase 6: 20-32 hours after dosing (second light cycle); and

[0265] • Phase 7: 32 to 44 hours after dosing (second dark cycle).

[0266] analyze

[0267] Blood pressure was measured over 44 hours using an implanted telemetry device. The primary outcome measure was systolic blood pressure.

[0268] Statistical analyses were performed using all available data points and weighted to reflect the uneven timing of measurements. Estimates of treatment effects were calculated using the estimated differences between the two treatments using mixed models with a direct multiplicative autoregressive correlation structure (SAS 9.4, SAS Institute, Cary, NC) to account for repeated measurements within individuals over time.

[0269] result

[0270] The study began with eight animals. However, one animal's telemetry transmitter malfunctioned. Consequently, complete data were available from seven animals.

[0271] The following table shows the difference in systolic blood pressure (mmHg) between treatments:

[0272] Table 5.

[0273]

[0274]

[0275] Figure 1 The mean systolic blood pressure (mmHg) over the period is shown by treatment. Figure 2 The mean diastolic blood pressure (mmHg) over the period is shown by treatment. Figure 3 Shows the average heart rate during the session by treatment.

[0276] In this non-limiting example, the results show that Combination 1 produced a significantly greater reduction in systolic blood pressure than Combination 3, and Combination 2 produced a significantly greater reduction in systolic blood pressure than either Combination 3 or 1. These differences persisted throughout the 44-hour observation period. The results show that Combination 1 and Combination 2 produced a significantly greater reduction in systolic blood pressure than Combination 3. These differences persisted throughout the 44-hour observation period. There were similar differences in DPB reduction among the three combinations, while there were no differences among the combinations in heart rate.

[0277] In this non-limiting example, these results demonstrate an unexpected difference between the combination of telmisartan, amlodipine besylate, indapamide and the combination of losartan, amlodipine besylate, hydrochlorothiazide. Specifically, the combination of telmisartan, amlodipine besylate and indapamide produced a significantly greater reduction in blood pressure at equal or lower doses than the combination of losartan, amlodipine besylate and hydrochlorothiazide. Since the dose of amlodipine besylate in combinations 2 and 3 was the same, the results demonstrate previously unknown differences in the effectiveness of specific angiotensin II receptor blockers and specific diuretics (such as thiazide diuretics and thiazide-like diuretics) when provided in parallel with amlodipine besylate.

[0278] Example 2: Triple combination therapy for treating hypertension

[0279] method

[0280] This study is a randomized, placebo-controlled, double-blind, crossover trial. The study is divided into three phases. In the first phase (4 weeks), participants are randomized (1:1) to receive either the triple combination therapy or placebo. This is followed by a two-week washout (placebo), after which participants are crossed over to the opposite group to receive the other treatment for four weeks. Participants are primarily recruited from the community through community general practices in Western Sydney, Australia.

[0281] Participants

[0282] Participants were eligible if they met the following inclusion criteria: 1) adults 18 years of age and older; 2) office SBP > 140 mmHg and / or DBP > 90 mmHg on two readings on separate days; plus baseline ambulatory SBP > 135 and / or DBP > 85; 3) not taking medication for hypertension. Exclusion criteria included: no confirmed contraindications to one or more of the components of the triple combination; the responsible physician's opinion that a change in current therapy would place the patient at risk; severe or accelerated hypertension; pregnancy; inability to provide informed consent; and a medical condition with a life expectancy of less than 3 months.

[0283] intervention

[0284] For these studies, triple combinations with each component at 50% of the lowest hypertension therapeutic dose (LHTD) or triple combinations with each component at 100% of the lowest hypertension therapeutic dose (LHTD) were tested.

[0285] If this study tests a triple combination in which each component is 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 specified amounts of the following three components: 10 mg of telmisartan, 1.25 mg of amlodipine besylate, and 0.625 mg of indapamide. The placebo capsule looks identical and contains a placebo tablet of similar weight to the pills in the triple combination composition.

[0286] If this study tested a triple combination in which each component was 100% of the lowest hypertension therapeutic dose (LHTD), the test composition was as follows. The triple combination composition was a single encapsulated pill containing the specified amounts of the following three components: telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg. The placebo capsules looked identical and contained placebo tablets of similar weight to the pills in the triple combination composition.

[0287] Participants were administered a single pill, ie, the triple combination composition or placebo, throughout the trial. Patients were instructed to take the tablets at the same time each day and encouraged to take them in the morning, but the time of day (morning or evening) was based on patient preference.

[0288] All trial drugs were prepared by TGA-cGMP (Therapeutic Goods Australia – Certification of Good Manufacturing Practice) licensed manufacturing facilities. Where appropriate, low-strength doses were obtained by bisecting half-strength doses using a pill splitting device without crushing, and weighing them to ensure the accuracy of the bisected doses. Subsequently, the low-strength doses were encapsulated using gelatin capsules (DBCaps-Capsugel). The capsules were stored in a cool, dry place and monitored using a temperature recorder until they were distributed.

[0289] Neither the researchers nor the participants were aware of the treatment assignments. In addition to the study medication, all participants received education about healthier lifestyle choices recommended by hypertension management guidelines.

[0290] Randomization

[0291] A computer-assisted randomization sequence was generated by a statistician and provided to the pharmaceutical packaging company. Research assistants, the recruitment team, and the investigators were blinded to this sequence. For each patient, i.e., assigned randomization number, the pills were packaged into three child-resistant packs corresponding to the three phases of the study. All packs had an identical appearance to ensure that the patients and investigators were blinded. The packs were then dispensed in an organized sequence.

[0292] Results and data collection

[0293] The primary outcome measure was the reduction in mean 24-hour systolic blood pressure (systolic BP) at week 4 using ambulatory blood pressure monitoring (ABP). Secondary outcomes included:

[0294] a. At 4 weeks, mean 24-hour diastolic blood pressure was reduced, as well as daytime and nighttime SBP and DBP

[0295] b. Reduction in office SBP and DBP as measured by a standardized automated blood pressure cuff

[0296] c. Proportion of patients with controlled blood pressure at 4 weeks, defined as 24-hour blood pressure <135 / 85 mmHg and office blood pressure <140 / 90 mmHg

[0297] d. Adverse events according to laboratory parameters and pre-specified adverse events: Transaminase (ALT / AST) elevation greater than 3x the upper limit of normal or doubled in the presence of known elevated baseline levels; Estimated glomerular filtration rate decrease >20% as estimated from serum creatinine, sodium, potassium, and uric acid levels

[0298] e. Acceptability and tolerability assessment

[0299] Patients underwent 4 24-hour ABP monitoring sessions: baseline (no study drug), 4 weeks (Phase 1 drug), 6 weeks (placebo), and 10 weeks (Phase 3 drug). To minimize inconvenience, patients were transferred to the laboratory for ABP monitoring. The ABP unit was calibrated regularly by the laboratory according to the manufacturer's instructions. To minimize variability, subsequent readings were repeated using the same brand of device from the same collection center. Participants were reimbursed for face value expenses to cover their transportation and parking costs. Study drugs and research were provided free of charge to participants. OMRON T9P (HEM-759-C1) was used to record office BP three times at each visit. The second and third readings were averaged for study analysis. In addition, at Weeks 4 and 10, patients underwent blood tests to assess biochemical side effects, questionnaires on clinical side effects were distributed to patients, and compliance was assessed by self-report and pill counting. When completing this questionnaire, patients were still blinded to their treatment allocation.

[0300] Medication acceptability and tolerability were also assessed at the end of the study. All adverse events were recorded. In addition, specific inquiries were made regarding the following clinical adverse events that may be related to the antihypertensive medication: dizziness, blurred vision, syncope / fainting, chest pain / angina, shortness of breath, cough, wheezing, foot edema, rash, and itching.

[0301] The trial had a simplified data safety and management committee with two core members with expertise in clinical medicine, trial, and statistics. A meeting was held when 10 patients were randomized to the trial to review safety and recommend that the study continue.

[0302] Statistical considerations

[0303] A sample size of 50 patients was planned to provide 90% power at p = 0.05 to detect a SBP difference of 12 mmHg between intervention and control, assuming an SD of 12 mmHg for the within-patient difference, allowing for a 10% probability of loss to follow-up.

[0304] Statistical methods

[0305] Analyses were performed on an intention-to-treat basis. All tests were two-sided and the nominal alpha level was 5%. All statistical analyses were not adjusted for prognostic covariates. We reported adherence to study medication using data on pills (doses) taken and doses missed during this period.

[0306] The effect of treatment on the change in blood pressure from baseline for each treatment period was estimated using a linear mixed model according to the method of Kenward and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010; 11(1): 1-17). To appropriately adjust for the baseline levels collected at the beginning of each treatment period (week 0, week 6), this method used all measurements (baseline and follow-up in both periods) as the outcome, but accounted for the covariance between measurements within individuals (Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analyses of change from baseline in clinical trials? Stat Med 2009; 28(20): 2509-30). Linear contrasts between the variables representing time period (first / second), measurement type (baseline / final), and treatment received (placebo / triple combination) produced unbiased estimates of the effect of the triple combination on blood pressure change compared with placebo. All available data were included in the model, and no missing data were imputed. If a patient had missing data in one time period, the data for the available time period were used. A sensitivity analysis was performed that included only patients with available data in both time periods to determine whether the treatment effect was altered. An adjustment for denominator degrees of freedom was also performed according to Kenward and Roger (2009), which is optimal for smaller sample sizes (Kenward MG, Roger JH. An improved approximation to the precision of fixed effects from restricted maximum likelihood. Computational Statistics & Data Analysis 2009; 53(7): 2583-95).

[0307] Carryover tests used unpaired t-tests for the primary measures, with order as an effect. Paired t-tests were used to test for period effects, comparing the primary measures for period 1 with the primary measures for period 2 from the same patient. Sensitivity analyses were also performed using normal paired t-tests to compare the primary measures between different periods (different treatments) from the same patient, ignoring the baseline level for each period.

[0308] Continuous secondary endpoints (e.g., daytime / nighttime dynamic SBP / DBP) with baseline values ​​were analyzed similarly to the primary endpoint. Paired t-test was used to analyze other continuous variables without baseline values ​​in each period. The counts and percentages of all adverse events were reported. As a sensitivity analysis, the analysis was repeated for complete cases (i.e., complete data for each measurement period).

[0309] The relationship between treatment effect and age (<=60 years and >60 years), gender and BMI (<=30 kg / m 2 and <30kg / m 2 ) were tested for interaction effects. Subgroup analyses were also performed for each variable. All analyses were performed using SAS 9.4 (Cary, NC, USA).

[0310] Example 3: Comparative study of triple combination therapy with standard dose monotherapy for the treatment of hypertension

[0311] The primary objective of this study was to investigate in a double-blind, randomized, controlled trial whether initial treatment with a triple combination therapy would lower blood pressure more effectively and with fewer side effects in patients with hypertension than initial standard-dose monotherapy according to current guidelines. Secondary objectives were to assess whether this approach was safe and had fewer side effects than standard care.

[0312] Study Design

[0313] This was a 12-week, double-blind, randomized, controlled trial (1:1) in 650 patients with grade 1 and 2 essential hypertension. Participants were randomized by a central computer-based randomization service to receive initial therapy with a triple combination or an angiotensin receptor blocker (ARB) according to current Australian hypertension guidelines (with the option to add a calcium channel blocker (CCB) as needed). The primary outcome measure was the reduction in mean systolic blood pressure (BP) at 12 weeks using a standardized automated BP cuff. Secondary outcomes included the proportion with controlled BP at 6 and 12 weeks, ambulatory BP (ABP) measurements, and tolerability / occurrence of adverse events.

[0314] Eligibility Criteria

[0315] Inclusion criteria were as follows:

[0316] -Adults (≥18 years)

[0317] - Treatment naive, or not currently receiving treatment (not in the past 4 weeks), or taking a blood pressure lowering medication (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta blocker, aldosterone antagonist, alpha blocker)

[0318] - SBP 140-179 mmHg and / or DBP 90-109 mmHg recorded on two occasions more than one week apart

[0319] - At least one measurement should be recorded by the researcher using the study automated BP device or as daytime average SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg on 24-hour ambulatory BP monitoring

[0320] - At least one of these measurements should be recent (within the past 12 weeks)

[0321] - Daytime mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg on 24-hour ambulatory BP monitoring—recorded within 12 weeks of randomization.

[0322] Exclusion criteria were as follows:

[0323] - Contraindications to telmisartan, amlodipine, or indapamide

[0324] -Evidence of a secondary cause of hypertension (eg, renal artery stenosis; significant renal impairment (eGRF <50); elevated serum potassium (above normal laboratory limits)

[0325] - Pregnant women, lactating women, and / or women of childbearing potential who are not using a medically acceptable form of contraception (pharmacological or barrier method) throughout the study

[0326] - Concomitant illness, physical impairment, or mental condition that, in the opinion of the research team / primary physician, may interfere with the conduct of the study, including outcome assessments

[0327] - Participation in concurrent interventional medical research or clinical trials. Patients enrolled in observational studies, natural history studies, and / or epidemiological studies not involving intervention are eligible

[0328] - The participant's primary care physician or other responsible physician believes that it is inappropriate for the participant to change the current monotherapy

[0329] - Unable or unwilling to provide written informed consent

[0330] - Unable to complete study procedures including 24-hour ambulatory BP

[0331] - There is a clear indication for combination therapy

[0332] Study Treatment

[0333] For these studies, triple combinations with each component at 50% of the lowest hypertension therapeutic dose (LHTD) or triple combinations with each component at 100% of the lowest hypertension therapeutic dose (LHTD) were tested.

[0334] If the study tests a triple combination where each component is 50% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients meeting the inclusion criteria are randomly assigned to receive: 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.

[0335] If this study tests a triple combination where each component is 100% of the lowest hypertension therapeutic dose (LHTD), the test composition is as follows: Patients meeting the inclusion criteria are randomly assigned to receive: 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.

[0336] Patients currently on monotherapy were asked to discontinue their treatment while they were on study treatment.At 6 weeks, if blood pressure was greater than 140 / 90 mmHg in either group, amlodipine besylate (5 mg) was added by the investigator.

[0337] Measurement indicators

[0338] The primary outcome measure was the between-group difference in mean automated office-based systolic blood pressure at 12 weeks, adjusted for baseline values.

[0339] Secondary measures included the following:

[0340] -24-hour ambulatory blood pressure measurement

[0341] a. Differences in mean 24-hour SBP and DBP between groups at 12 weeks

[0342] b. Between-group differences in mean changes in 24-hour SBP and DBP from 0 to 12 weeks

[0343] c. Differences in mean daytime SBP and DBP between groups at 12 weeks

[0344] Between-group differences in mean nocturnal SBP and DBP at 12 weeks

[0345] d. Between-group differences in daytime, nighttime, and 24-hour BP load (percentage of the area under the blood pressure curve above normal daytime, nighttime, and 24-hour values ​​according to the NHFA Guide to Management of Hypertension 2008)

[0346] e. Between-group differences in the proportion of non-dippers (nighttime BP not more than 10% lower than the mean daytime BP according to the NHFA Hypertension Management Guidelines 2008) and the coefficient of variation of BP (O'Brien, E., G. Parati and G. Stergiou, Hypertension, 2013. 62(6): p. 988-94).

[0347] - Other blood pressure measurements in the triple therapy group and the control group:

[0348] a. Change in mean diastolic blood pressure from baseline to week 12

[0349] b. Hypertension control (percentage of patients with SBP < 140 mmHg and DBP < 90 mmHg) at 6 and 12 weeks

[0350] c. Percentage requiring step-up treatment at 6 weeks

[0351] d. Percentage of patients with blood pressure controlled (as defined above) and without adverse events

[0352] e. Intergroup differences in SBP and DBP variability

[0353] -Tolerance

[0354] a. Differences between groups in potentially relevant side effects (dizziness, blurred vision, syncope / fainting / falls, chest pain / angina, shortness of breath, cough, wheezing, ankle edema, rash, itching, gout, hyperkalemia, hypokalemia, hyponatremia, and others)

[0355] b. Differences between groups in mean potassium, uric acid, blood glucose, cholesterol and fraction, ALT, AST, UACR (urine albumin / creatinine ratio), and creatinine levels

[0356] c. Between-group differences in participants dropping out of treatment

[0357] Statistical methods

[0358] All analyses of study measures were performed according to the intention-to-treat principle. The primary analysis of change in systolic blood pressure (SBP) at 12 weeks was performed using analysis of covariance (ANCOVA) including treatment group and baseline SBP as covariates. Continuous secondary measures were analyzed similarly. Additional analyses included 6-week and 12-week measurements in a longitudinal model, including treatment group, visit, and treatment-by-visit interaction effects as well as baseline measures. Intra-patient correlations were modeled using generalized estimating equations. Similar approaches were applied to binary endpoints (e.g., hypertension control), using log-binomial regression instead of linear regression. There were also predefined subgroup analyses, including those based on baseline blood pressure, sex, age, and history of hypertension treatment. A detailed analysis plan was developed before unblinding.

[0359] Example 4: Pharmaceutical Composition 1

[0360] The following pharmaceutical compositions are prepared according to the specified ingredients and dosages shown in the table below.

[0361] Table 6.

[0362]

[0363] Example 5: Pharmaceutical Composition 2

[0364] The following pharmaceutical compositions are prepared according to the specified ingredients and dosages shown in the table below.

[0365] Table 7.

[0366]

[0367] Example 6: Pharmaceutical Composition 3

[0368] The following pharmaceutical compositions are prepared according to the specified ingredients and dosages shown in the table below.

[0369] Table 8.

[0370]

[0371]

[0372] Implementation Plan

[0373] Embodiment 1. A pharmaceutical composition comprising

[0374] (a) Angiotensin II receptor blockers;

[0375] (b) diuretics; and

[0376] (c) Calcium channel blockers

[0377] wherein the dosage of each of (a), (b) and (c) is from about 40% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0378] Embodiment 2. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition comprises a blood pressure lowering combination of blood pressure lowering active agents, wherein the blood pressure lowering active agents consist of angiotensin II receptor blockers, diuretics and calcium channel blockers.

[0379] Embodiment 3. The pharmaceutical composition according to embodiment 1 or 2, wherein the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof.

[0380] Embodiment 4. The pharmaceutical composition of any one of Embodiments 1-3, wherein the pharmaceutical composition is substantially free of a beta-blocker or a pharmaceutically acceptable salt thereof.

[0381] Embodiment 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition is substantially free of lipid regulating agents, platelet function altering agents, serum homocysteine ​​lowering agents, or a combination thereof.

[0382] Embodiment 6. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is substantially free of lipid regulating agents.

[0383] Embodiment 7. The pharmaceutical composition according to embodiment 6, wherein the lipid modulator is atorvastatin, simvastatin, cerivastatin, fluvastatin or pravastatin.

[0384] Embodiment 8. The pharmaceutical composition according to embodiment 6 or 7, wherein the lipid modulator is atorvastatin or simvastatin.

[0385] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is substantially free of platelet function-altering agents.

[0386] Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the platelet function-altering agent is aspirin, ticlopidine, dipyridamole, clopidogrel, abciximab, or ibuprofen.

[0387] Embodiment 11. The pharmaceutical composition of embodiment 9 or 10, wherein the platelet function-altering agent is aspirin.

[0388] Embodiment 12. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition is substantially free of a serum homocysteine ​​lowering agent.

[0389] Embodiment 13. The pharmaceutical composition of embodiment 12, wherein the serum homocysteine ​​lowering agent is folic acid, vitamin B6, vitamin B12, or a combination thereof.

[0390] Embodiment 14. The pharmaceutical composition of embodiment 12 or 13, wherein the serum homocysteine ​​lowering agent is folic acid.

[0391] Embodiment 15. The pharmaceutical composition of any one of Embodiments 1-14, wherein the diuretic is a thiazide diuretic.

[0392] Embodiment 16. The pharmaceutical composition according to embodiment 15, wherein the thiazide diuretic is althiazide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, hydrochlorothiazide, hydroflumethiazide, mebutiazide, methylchlorothiazide, polythiazide, trichlorothiazide or a pharmaceutically acceptable salt or hydrate thereof.

[0393] Embodiment 17. The pharmaceutical composition of embodiment 16, wherein the thiazide diuretic is hydrochlorothiazide.

[0394] Embodiment 18. The pharmaceutical composition of any one of Embodiments 1-14, wherein the diuretic is a thiazide-like diuretic.

[0395] Embodiment 19. The pharmaceutical composition according to embodiment 18, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticolamine, xipamide, indapamide, cloxolone, fenquinazole or a pharmaceutically acceptable salt or hydrate thereof.

[0396] Embodiment 20. The pharmaceutical composition according to embodiment 19, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0397] Embodiment 21. The pharmaceutical composition of embodiment 20, wherein the thiazide-like diuretic is indapamide.

[0398] Embodiment 22. The pharmaceutical composition of embodiment 19, wherein the thiazide-like diuretic is chlorthalidone.

[0399] Embodiment 23. The pharmaceutical composition of any one of Embodiments 1-14, wherein the diuretic is a loop diuretic.

[0400] Embodiment 24. The pharmaceutical composition of embodiment 23, wherein the loop diuretic is furosemide, bumetanide, ethacrynic acid, etazolin, mozolomide, oxazolidinone, piretanide, tinic acid, torsemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0401] Embodiment 25. The pharmaceutical composition of any one of embodiments 1-14, wherein the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof.

[0402] Embodiment 26. The pharmaceutical composition of any one of embodiments 1-25, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, a dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalidomide, diprofenalin, or a pharmaceutically acceptable salt or hydrate thereof.

[0403] Embodiment 27. The pharmaceutical composition of embodiment 26, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0404] Embodiment 28. The pharmaceutical composition of embodiment 27, wherein the calcium channel blocker is amlodipine besylate.

[0405] Embodiment 29. The pharmaceutical composition of any one of embodiments 1-28, wherein the angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof.

[0406] Embodiment 30. The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is irbesartan.

[0407] Embodiment 31. The pharmaceutical composition of embodiment 29, wherein the angiotensin II receptor blocker is telmisartan.

[0408] Embodiment 32. The pharmaceutical composition of any one of embodiments 1-31, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0409] Embodiment 33. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide diuretic and the dose of the thiazide diuretic is about 50% of the lowest hypertension therapeutic dose (LHTD) of the thiazide diuretic.

[0410] Embodiment 34. The pharmaceutical composition of embodiment 33, wherein the thiazide diuretic is hydrochlorothiazide and the dose of hydrochlorothiazide is about 6.25 mg.

[0411] Embodiment 35. The pharmaceutical composition of embodiment 32, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 50% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic.

[0412] Embodiment 36. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 0.625 mg.

[0413] Embodiment 37. The pharmaceutical composition of embodiment 35, wherein the thiazide-like diuretic is chlorthalidone and the dose of chlorthalidone is about 12.5 mg.

[0414] Embodiment 38. The pharmaceutical composition of embodiment 32, wherein the diuretic is a loop diuretic and the dose of the loop diuretic is about 50% of the lowest hypertension therapeutic dose (LHTD) of the loop diuretic.

[0415] Embodiment 39. The pharmaceutical composition of any one of embodiments 32-38, wherein the dose of the calcium channel blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0416] Embodiment 40. The pharmaceutical composition of embodiment 39, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.25 mg.

[0417] Embodiment 41. The pharmaceutical composition of any one of Embodiments 32-40, wherein the dose of the angiotensin II receptor blocker is about 50% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0418] Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is irbesartan, and the dose of irbesartan is about 37.5 mg.

[0419] Embodiment 43. The pharmaceutical composition of embodiment 41, wherein the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 10 mg.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] Embodiment 62. The pharmaceutical composition of any one of embodiments 1-31, wherein the dose of each of (a), (b), and (c) is about 60% to about 80% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0439] Embodiment 63. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide diuretic and the dose of the thiazide diuretic is about 66% of the lowest hypertension therapeutic dose (LHTD) of the thiazide diuretic.

[0440] Embodiment 64. The pharmaceutical composition of embodiment 63, wherein the thiazide diuretic is hydrochlorothiazide and the dose of hydrochlorothiazide is about 8.25 mg.

[0441] Embodiment 65. The pharmaceutical composition of embodiment 62, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 66% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic.

[0442] Embodiment 66. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 0.825 mg.

[0443] Embodiment 67. The pharmaceutical composition of embodiment 65, wherein the thiazide-like diuretic is chlorthalidone and the dose of chlorthalidone is about 16.5 mg.

[0444] Embodiment 68. The pharmaceutical composition of embodiment 62, wherein the diuretic is a loop diuretic and the dose of the loop diuretic is about 66% of the lowest hypertension therapeutic dose (LHTD) of the loop diuretic.

[0445] Embodiment 69. The pharmaceutical composition of any one of embodiments 62-68, wherein the dose of the calcium channel blocker is about 66% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0446] Embodiment 70. The pharmaceutical composition of embodiment 69, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 1.65 mg.

[0447] Embodiment 71. The pharmaceutical composition of any one of embodiments 62-70, wherein the dose of the angiotensin II receptor blocker is about 66% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0448] Embodiment 72. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is irbesartan, and the dose of irbesartan is about 49.5 mg.

[0449] Embodiment 73. The pharmaceutical composition of embodiment 71, wherein the angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is about 13.2 mg.

[0450] 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.

[0451] 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.

[0452] 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.

[0453] 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.

[0454] 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.

[0455] 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.

[0456] 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] Embodiment 84. The pharmaceutical composition of embodiment 83, wherein the dose of telmisartan is about 12 mg to about 16 mg, the dose of indapamide is about 0.75 mg to about 1.0 mg, and the dose of amlodipine besylate is about 1.5 mg to about 2 mg.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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.

[0468] Embodiment 92. The pharmaceutical composition of any one of Embodiments 1-91, wherein the dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0469] Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the dose of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0470] Embodiment 94. The pharmaceutical composition of embodiment 92, wherein the dose of the diuretic is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0471] Embodiment 95. The pharmaceutical composition of embodiment 92, wherein the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0472] Embodiment 96. The pharmaceutical composition of any one of embodiments 92-95, wherein the dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0473] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0474] Embodiment 98. The pharmaceutical composition of embodiment 97, wherein the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0475] Embodiment 99. The pharmaceutical composition of embodiment 96, wherein the dose of the diuretic is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0476] Embodiment 100. The pharmaceutical composition of embodiment 99, wherein the dose of the diuretic is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0477] Embodiment 101. The pharmaceutical composition of embodiment 96, wherein the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0478] Embodiment 102. The pharmaceutical composition of embodiment 101, wherein the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0479] Embodiment 103. The pharmaceutical composition of any one of Embodiments 92-95, wherein the dose of any one of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0480] Embodiment 104. The pharmaceutical composition of embodiment 103, wherein the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0481] Embodiment 105. The pharmaceutical composition of embodiment 104, wherein the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0482] Embodiment 106. The pharmaceutical composition of embodiment 103, wherein the dose of the diuretic is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0483] Embodiment 107. The pharmaceutical composition of embodiment 106, wherein the dose of the diuretic is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0484] Embodiment 108. The pharmaceutical composition of embodiment 103, wherein the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0485] Embodiment 109. The pharmaceutical composition according to any embodiment 108, wherein the dose of the calcium channel blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0486] Embodiment 110. The pharmaceutical composition of any one of Embodiments 1-91, wherein the dosage of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0487] Embodiment 111. The pharmaceutical composition of embodiment 110, wherein the dose of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0488] Embodiment 112. The pharmaceutical composition of embodiment 110, wherein the dose of the diuretic is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0489] Embodiment 113. The pharmaceutical composition of embodiment 110, wherein the dose of the calcium channel blocker is replaced by about 80% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0490] Embodiment 114. The pharmaceutical composition of any one of Embodiments 110-113, wherein the dosage of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0491] Embodiment 115. The pharmaceutical composition of embodiment 114, wherein the dose of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0492] Embodiment 116. The pharmaceutical composition of embodiment 115, wherein the dose of the angiotensin II receptor blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0493] Embodiment 117. The pharmaceutical composition of embodiment 114, wherein the dose of the diuretic is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0494] Embodiment 118. The pharmaceutical composition of embodiment 117, wherein the dose of the diuretic is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0495] Embodiment 119. The pharmaceutical composition of embodiment 114, wherein the dose of the calcium channel blocker is replaced by about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0496] Embodiment 120. The pharmaceutical composition of embodiment 119, wherein the dose of the calcium channel blocker is replaced by about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0497] Embodiment 121. The pharmaceutical composition of any one of Embodiments 110-113, wherein the dosage of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0498] Embodiment 122. The pharmaceutical composition of embodiment 121, wherein the dose of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0499] Embodiment 123. The pharmaceutical composition of embodiment 122, wherein the dose of the angiotensin II receptor blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the angiotensin II receptor blocker.

[0500] Embodiment 124. The pharmaceutical composition of embodiment 121, wherein the dose of the diuretic is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0501] Embodiment 125. The pharmaceutical composition of embodiment 124, wherein the dose of the diuretic is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the diuretic.

[0502] Embodiment 126. The pharmaceutical composition of embodiment 121, wherein the dose of the calcium channel blocker is replaced by about 150% to about 250% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0503] Embodiment 127. The pharmaceutical composition according to any embodiment 126, wherein the dose of the calcium channel blocker is replaced by about 200% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0504] Embodiment 128: A pharmaceutical composition comprising

[0505] (a) Telmisartan;

[0506] (b) thiazide-like diuretics; and

[0507] (c) Calcium channel blockers

[0508] wherein the dosage of each of (a), (b) and (c) is from about 80% to about 150% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b) and (c).

[0509] Embodiment 129: The pharmaceutical composition of embodiment 128, wherein the pharmaceutical composition is substantially free of angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a lipid-lowering agent, a platelet function-altering agent, a serum homocysteine-lowering agent, or a combination thereof.

[0510] Embodiment 130: The pharmaceutical composition according to embodiment 128 or 129, wherein the thiazide-like diuretic is quinethazone, clopamide, chlorthalidone, mefruside, chlorphenamide, metolazone, meticolamine, xipamide, indapamide, cloxolone, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof.

[0511] Embodiment 131: The pharmaceutical composition according to embodiment 130, wherein the thiazide-like diuretic is indapamide or a hydrate thereof.

[0512] Embodiment 132: The pharmaceutical composition of Embodiment 131, wherein the thiazide-like diuretic is indapamide.

[0513] Embodiment 133: The pharmaceutical composition of any one of Embodiments 128-132, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, a dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, miradil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, dothalipine, diprofenicline, or a pharmaceutically acceptable salt or hydrate thereof.

[0514] Embodiment 134: The pharmaceutical composition according to Embodiment 133, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

[0515] Embodiment 135: The pharmaceutical composition of Embodiment 134, wherein the calcium channel blocker is amlodipine besylate.

[0516] Embodiment 136: The pharmaceutical composition of any one of Embodiments 128-135, wherein the dose of each of (a), (b), and (c) is about 80% to about 120% of the lowest hypertension therapeutic dose (LHTD) of each of (a), (b), and (c).

[0517] Embodiment 137: The pharmaceutical composition of embodiment 136, wherein the dose of the thiazide-like diuretic is about 100% of the lowest hypertension therapeutic dose (LHTD) of the thiazide-like diuretic.

[0518] Embodiment 138: The pharmaceutical composition of Embodiment 137, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg.

[0519] Embodiment 139: The pharmaceutical composition of any one of Embodiments 136-138, wherein the dose of the calcium channel blocker is about 100% of the lowest hypertension therapeutic dose (LHTD) of the calcium channel blocker.

[0520] Embodiment 140: The pharmaceutical composition of Embodiment 139, wherein the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg.

[0521] Embodiment 141: The pharmaceutical composition according to any one of Embodiments 136-140, wherein the dose of telmisartan is about 100% of the lowest hypertension therapeutic dose (LHTD) of telmisartan.

[0522] Embodiment 142: The pharmaceutical composition according to embodiment 141, wherein the dose of telmisartan is about 20 mg.

[0523] Embodiment 143: The pharmaceutical composition of Embodiment 136, wherein the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate.

[0524] 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.

[0525] 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.

[0526] Embodiment 146. The pharmaceutical composition of any one of Embodiments 1-145, wherein (a), (b) and (c) are provided in one formulation.

[0527] Embodiment 147. The pharmaceutical composition of any one of Embodiments 1-145, wherein (a), (b) and (c) are each provided in separate formulations.

[0528] Embodiment 148. The pharmaceutical composition of any one of Embodiments 1-145, wherein two of (a), (b), and (c) are provided in one formulation.

[0529] Embodiment 149. The pharmaceutical composition of any one of Embodiments 1-148, wherein the pharmaceutical composition is in the form of a pill, tablet, or capsule.

[0530] Embodiment 150. The pharmaceutical composition of any one of Embodiments 1-149, wherein the pharmaceutical composition is suitable for oral administration.

[0531] Embodiment 151. A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of any one of Embodiments 1-150.

[0532] Embodiment 152. The method of embodiment 151, wherein the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg.

[0533] Embodiment 153. The method of embodiment 150 or 151, wherein the treatment results in a reduction in systolic blood pressure (SBP) of about 10 mmHg or more.

[0534] Embodiment 154. The method of any one of embodiments 150-153, wherein the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg.

[0535] Embodiment 155. The method of any one of embodiments 150-154, wherein the treatment results in a decrease in diastolic blood pressure (DBP) by about 5 mmHg or more.

[0536] Embodiment 156. The method of any one of embodiments 150-155, wherein treatment results in a reduction in systolic blood pressure (SBP) that is greater than the reduction achieved with the full minimum hypertension treatment dose of any one of (a), (b), and (c) of the pharmaceutical composition.

[0537] Embodiment 157. The method of any one of embodiments 150-156, wherein treatment results in a reduction in diastolic blood pressure (DBP) that is greater than the reduction achieved with the full minimum hypertension treatment dose of any one of (a), (b), and (c) of the pharmaceutical composition.

[0538] Embodiment 158. The method of any one of embodiments 150-157, wherein the treatment results in greater long-term tolerability and reduced risk of side effects compared to treatment with the full minimum hypertension treatment dose of any one of (a), (b), and (c) in the pharmaceutical composition.

[0539] Embodiment 159. The method of any one of Embodiments 150-158, wherein the treatment is the initial or first-line treatment of hypertension.

[0540] Embodiment 160. The method of any one of embodiments 150-159, wherein the subject has not received any previous therapy for hypertension prior to treatment.

[0541] Although preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Without departing from the present disclosure, those skilled in the art will now appreciate that many variations, changes, and substitutions may be made. It should be understood that various alternatives to the disclosed embodiments described herein may be used to practice the present disclosure. It is intended that the scope of the present disclosure be defined by the following claims, and that methods and structures within the scope of these claims and their equivalents be encompassed thereby.

Claims

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

2. The pharmaceutical composition of claim 1, wherein the dose of indapamide is about 0.625 mg.

3. The pharmaceutical composition according to claim 1, wherein the dose of amlodipine besylate is 1 to 1.5 mg.

4. The pharmaceutical composition according to claim 1, wherein the dose of amlodipine besylate is 1.5 to 2 mg.

5. The pharmaceutical composition of claim 1, wherein the dose of telmisartan is about 10 mg.

6. The pharmaceutical composition of claim 1, wherein the dose of indapamide is about 0.625 mg, the dose of amlodipine besylate is 1.5 to 2 mg, and the dose of telmisartan is about 10 mg.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is formulated for oral administration.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

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

10. The pharmaceutical composition according to claim 9, wherein the dose of amlodipine besylate is 2 mg to 3.75 mg.

11. The pharmaceutical composition according to claim 9, wherein the dose of amlodipine besylate is 2 mg to 3 mg.

12. The pharmaceutical composition according to claim 9, wherein the dose of amlodipine besylate is 2.25 mg to 2.75 mg.

13. The pharmaceutical composition according to claim 9, wherein the dose of amlodipine besylate is 3.75 mg to 6.25 mg.

14. The pharmaceutical composition of claim 9, wherein the dose of indapamide is about 1.25 mg.

15. The pharmaceutical composition of claim 9, wherein the dose of telmisartan is about 20 mg.

16. The pharmaceutical composition of claim 9, wherein the dose of indapamide is about 1.25 mg, the dose of amlodipine besylate is 2 mg to 3.75 mg, and the dose of telmisartan is about 20 mg.

17. The pharmaceutical composition according to any one of claims 9 to 16, wherein the pharmaceutical composition is formulated for oral administration.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

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