Composition for the treatment of hypertension

Abstract

A pharmaceutical composition for use in a new treatment for reducing hypertension that is effective and tolerable is provided. [Solution] A pharmaceutical composition for use in treating hypertension, comprising (a) telmisartan, (b) indapamide, and (c) amlodipine besylate, wherein the dosage of telmisartan is about 8 mg to about 12 mg, the dosage of indapamide is about 0.5 mg to about 0.75 mg, and the dosage of amlodipine besylate is about 1 mg to about 1.5 mg, and wherein the pharmaceutical composition does not contain an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a lipid-regulating agent, a platelet function-modifying agent, a serum homocysteine-lowering agent, or a combination thereof, for use in treating hypertension.

Description

Technical Field

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

Background Art

[0002] Hypertension, also known as high blood pressure, is a major cause of preventable morbidity and mortality, and it is well established that treatment to lower blood pressure (BP) is beneficial. However, despite the availability of drugs to lower excessive blood pressure, many patients continue to have poor blood pressure control, as demonstrated by numerous large-scale population studies. Poor blood pressure control is due to factors including poor adherence, complex guidelines recommending multiple up-titration steps, and treatment inertia. Furthermore, the majority of treated patients receive only monotherapy, which has limited efficacy even at high doses, increased side effects, and decreased durability. Therefore, there is a need for new treatments to lower blood pressure that are effective and durable.

Summary of the Invention

[0003] Provided herein, in one aspect, is a pharmaceutical composition comprising (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker wherein the dosage of each of (a), (b), and (c) is about 40% to about 80% of the lowest hypertension treatment dose (LHTD) for each of (a), (b), and (c).

[0004] ​In some embodiments, the pharmaceutical composition is essentially free from angiotensin-converting enzyme inhibitors or pharmaceutically acceptable salts thereof, beta-blockers or pharmaceutically acceptable salts thereof, lipid modifiers, platelet function-altering agents, serum homocysteine-lowering agents, or combinations thereof.

[0005] In some embodiments, the diuretic is a thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xypamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or its hydrate. In some embodiments, the thiazide-like diuretic is indapamide.

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

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

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

[0009] In another embodiment, a pharmaceutical composition is provided, and the pharmaceutical composition is (a) Telmisartan; (b) Thiazide diuretics; and (c) Calcium channel blockers Includes, Here, the respective doses of (a), (b), and (c) are approximately 80% to 150% of the minimum hypertension-treating dose (LHTD) for each of (a), (b), and (c).

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

[0011] In some embodiments, the thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xypamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide or its hydrate. In some embodiments, the thiazide-like diuretic is indapamide.

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

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

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

[0015] This specification also provides a method for treating hypertension in a subject requiring treatment, comprising the step of administering any one of the pharmaceutical compositions disclosed herein. In some embodiments, the treatment results in a systolic blood pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a reduction of systolic blood pressure (SBP) of about 10 mmHg or more. In some embodiments, the treatment results in a diastolic blood pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a reduction of diastolic blood pressure (DBP) of about 5 mmHg or more. In some embodiments, the treatment results in a reduction of systolic blood pressure (SBP) greater than the reduction obtained with any one of the complete minimum hypertension therapeutic doses of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in a reduction of diastolic blood pressure (DBP) greater than the reduction obtained with any one of the complete minimum hypertension therapeutic doses of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in greater long-term tolerance and a reduced risk of side effects compared to treatment with any one of the minimum hypertensive therapeutic doses of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment is an initial or primary treatment for hypertension. In some embodiments, the subject does not receive the aforementioned hypertensive treatment prior to the treatment.

[0016] This specification provides a pharmaceutical composition in another embodiment, the pharmaceutical composition is (a) Angiotensin II receptor blockers; (b) Diuretics; and (c) Calcium channel blockers It essentially consists of, Here, the respective doses of (a), (b), and (c) are approximately 40% to 80% of the minimum hypertension-treating dose (LHTD) for each of (a), (b), and (c).

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

[0018] Incorporation by reference All applications, patents, and patent applications mentioned in this specification are hereby incorporated by reference into this specification to the same extent as if each individual application, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0019] The novel features of the present disclosure are described, among other things, in the appended claims. A better understanding of the features and advantages of the present disclosure can be obtained by reference to the following detailed description, which describes exemplary embodiments in which the principles of the present disclosure are used, and the accompanying drawings: [Figure 1] Shows the average systolic blood pressure (mmHg) over a time period by treatment. [Figure 2] Shows the average diastolic blood pressure (mmHg) over a time period by treatment. [Figure 3] Shows the average heart rate over a time period by treatment.

Modes for Carrying Out the Invention

[0020] This specification provides a pharmaceutical composition for the treatment of hypertension, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. In some embodiments, the dosage of each component is less than the minimum dosage approved for the treatment of hypertension. The present disclosure recognizes the technical effects of the low-dose combination therapies described herein, which include, but are not limited to, the use of low doses to avoid or improve side effects while maintaining or improving benefits, the synergistic therapeutic effects of specific drug combinations, and the early introduction of combination therapies to improve therapeutic effects. In one aspect, this specification describes a low-dose combination composition for the treatment of hypertension, including the initial or primary treatment of hypertension.

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

[0022] definition As used in the specification and the attached claims, unless otherwise specified, the following terms have the meanings set forth below.

[0023] "Pharmacologically acceptable salt" includes both acid addition salts and base addition salts as used herein. In some embodiments, any one of the compounds described herein is a form approved for use by the U.S. Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0024] "Pharmacologically acceptable acid addition salts" refer to salts that retain the biological effects and properties of a free base and are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. Salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids are also included, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Similarly, salts of amino acids such as alginates, glucons, and galacturonic acids are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)), which is incorporated herein by reference in whole). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

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

[0026] As used herein, “hydrate” is a compound comprising a stoichiometric or non-stoichiometric amount of water, formed in some embodiments during the process of crystallization in water. A hydrate means comprising any one of the compounds described herein that is approved for use by the U.S. Food and Drug Administration.

[0027] As used herein, with respect to formulations, compositions, or components, the term “acceptable” means that it does not cause any lasting adverse effects on the overall health of the subject being treated.

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

[0029] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, a mammal is a human.

[0030] As used herein, “treatment” or “to treat,” or “to alleviate” or “to improve,” are interchangeable herein. These terms refer to methods for obtaining beneficial or desirable outcomes, including, but not limited to, therapeutic and / or preventive effects. “Therapeutic effect” means the eradication or remission of the underlying disease being treated. Similarly, therapeutic effect is achieved by the eradication or remission of one or more physiological symptoms associated with the underlying disease, such that improvement in the patient is observed, even though the patient may still be affected by the underlying disease. With respect to preventive effects, compositions may be administered to patients at risk of progression of a particular disease, or to patients reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0031] Triple Compositions This specification describes pharmaceutical compositions comprising (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker; wherein the dose of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 60% to 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 66% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

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

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

[0034] In some embodiments, the pharmaceutical compositions disclosed herein are essentially free from 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.

[0035] This specification also describes pharmaceutical compositions comprising substantially (a) an angiotensin II receptor blocker; (b) a diuretic; and (c) a calcium channel blocker, where the dose of each of (a), (b), and (c) is about 40% to about 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 60% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 50% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 60% to 80% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 66% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0036] This specification also describes pharmaceutical compositions comprising (a) an angiotensin II receptor blocker such as telmisartan; (b) a thiazide-like diuretic; and (c) a calcium channel blocker, where the dose of each of (a), (b), and (c) is about 80% to about 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 80% to about 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the dose of each of (a), (b), and (c) is about 90% to about 110% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 95% to 105% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c). In some embodiments, the respective doses of (a), (b), and (c) are approximately 100% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

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

[0038] Beta-blockers In some embodiments, the pharmaceutical compositions disclosed herein are essentially free of beta-blockers or pharmaceutically acceptable salts thereof. In some embodiments, a beta-blocker is a compound that inhibits receptor sites for endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic β-receptors of the sympathetic nervous system. In some embodiments, a beta-blocker includes, but is not limited to, a beta-adrenergic blocker, a beta-antagonist, a beta-adrenergic antagonist, a beta-adrenergic receptor antagonist, or a beta-adrenergic receptor blocker. In some embodiments, a beta-blocker inhibits the activation of all types of beta-adrenergic receptors. In some embodiments, a beta-blocker inhibits both beta-adrenergic receptors and α-adrenergic receptors. In some embodiments, a beta-blocker is selective for one of the following beta-receptors: beta1, beta2, and beta3 receptors.

[0039] In some embodiments, the β-blocker is a non-selective β-adrenergic receptor antagonist. Examples of non-selective β-adrenergic receptor antagonists include, but are not limited to, pindolol, propranolol, oxprenolol, sotalol, timolol, carteolol, penbutolol, and nadolol. In some embodiments, the β-blocker is a compound having a combination of β-adrenergic receptors and α-adrenergic receptors that block the action of. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the β-blocker is a β1-selective adrenergic receptor antagonist. Examples of β1-selective adrenergic receptor antagonists include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nevivolol, and acebutolol. In some embodiments, the beta-blocker is a β2-selective adrenergic receptor antagonist such as butoxamine.

[0040] In some embodiments, the β-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebiborol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, ceriprolol, oxprenolol, levovunolol, practolol, metipranolol, landiolol, bopindolol, pronetalol, butoxamine, bevantolol, tertatolol, arotinolol, levobetaxolol, befnolol, amosuralol, chirisolol, or pharmaceutically acceptable salts or hydrates thereof. In some embodiments, the beta-blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebiborol, pindolol, sotalol, propranolol, carvedilol, labetalol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta-blocker is acebutolol, atenolol, betaxolol, bisoprolol, ceriprolol, oxprenolol, metoprolol, nadolol, nebiborol, 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.

[0041] Lipid-regulating drugs In some embodiments, the pharmaceutical compositions disclosed herein essentially do not contain lipid modifiers, platelet function modifiers, serum homocysteine ​​lowering agents, or combinations thereof.

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

[0043] Platelet function modifiers In some embodiments, the pharmaceutical compositions disclosed herein essentially do not contain a platelet function modifier. In some embodiments, the platelet function modifier is aspirin, ticlopidine, dipyridamole, or clopidogrel. In some embodiments, the platelet function modifier is a glycoprotein IIb / IIIa receptor inhibitor such as absiximab. In some embodiments, the platelet function modifier is a nonsteroidal anti-inflammatory drug such as ibuprofen. In some embodiments, the platelet function modifier is aspirin, ticlopidine, dipyridamole, clopidogrel, absiximab, or ibuprofen. In some embodiments, the platelet function modifier is aspirin.

[0044] Serum homocysteine ​​lowering drugs In some embodiments, the pharmaceutical compositions disclosed herein do not essentially contain a serum homocysteine-lowering agent. In some embodiments, the serum homocysteine-lowering agent is folic acid, vitamin B6, or vitamin B12, or a combination thereof. In some embodiments, the serum homocysteine-lowering agent is folic acid.

[0045] Angiotensin II receptor blockers / blockers As used herein, an angiotensin II receptor blocker or antagonist (ARB) is a compound that modulates the action of angiotensin II by preventing angiotensin II from binding to angiotensin II receptors on the muscles surrounding blood vessels. In some embodiments, the angiotensin II receptor blocker is losartan, valsartan, candesartan, eprosartan, irbesartan, telmisartan, or a 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.

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

[0047] In some embodiments, the pharmaceutical compositions disclosed herein include thiazide diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include thiazide-like diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include loop diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include osmotic diuretics. In some embodiments, the pharmaceutical compositions disclosed herein include carbonic anhydrase inhibitors. In some embodiments, the pharmaceutical compositions disclosed herein include potassium-sparing diuretics.

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

[0049] Thiazide-like diuretics As used herein, thiazide-like diuretics are sulfonamide diuretics that have similar physiological properties to thiazide diuretics but lack the chemical properties of thiazide compounds (i.e., they do not have a benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, and fenquizone.

[0050] In some embodiments, the thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is kinesazone. In some embodiments, the thiazide-like diuretic is clofenamide. In some embodiments, the thiazide-like diuretic is chlorthalidone. In some embodiments, the thiazide-like diuretic is mefluside. In some embodiments, the thiazide-like diuretic is clofenamide. In some embodiments, the thiazide-like diuretic is metrazone. In some embodiments, the thiazide-like diuretic is meticran. In some embodiments, the thiazide-like diuretic is xipamide. In some embodiments, the thiazide-like diuretic is indapamide or its hydrate. In some embodiments, the thiazide-like diuretic is indapamide. In some embodiments, the thiazide-like diuretic is chlorexolone. In some embodiments, the thiazide-like diuretic is fenquizone.

[0051] Loop diuretics As used herein, loop diuretics are compounds that act on the Na+ / K+ / 2Cl- cotransporter in the thick ascending loop of Henle to inhibit the reabsorption of sodium, chloride, and potassium. Examples of loop diuretics, but not limited to, include furosemide, bumetanide, ethacrine, ethozolin, muzolimin, ozolinone, pyretanide, thienilic acid, and torasemide. In some embodiments, the loop diuretic is furosemide, bumetanide, ethacrine, ethozolin, muzolimin, ozolinone, pyretanide, thienilic acid, torasemide, or pharmaceutically acceptable salts or hydrates thereof.

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

[0053] Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors are compounds that inhibit carbonic anhydrase, as used herein. In some embodiments, carbonic anhydrase inhibitors increase the excretion of bicarbonates, including incidental sodium, potassium, and water, resulting in an increased flow of alkaline urine. In some embodiments, carbonic anhydrase inhibitors inhibit the transport of bicarbonates from the proximal tubular flexure to the interstitium, resulting in only small amounts of sodium reabsorption and greater loss of sodium, bicarbonates, and water in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorphenamide, and metazolamides.

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

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

[0056] In some embodiments, the diuretic is dichlorphenamide, amiloride, pamabrom, mannitol, acetazolamide, metazolamide, 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 metazolamide. In some embodiments, the diuretic is spironolactone. In some embodiments, the diuretic is triamterene.

[0057] Calcium channel blockers As used herein, calcium channel blockers are compounds that promote 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, clebidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, mibeflazil, bepridil, barnidipine, nilvadipine, garopamil, lidoflazine, aranidipine, dotaridine, diproteverine, or pharmaceutically acceptable salts or hydrates 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 silate. 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 crevizine.

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

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

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

[0061] In some embodiments, the diuretic dose is approximately 40% to 80% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 40% to 70% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 40% to 60% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 40% to 50% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 45% to 55% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 50% to 80% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 50% to 70% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 50% to 60% of the minimum hypertension treatment dose. In some embodiments, the diuretic dose is approximately 60% to 80% of the minimum hypertension treatment dose. In some embodiments, the dose of the diuretic is approximately 60% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of the diuretic is approximately 70% to 80% of the minimum dose for treating hypertension.

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

[0063] In some embodiments, the dose of thiazide diuretics is approximately 40% to 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 40% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 40% to 60% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 40% to 50% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 45% to 55% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 50% to 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 50% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 50% to 60% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 60% to 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 60% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is approximately 70% to 80% of the minimum dose for treating hypertension.

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

[0065] In some embodiments, the dose of thiazide-like diuretics is about 40% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 40% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 40% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 40% to about 50% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 45% to about 55% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 50% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is about 50% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 50% to 60% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 60% to 80% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 60% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 70% to 80% of the minimum dose for treating hypertension.

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

[0067] In some embodiments, the dose of loop diuretic is about 40% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 40% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 40% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 40% to about 50% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 45% to about 55% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 50% to about 80% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 50% to about 70% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is about 50% to about 60% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is approximately 60% to 80% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is approximately 60% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is approximately 70% to 80% of the minimum dose for treating hypertension.

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

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

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

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

[0072] [Table 1]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0089] In several embodiments, the dose of angiotensin II receptor blocker was approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, and 98% of the minimum dose for treating hypertension. These are approximately 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, or 120%. In some embodiments, the dose of angiotensin II receptor blocker is approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, or 110%. In some embodiments, the dose of angiotensin II receptor blocker is approximately 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, or 105%. In some embodiments, the dose of angiotensin II receptor blocker is approximately 100% of the minimum dose for treating hypertension.

[0090] In some embodiments, the dose of thiazide-like diuretics is approximately 80% to 150% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 80% to 140% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 80% to 130% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 80% to 120% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 80% to 110% of the minimum dose for treating hypertension.

[0091] In some embodiments, the dose of thiazide-like diuretics is approximately 85% to 145% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 85% to 135% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 85% to 125% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 85% to 115% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 85% to 105% of the minimum dose for treating hypertension.

[0092] In some embodiments, the dose of thiazide-like diuretics is approximately 90% to 140% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 90% to 130% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 90% to 120% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 90% to 110% of the minimum dose for treating hypertension.

[0093] In some embodiments, the dose of thiazide-like diuretics is approximately 95% to 135% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 95% to 125% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 95% to 115% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide-like diuretics is approximately 95% to 105% of the minimum dose for treating hypertension.

[0094] In several embodiments, the dose of thiazide-like diuretics was approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 9 The percentages are 9%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, or approximately 120%. In some embodiments, the dose of thiazide-like diuretics is approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, or 110%. In some embodiments, the dose of thiazide-like diuretics is approximately 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, or 105%. In some embodiments, the dose of thiazide-like diuretics is approximately 100% of the minimum dose used to treat hypertension.

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

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

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

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

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

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

[0101] [Table 2-1]

[0102] [Table 2-2]

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

[0104] In some embodiments, the dosage of any two of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers, diuretics, or calcium channel blockers. In some embodiments, the dosage of angiotensin II receptor blockers is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. In some embodiments, the dosage of diuretics is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dosage of calcium channel blockers is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for calcium channel blockers. In some embodiments, the dosage of any two of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers, diuretics, or calcium channel blockers. In some embodiments, the dosage of angiotensin II receptor blockers is replaced by approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. In some embodiments, the dosage of angiotensin II receptor blockers is replaced by approximately 100% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. In some embodiments, the dosage of diuretics is replaced by approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dosage of diuretics is replaced by approximately 100% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dosage of the calcium channel blocker is replaced by approximately 80% to 150% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dosage of the calcium channel blocker is replaced by approximately 100% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.In some embodiments, the dosage of any two of angiotensin II receptor blockers, diuretics, and calcium channel blockers is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers, diuretics, or calcium channel blockers. In some embodiments, the dosage of angiotensin II receptor blockers is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. In some embodiments, the dosage of angiotensin II receptor blockers is replaced by approximately 200% of the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. In some embodiments, the dosage of diuretics is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dose of a diuretic is replaced with approximately 200% of the minimum therapeutic dose (LHTD) for the diuretic. In some embodiments, the dose of a calcium channel blocker is replaced with approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for the calcium channel blocker. In some embodiments, the dose of a calcium channel blocker is replaced with approximately 200% of the minimum therapeutic dose (LHTD) for the calcium channel blocker.

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

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

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

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

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

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

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

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

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

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

[0115] Other suitable formulations, but not limited to those suitable for rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, depend on the degree and severity of the disease being treated and the nature of the specific compound being used. For example, the disclosed compositions may be formulated as unit doses.

[0116] A typical pharmaceutical composition may be used in the form of a pharmaceutical formulation, for example, a solid, semi-solid, or liquid, which contains one or more of the disclosed compounds as an active ingredient, mixed with an organic or inorganic carrier or excipient suitable for external, intra-intestinal, or parenteral use. The active ingredient may be synthesized with a carrier that is usually non-toxic and pharmaceutically acceptable, for example, in the form of tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. The active target compound is contained in a pharmaceutical composition in an amount sufficient to exert the desired effect against the disease process or condition.

[0117] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, such as conventional tableting components such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or rubber, and other pharmaceutical diluents, such as water, to form a solid preliminary formulation composition comprising a homogeneous mixture of the disclosed compound or a non-toxic, pharmaceutically acceptable salt thereof. When such a preliminary formulation composition is referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0118] For solid dosage forms for oral administration (capsules, tablets, pills, dragées, powders, granules, etc.), the composition may be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) diluents such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution slowing agents such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) kaolin and bentonite clay. (9) Absorbent substances such as clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain buffering agents. Similar types of solid compositions may be used as fillers in soft or hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycol.

[0119] Tablets may be made by compression or molding, with one or more adjuncts as optional. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets may be made by molding a mixture of the composition to be used, moistened with an inert liquid diluent, in a suitable machine. In some embodiments, capsules are prepared by encapsulating tablets in hard gelatin capsules (e.g., over-encapsulation). Tablets and other solid dosage forms such as dragées, capsules, pills, and granules may be scored or prepared as optional with coatings and shells, such as enteric coatings or other coatings known in the field of pharmaceutical formulation.

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

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

[0122] In some embodiments, the treatment results in a reduction of systolic blood pressure (SBP) greater than the reduction obtained by a complete minimum hypertension-treating dose of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers in the pharmaceutical composition.

[0123] In some embodiments, the treatment results in a reduction of diastolic blood pressure (DBP) greater than the reduction obtained by a complete minimum hypertension-treating dose of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers in the pharmaceutical composition.

[0124] In some embodiments, the treatment results in greater long-term tolerance and a reduced risk of side effects compared to treatment with a complete minimum hypertension-treating dose of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers in the pharmaceutical composition.

[0125] In some embodiments, the treatment results in a reduction of systolic blood pressure (SBP) greater than the reduction obtained by any two combinations of angiotensin II receptor blockers, diuretics, and calcium channel blockers in the pharmaceutical composition, where the doses of each angiotensin II receptor blocker, diuretic, and calcium channel blocker are approximately 50% of the minimum hypertension treatment dose. In some embodiments, the treatment results in a reduction of diastolic blood pressure (DBP) greater than the reduction obtained by any two combinations of angiotensin II receptor blockers, diuretics, and calcium channel blockers in the pharmaceutical composition, where the doses of each angiotensin II receptor blocker, diuretic, and calcium channel blocker are approximately 50% of the minimum hypertension treatment dose. In some embodiments, the treatment results in greater long-term tolerance and a reduced risk of side effects compared to treatment with any two combinations of angiotensin II receptor blockers, diuretics, and calcium channel blockers in a pharmaceutical composition, where the respective doses of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are approximately 50% of the minimum dose for treating hypertension.

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

[0127] This disclosure recognizes that the use of angiotensin II receptor blockers in the pharmaceutical compositions disclosed herein results in beneficial therapeutic effects, in some embodiments, including but not limited to a substantial reduction in blood pressure, a substantial reduction in blood pressure among subjects with mildly elevated blood pressure, greater long-term tolerance, and a reduced risk of side effects. This disclosure also recognizes that, in some embodiments, beneficial therapeutic effects, including but not limited to a substantial reduction in blood pressure, a substantial reduction in blood pressure among subjects with mildly elevated blood pressure, greater long-term tolerance, and a reduced risk of side effects, are achieved by excluding lipid modifiers, platelet function modifiers, serum homocysteine ​​lowering agents, or combinations thereof, in the pharmaceutical compositions disclosed herein.

[0128] Furthermore, it is recognized that in several embodiments, the triple combinations described herein, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each in an amount of approximately 40% to approximately 80% of the minimum therapeutic dose for hypertension, result in a significantly greater reduction in blood pressure (systolic blood pressure, diastolic blood pressure, or both) than the triple combination comprising an angiotensin II receptor blocker (such as losartan), a diuretic (such as hydrochlorothiazide), and a calcium channel blocker (such as amlodipine besylate), each in an amount of 100% of the minimum therapeutic dose for hypertension. In some embodiments, the triple combinations described herein, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker, each in an amount of approximately 40% to approximately 60% of the minimum therapeutic dose for hypertension, result in a significantly greater reduction in blood pressure (systolic blood pressure, diastolic blood pressure, or both) than the triple combination comprising an angiotensin II receptor blocker (such as losartan), a diuretic (such as hydrochlorothiazide), and a calcium channel blocker (such as amlodipine besylate), each in an amount of 100% of the minimum therapeutic dose for hypertension.

[0129] Furthermore, it is recognized that in several embodiments, the triple combination described herein, comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker, each component at approximately 80% to approximately 150% of the minimum therapeutic dose, results in a significantly greater reduction in blood pressure (systolic blood pressure, diastolic blood pressure, or both) than the triple combination comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (such as hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate). [Examples]

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

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

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

[0133] 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). Drug doses were calculated using standard relative scaling and data from published literature for Cmax and AUC for each of the six antihypertensive drugs. Each animal was exposed to a single dose of all the combined drugs in a Latin square arrangement.

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

[0135] The following animals were used in the study: spontaneously hypertensive rats (SHR / NCrl). Rats were obtained from Charles River Laboratories, Inc., Kingston, New York. The age at the start of treatment was approximately 12 weeks. Thirteen male rats were used for adaptation. Eight male rats were used for the study. Animals were identified by cage cards and tattoos.

[0136] Telemetry implantation: Animals were implanted with Data Science International transmitters (HD-S10) for collecting blood pressure and heart rate data. No medication was administered to the animals for at least 10 days post-surgery.

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

[0138] Diet: Unless otherwise specified, Teklad Global Diet-Rodent 2014 (Envigo RMS, Inc.) was administered as appropriate. In some cases, this diet was given to animals in food form, as indicated by their health condition.

[0139] Water: Tap water from undeveloped areas was provided as needed.

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

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

[0142] Adaptation (pre-administration phase): The adaptation phase lasted up to one week.

[0143] Environmental and dietary enrichment: Animals were given various cage enrichment devices and dietary enrichments (without requiring statistical analysis).

[0144] Randomization: Animals were arbitrarily selected based on the mean arterial pressure value at the pre-treatment stage.

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

[0146] [Table 3]

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

[0148] [Table 4]

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

[0150] Administration Procedure: For pre-administration handling, the test combination formulation was allowed to equalize to near room temperature for at least 30 minutes prior to administration. The animals were administered a volume of 10 mL / kg, with the actual dose volume based on the most recent body weight. The dose was administered using oral gastric tube feeding. The dose interval was once daily on days 1, 8, 15, and 22. After administration, the remaining test combination formulation was disposed of according to standard disposal procedures.

[0151] Telemetry Collection: Animals were undisturbed or handled skillfully immediately before and during the collection of telemetry data without prior consent. Such disturbances include, but are not limited to, changes in cages, bedding, wiping, public health, or any disturbance to the natural, quiet environment that was important for the collection of cardiovascular telemetry data.

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

[0153] Body weight: Body weight was measured at least once during the pre-administration phase and before each scheduled dose. Where appropriate, additional body weight was recorded to monitor the animal's health. Animals were equipped with transmitters, and representative transmitters and leads were used to balance (tare) the animals before collecting body weight for dosage calculation.

[0154] Telemetry data collection: Raw arterial pressure signals were counted at a sampling rate of 500 Hz. The parameters derived during the pre-administration and administration phases were the same. For pre-administration data collection, all embedded telemetry devices were checked for signal consistency and to verify that the telemetry signals were acceptable for analysis. Signal check consisted of at least one telemetry record obtained from each rat under consideration. Telemetry data was recorded continuously for approximately 24 hours. The telemetry data was examined to determine whether the rats were eligible for the study. The data was stored in the study record and used to calculate the nominal 24-hour intermediate arterial pressure mean to assist in randomization of animals. For administration phase data collection, continuous telemetry data was collected during the administration phase, starting at least 90 minutes before administration and continuing for approximately 48 hours after administration.

[0155] Nominal Dosage Time: Telemetry collection time points were based on a single nominal dosage time for all animals. The nominal dosage time for each administration stage was the end of the first half of the administration for the animals administered on that day, as recorded on each computer for all animals based on calculations.

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

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

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

[0159] result The study began with eight animals; however, the telemetry transmitter did not work in one animal. As a result, complete data was available from seven animals.

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

[0161] [Table 5]

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

[0163] In this non-restrictive example, the results demonstrated that combination 1 resulted in a significantly greater reduction in systolic blood pressure than combination 3, and that combination 2 resulted in a significantly greater reduction in systolic blood pressure than either combination 3 or 1. These differences persisted over the full 44-hour observation period. The results demonstrated that both combination 1 and combination 2 resulted in a significantly greater reduction in systolic blood pressure than combination 3. These differences persisted over the full 44-hour observation period. Similar differences were observed among the three combinations in DPB reduction, and no differences were observed among these combinations in heart rate.

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

[0165] Example 2: Treatment with a triple combination composition for the treatment of hypertension method This study is a randomized, placebo-controlled, double-blind, crossover trial. The study is divided into three phases. During Phase 1 (4 weeks), participants will be randomized (1:1) to receive either a triple combination composition treatment or a placebo. This will be followed by a 2-week washout (placebo), after which participants will switch to the opposite group and receive a different treatment for 4 weeks. Participants will be recruited through community practices, primarily within the Western Sydney, Australia community.

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

[0167] intervention For these studies, we will test either a triple combination containing each component at 50% of the minimum therapeutic dose (LHTD), or a triple combination containing each component at 100% of the minimum therapeutic dose (LHTD).

[0168] When a study tests a triple combination containing each component at 50% of the minimum hypertension-treating dose (LHTD), the test composition is as follows: The triple combination composition is a single encapsulated pill containing the following three components in specific amounts: telmisartan 10 mg, amlodipine besylate 1.25 mg, and indapamide 0.625 mg. Placebo capsules appear identically and contain placebo tablets of the same weight as those in the triple combination composition.

[0169] When a study tests a triple combination containing each component at 100% of the minimum hypertension therapeutic dose (LHTD), the test composition is as follows: The triple combination composition is a single encapsulated pill containing the following three components in specific amounts: telmisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg. Placebo capsules appear identically and contain placebo tablets of the same weight as those in the triple combination composition.

[0170] Participants will be administered a single pill, a triple combination composition, or a placebo throughout the study. Patients will be instructed to take the tablets simultaneously each day and encouraged to take them in the morning, but the time of day (morning or evening) will be at the patient's discretion.

[0171] All test reagents are prepared in a manufacturing facility licensed under TGA-cGMP (Therapeutic Goods Australia - Certificate of Good Manufacturing Practice). Where appropriate, low-strength doses are obtained by dividing a half-strength dose in half using a pill divider without crushing, and these are weighed to ensure accuracy in halving the dose. The low-strength doses are then encapsulated in gelatin capsules (DBCaps-Capsugel). The capsules are stored in a cool, dry place and monitored using a temperature logger until dispensing.

[0172] Treatment assignments will be blinded to both research staff and participants. In addition to the investigational drug, all participants will be provided with education on healthy lifestyle options, such as those recommended by guidelines for managing hypertension.

[0173] Randomization A computer-aided randomization sequence is created by a statistician and provided to a pharmaceutical packaging company. Research assistants, supplementary teams, and investigators are blinded to this sequence. For each patient, i.e., the assigned number of randomized patients, the pill is packaged into three child-safe packs, corresponding to a three-stage study. All packs have an identical appearance to ensure blinding of patients and research staff. The drug packs are then prescribed in the organized sequence.

[0174] Results and Data Collection The primary endpoint is the mean 24-hour reduction in systolic blood pressure over 4 weeks using ambulatory blood pressure monitoring (ABP). Secondary endpoints include: a. Average 24-hour diastolic blood pressure, and reductions in daytime and nighttime SBP and DBP over 4 weeks. b. Reduction of office SBP and DBP as measured by a standardized automated blood measurement cuff. c. Ratio of controlled blood pressure over 4 weeks, defined as 24-hour BP <135 / 85 mmHg and office BP <140 / 90 mmHg. d. Adverse events and adverse events identified in advance by laboratory parameters: elevated transaminase (ALT / AST) levels more than 3 times above the upper limit of normal, or 2 times when baseline levels are known to be elevated; >20% decrease in estimated glomerular filtration rate, such as as assessed from serum creatinine; sodium, potassium, and uric acid levels. e. Evaluation of acceptability and tolerance

[0175] Patients will undergo 24-hour ABP monitoring four times: baseline (investigational drug cessation), 4 weeks (Phase 1 drug), 6 weeks (placebo), and 10 weeks (Phase 3 drug). To minimize inconvenience, patients will refer their ABP to the laboratory. ABP units will be calibrated at equal intervals by the laboratory according to manufacturer specifications. To minimize variability, follow-up readings will be repeated from the same collection center using the same brand of equipment. Participants will receive reimbursement of face value, including travel and parking expenses. Study drugs and surveys will be provided to participants free of charge. Office BP will be recorded three times at each visit using an OMRON T9P (HEM-759-C1). The second and third readings will be averaged for study analysis. In addition, at weeks 4 and 10, patients will undergo blood tests to assess biochemical adverse reactions, complete a questionnaire for clinical adverse reactions, and assess compliance by self-report and pill count. Once patients complete this questionnaire, they will remain blinded to their treatment assignments.

[0176] Drug acceptance and tolerance will also be assessed at the end of the study. All adverse events will be recorded. In addition, specific clinical adverse events likely associated with antihypertensive drugs will be asked about: dizziness, visual impairment, loss of consciousness / collapse, chest pain / angina, shortness of breath, cough, wheeze, pediatric edema, rash, and itching.

[0177] The trial involves simplified data safety and management by two core members with expertise in clinical medicine, trials, and statistics. Once 10 patients are randomized to the trial to assess safety, a meeting is convened to advise whether to continue the study.

[0178] Statistical considerations We planned a sample size of 50 patients, obtained 90% power at p=0.05, detected a 12 mmHg SBP difference between intervention and control, assumed SD within the 12 mmHg patient difference, and accounted for a potential 10% loss for follow-up.

[0179] Statistical methods Statistical analysis was performed with respect to the underlying intent. All studies were two-sided, and the nominal level of alpha was 5%. All statistical analyses were unadjusted for prognostic covariates. Medication adherence to the investigational drug was reported using data on the obtained pills (dosage) and the amount lost over time.

[0180] Following the method of Kenward and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 2010;11(1):1-17), a linear mixed model was used to evaluate the effect of the treatment on the change in blood pressure from baseline during each treatment period. To appropriately adjust for baseline levels, collected at the beginning of each treatment period (week 0 and week 6), this method consequently uses all measurements (baseline and follow-up in both periods), but accounts for the covariance between measurements within the individual (Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analysis of change from baseline in clinical trials? Stat Med 2009;28(20):2509-30). Linear contrasts between variability, representing period (first / second), measurement type (baseline / final), and treatment received (placebo / triple combination composition), provide an unbiased estimate of the effect of the triple combination composition on blood pressure change compared to placebo. All available data are included in the model, and data loss is not attributed. If a patient has lost data over a period, data from the valid period is used. A sensitivity analysis is performed including only patients with available data from both periods to determine whether the effect of the treatment was modified. Kenward and Roger (2009) also have an improved approximation to the precision of fixed effects from restricted maximum likelihood (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), which is optimal for smaller sample sizes.

[0181] For carryover testing, an unpaired t-test is used for the primary outcome with order as the effect. Time effects are tested using a paired t-test comparing the primary outcome of period 1 to the primary outcome of period 2 from the same patient. Sensitivity analysis is also performed using a standard paired t-test to compare the primary endpoint between different periods (different treatments) from the same patient, with baseline levels for each period ignored.

[0182] Continuous secondary endpoints at baseline values ​​(e.g., daytime / nighttime ambulatory SBP / DBP) are similarly analyzed against the primary endpoint. Other continuous variables without baseline values ​​for each period are analyzed using paired t-tests. The number and percentage of all adverse events are reported. For sensitivity analysis, the analysis is repeated for complete cases (i.e., complete data for each measurement period).

[0183] Age (<=60 vs >60 years), gender, and BMI (<=30 vs <30 kg / m²) 2 A study on the interaction of therapeutic effects in ). Subgroup analysis will also be performed for each variation. All analyses will be performed using SAS 9.4 (Cary, NC, USA) software.

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

[0185] research design This was a 12-week, double-blind, randomized, controlled (1:1) trial involving 650 patients with grade 1 and 2 essential hypertension. Participants were randomized via a central computer-based randomization service in accordance with current Australian hypertension guidelines to begin treatment with either a triple combination composition or an angiotensin receptor blocker (ARB), with the option of adding a calcium channel blocker (CCB) as needed. The primary endpoint was the reduction in mean systolic blood pressure using a standardized automated blood pressure cuff over 12 weeks. Secondary endpoints included the ratio to controlled blood pressure at 6 weeks and 12 weeks, ambulatory blood pressure (ABP) measurements, and tolerance / incidence of adverse events.

[0186] Eligibility Criteria The inclusion criteria are as follows: - Adults (≥18 years old) - Treatment naive, or currently not receiving treatment (i.e., not taking medication within the last 4 weeks), or taking one blood glucose-lowering medication (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta-blocker, aldosterone antagonist, alpha-blocker) - SBP 140-179 mmHg and / or DBP 90-109 mmHg separately documented in two cases of more than one week. - At least one measurement must be documented by the research staff, and the automated BP device OR of the study recorded daytime mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg during 24-hour ambulatory BP monitoring. - At least one of these measurements must be recent (within the last 12 weeks). - 24-hour outpatient BP monitoring shows a daytime mean SBP ≥ 135 mmHg and / or DBP ≥ 85 mmHg documented within 12 weeks of randomization.

[0187] The exclusion criteria are as follows: - Contraindications for telmisartan, amlodipine, or indapamide - Evidence of secondary causes of hypertension, e.g., renal artery stenosis; significant renal dysfunction (eGRF < 50), elevated serum potassium (above the laboratory normal limit) - Women who are pregnant, breastfeeding, and / or of childbearing potential, and who do not use medically acceptable contraception (pharmaceutical or barrier methods) throughout the study. - In the opinion of the research team / primary care physician, any accompanying illness, physical impairment, or mental condition that could interfere with the conduct of the study, including the evaluation of results. - Participation in a concurrent interventional medical study or clinical trial. Patients in observational natural studies and / or epidemiological studies that do not involve intervention are eligible. - The participant's trusted primary care provider or other trusted physician believes that switching from their current monotherapy is not appropriate for the participant. - Unable to provide written informed consent, or unwilling to do so. - Unable to complete research procedures, including BP, under 24 hours of free movement. - Clear indicators for combination therapy

[0188] Research treatment For these studies, we will test either a triple combination containing each component at 50% of the minimum therapeutic dose (LHTD), or a triple combination containing each component at 100% of the minimum therapeutic dose (LHTD).

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

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

[0191] Patients currently receiving monotherapy will be asked to discontinue their treatment while undergoing the study procedure. If blood pressure (BP) is greater than 140 / 90 mmHg in either group after 6 weeks, amlodipine besylate (5 mg) will be added by the research staff.

[0192] result The primary endpoint is the difference between groups in mean automated office systolic blood pressure over 12 weeks, adjusted for baseline values.

[0193] The secondary evaluation criteria include the following: - 24-hour ambulatory blood pressure monitoring a. Differences between groups in average 24-hour SBP and DBP over 12 weeks. b. Differences between groups in mean changes in 24-hour SBP and DBP over weeks 0-12. c. Differences between groups in mean daytime SBP and DBP over 12 weeks, and differences between groups in mean nighttime SBP and DBP over 12 weeks. d. Differences between groups in daytime, nighttime, and 24-hour BP load (percentage of area under the blood pressure curve above normal daytime, nighttime, and 24-hour values, according to the NHFA Guide to management of hypertension 2008) e. Differences between groups in the proportion of cases with no nocturnal blood pressure reduction (nocturnal BP is at most 10% lower than the average daytime BP, according to the NHFA Guide to management of hypertension 2008), and in the coefficient of BP variability (O'Brien, E., G. Parati, and G. Stergiou, Hypertension, 2013.62(6):p.988-94). -Other blood pressure measurements in the triple group-versus-control group: a. Mean change in diastolic blood pressure from baseline to 12 weeks b. Hypertension control at 6 and 12 weeks (percentage with SBP < 140 mmHg and DBP < 90 mmHg) c. Percentage of patients requiring a step-up in treatment within 6 weeks d. Percentage with BP control (as defined above) and without adverse events. e. Differences between groups in the variability of SBP and DBP -Durability a. Differences between groups in possible related side effects (dizziness, visual impairment, loss / decreased consciousness, chest pain / angina, shortness of breath, cough, wheezing, ankle edema, rash, itching, gout, hyperkalemia, hypokalemia, hyponatremia, etc.) b. Differences between groups in mean levels of potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UACR (urinary albumin-creatinine ratio), and creatinine. c. Differences between groups in participants who discontinued treatment.

[0194] statistical methods All statistical analyses of the study results will be performed according to the principle of comprehensive analysis. The primary analysis of the change in systolic blood pressure (SBP) over 12 weeks will be performed using analysis of covariance (ANCOVA) with treatment group and baseline SBP as covariates. Continuous secondary endpoints will be analyzed similarly. Additional analyses will include measurements at 6 and 12 weeks in a longitudinal model, including treatment group, visits, and visit interactions, as well as baseline measurements. Within-patient correlations will be modeled using a general assessment equation. A similar approach will be applied to two-variable endpoints (e.g., hypertensive controls) with log-binomial regression used instead of linear regression. Predefined subgroup analyses will also exist, including baseline blood pressure, sex, age, and history of hypertension treatment. Detailed analysis plans will be developed before open-blinding.

[0195] Example 4: Pharmaceutical composition 1 The following pharmaceutical compositions are prepared with the specific components and dosages shown in the table below.

[0196] [Table 6]

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

[0198] [Table 7]

[0199] Example 6: Pharmaceutical composition 3 The following pharmaceutical compositions are prepared with the specific components and dosages shown in the table below.

[0200] [Table 8]

[0201] Embodiment Embodiment 1. A pharmaceutical composition, (a) Angiotensin II receptor blockers; (b) Diuretics; and (c) Calcium channel blockers Includes, Herein, the dosage of (a), (b), and (c) is approximately 40% to approximately 80% of the minimum hypertension-treating dose (LHTD) for each of (a), (b), and (c), in a pharmaceutical composition.

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

[0203] Embodiment 3. The pharmaceutical composition according to Embodiment 1 or 2, wherein the pharmaceutical composition essentially does not contain an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof.

[0204] Embodiment 4. The pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the pharmaceutical composition essentially does not contain a beta-blocker or a pharmaceutically acceptable salt thereof.

[0205] Embodiment 5. The pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition essentially does not contain a lipid modifier, a platelet function modifier, a serum homocysteine ​​lowering agent, or a combination thereof.

[0206] Embodiment 6. The pharmaceutical composition according to Embodiment 5, wherein the pharmaceutical composition essentially does not contain a lipid modulating agent.

[0207] Embodiment 7. The pharmaceutical composition according to Embodiment 6, wherein the lipid modulating agent is atorvastatin, simvastatin, cerivastatin, fluvastatin, or pravastatin.

[0208] Embodiment 8. The pharmaceutical composition according to Embodiment 6 or 7, wherein the lipid modulating agent is atorvastatin or simvastatin.

[0209] Embodiment 9. The pharmaceutical composition according to Embodiment 5, wherein the pharmaceutical composition essentially does not contain a platelet function modifier.

[0210] Embodiment 10. The pharmaceutical composition according to Embodiment 9, wherein the platelet function modifier is aspirin, ticlopidine, dipyridamole, clopidogrel, absiximab, or ibuprofen.

[0211] Embodiment 11. The pharmaceutical composition according to Embodiment 9 or 10, wherein the platelet function modifier is aspirin.

[0212] Embodiment 12. The pharmaceutical composition according to Embodiment 5, wherein the pharmaceutical composition essentially does not contain a serum homocysteine-lowering agent.

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

[0214] Embodiment 14. The pharmaceutical composition according to Embodiment 12 or 13, wherein the serum homocysteine-lowering agent is folic acid.

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

[0216] Embodiment 16. The pharmaceutical composition according to Embodiment 15, wherein the thiazide diuretic is artizide, bendroflumethiazide, chlorothiazide, cyclopentiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, meticlothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

[0219] Embodiment 19. The pharmaceutical composition according to Embodiment 18, wherein the thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0220] Embodiment 20. The pharmaceutical composition according to Embodiment 19, wherein the thiazide-like diuretic is indapamide or its hydrate.

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

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

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

[0224] Embodiment 24. The pharmaceutical composition according to Embodiment 23, wherein the loop diuretic is furosemide, bumetanide, ethacrine, etozolin, muzolimin, ozolinone, pyretanide, thienilic acid, torasemide, or a pharmaceutically acceptable salt or hydrate thereof.

[0225] Embodiment 25. The pharmaceutical composition according to any one of Embodiments 1 to 14, wherein the diuretic is dichlorfenamide, amiloride, pamabrom, mannitol, acetazolamide, metazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof.

[0226] Embodiment 26. The pharmaceutical composition according to any one of Embodiments 1 to 25, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clebidipine, dihydropyridine, relcanidipine, nitrendipine, cilnidipine, manidipine, mibeflazil, bepridil, barnidipine, nilvadipine, garopamil, lidoflazine, aranidipine, dotaridine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0227] Embodiment 27. The pharmaceutical composition according to Embodiment 26, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0233] Embodiment 33. The pharmaceutical composition according to Embodiment 32, wherein the urinary agent is a thiazide diuretic, and the dose of the thiazide diuretic is approximately 50% of the minimum hypertension-treating dose (LHTD) for the thiazide diuretic.

[0234] Embodiment 34. The pharmaceutical composition according to Embodiment 33, wherein the thiazide diuretic is hydrochlorothiazide, and the dose of hydrochlorothiazide is approximately 6.25 mg.

[0235] Embodiment 35. The pharmaceutical composition according to Embodiment 32, wherein the diuretic is a thiazide-like diuretic, and the dose of the thiazide-like diuretic is approximately 50% of the minimum hypertension-treating dose (LHTD) for the thiazide-like diuretic.

[0236] Embodiment 36. The pharmaceutical composition according to Embodiment 35, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 0.625 mg.

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

[0238] Embodiment 38. The diuretic is a loop diuretic, and the dosage of the loop diuretic is about 50% of the lowest hypertensive treatment dose (LHTD) for the loop diuretic, the pharmaceutical composition according to Embodiment 32.

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

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

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

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

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

[0244] Embodiment 44. The angiotensin II receptor blocker is irbesartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate, the pharmaceutical composition according to Embodiment 32.

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

[0246] Embodiment 46. The pharmaceutical composition according to Embodiment 45, wherein the dosage of irbesartan is about 37.5 mg, the dosage of hydrochlorothiazide is about 6.25 mg, and the dosage of amlodipine besylate is about 1.25 mg.

[0247] Embodiment 47. The pharmaceutical composition according to Embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

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

[0249] Embodiment 49. The pharmaceutical composition according to Embodiment 48, wherein the dosage of telmisartan is about 10 mg, the dosage of hydrochlorothiazide is about 6.25 mg, and the dosage of amlodipine besylate is about 1.25 mg.

[0250] Embodiment 50. The pharmaceutical composition according to Embodiment 32, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

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

[0252] Embodiment 52. The pharmaceutical composition according to Embodiment 51, wherein the dose of irbesartan is approximately 37.5 mg, the dose of indapamide is approximately 0.625 mg, and the dose of amlodipine is approximately 1.25 mg.

[0253] Embodiment 53. The pharmaceutical composition according to Embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

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

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

[0256] Embodiment 56. The pharmaceutical composition according to Embodiment 32, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

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

[0258] Embodiment 58. The pharmaceutical composition according to Embodiment 57, wherein the dose of telmisartan is approximately 10 mg, the dose of chlorthalidone is approximately 12.5 mg, and the dose of amlodipine besylate is approximately 1.25 mg.

[0259] Embodiment 59. The pharmaceutical composition according to Embodiment 32, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

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

[0261] Embodiment 61. The pharmaceutical composition according to Embodiment 60, wherein the dose of irbesartan is approximately 37.5 mg, the dose of chlorthalidone is approximately 12.5 mg, and the dose of amlodipine besylate is approximately 1.25 mg.

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

[0263] Embodiment 63. The pharmaceutical composition according to Embodiment 62, wherein the urinary agent is a thiazide diuretic, and the dose of the thiazide diuretic is approximately 66% of the minimum hypertension therapeutic dose (LHTD) for the thiazide diuretic.

[0264] Embodiment 64. The pharmaceutical composition according to Embodiment 63, wherein the thiazide diuretic is hydrochlorothiazide, and the dose of hydrochlorothiazide is approximately 8.25 mg.

[0265] Embodiment 65. The pharmaceutical composition according to Embodiment 62, wherein the diuretic is a thiazide-like diuretic, and the dose of the thiazide-like diuretic is approximately 66% of the minimum hypertension-treating dose (LHTD) for the thiazide-like diuretic.

[0266] Embodiment 66. The pharmaceutical composition according to Embodiment 65, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 0.825 mg.

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

[0268] Embodiment 68. The diuretic is a loop diuretic, and the dosage of the loop diuretic is about 66% of the lowest hypertensive treatment dose (LHTD) for the loop diuretic, the pharmaceutical composition according to Embodiment 62.

[0269] Embodiment 69. The dosage of the calcium channel blocker is about 66% of the lowest hypertensive treatment dose (LHTD) for the calcium channel blocker, the pharmaceutical composition according to any one of Embodiments 62 to 68.

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

[0271] Embodiment 71. The dosage of the angiotensin II receptor blocker is about 66% of the lowest hypertensive treatment dose (LHTD) for the angiotensin II receptor blocker, the pharmaceutical composition according to any one of Embodiments 62 to 70.

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

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

[0274] Embodiment 74. The angiotensin II receptor blocker is irbesartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate, the pharmaceutical composition according to Embodiment 62.

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

[0276] Embodiment 76. The pharmaceutical composition according to Embodiment 75, wherein the dose of irbesartan is approximately 49.5 mg, the dose of hydrochlorothiazide is approximately 8.25 mg, and the dose of amlodipine besylate is approximately 1.65 mg.

[0277] Embodiment 77. The pharmaceutical composition according to Embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is hydrochlorothiazide, and the calcium channel blocker is amlodipine besylate.

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

[0279] Embodiment 79. The pharmaceutical composition according to Embodiment 78, wherein the dose of telmisartan is approximately 13.2 mg, the dose of hydrochlorothiazide is approximately 8.25 mg, and the dose of amlodipine besylate is approximately 1.65 mg.

[0280] Embodiment 80. The pharmaceutical composition according to Embodiment 62, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

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

[0282] Embodiment 82. The pharmaceutical composition according to Embodiment 81, wherein the dose of irbesartan is approximately 49.5 mg, the dose of indapamide is approximately 0.825 mg, and the dose of amlodipine is approximately 1.65 mg.

[0283] Embodiment 83. The pharmaceutical composition according to Embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

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

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

[0286] Embodiment 86. The pharmaceutical composition according to Embodiment 62, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

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

[0288] Embodiment 88. The pharmaceutical composition according to Embodiment 87, wherein the dose of telmisartan is approximately 13.2 mg, the dose of chlorthalidone is approximately 16.5 mg, and the dose of amlodipine besylate is approximately 1.65 mg.

[0289] Embodiment 89. The pharmaceutical composition according to Embodiment 62, wherein the angiotensin II receptor blocker is irbesartan, the diuretic is chlorthalidone, and the calcium channel blocker is amlodipine besylate.

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

[0291] Embodiment 91. The pharmaceutical composition according to Embodiment 90, wherein the dose of irbesartan is approximately 49.5 mg, the dose of chlorthalidone is approximately 16.5 mg, and the dose of amlodipine besylate is approximately 1.65 mg.

[0292] Embodiment 92. The pharmaceutical composition according to any one of Embodiments 1 to 91, wherein the dosage of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers is substituted with approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0293] Embodiment 93. The pharmaceutical composition according to Embodiment 92, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 80% to approximately 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0294] Embodiment 94. The pharmaceutical composition according to Embodiment 92, wherein the dosage of the diuretic is replaced by approximately 80% to approximately 250% of the minimum hypertension-treating dose (LHTD) for the diuretic.

[0295] Embodiment 95. The pharmaceutical composition according to Embodiment 92, wherein the dosage of the calcium channel blocker is replaced by approximately 80% to approximately 250% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.

[0296] Embodiment 96. The pharmaceutical composition according to any one of Embodiments 92 to 95, wherein the dosage of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers is substituted with approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0297] Embodiment 97. The pharmaceutical composition according to Embodiment 96, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 80% to approximately 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

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

[0299] Embodiment 99. The pharmaceutical composition according to Embodiment 96, wherein the dosage of the diuretic is replaced by approximately 80% to approximately 150% of the minimum hypertension-treating dose (LHTD) for the diuretic.

[0300] Embodiment 100. The pharmaceutical composition according to Embodiment 99, wherein the dose of the diuretic is replaced by approximately 100% of the minimum hypertension-treating dose (LHTD) for the diuretic.

[0301] Embodiment 101. The pharmaceutical composition according to Embodiment 96, wherein the dosage of the calcium channel blocker is replaced by approximately 80% to approximately 150% of the minimum hypertension therapeutic dose (LHTD) for the calcium channel blocker.

[0302] Embodiment 102. The pharmaceutical composition according to Embodiment 101, wherein the dosage of the calcium channel blocker is replaced by approximately 100% of the minimum therapeutic dose (LHTD) for calcium channel blockers.

[0303] Embodiment 103. The pharmaceutical composition according to any one of Embodiments 92 to 95, wherein the dosage of any one of angiotensin II receptor blockers, diuretics, and calcium channel blockers is substituted with approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0304] Embodiment 104. The pharmaceutical composition according to Embodiment 103, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 150% to approximately 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0305] Embodiment 105. The pharmaceutical composition according to Embodiment 104, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0306] Embodiment 106. The pharmaceutical composition according to Embodiment 103, wherein the dosage of the diuretic is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose for hypertension (LHTD) of the diuretic.

[0307] Embodiment 107. The pharmaceutical composition according to Embodiment 106, wherein the dose of the diuretic is replaced by approximately 200% of the minimum therapeutic dose for hypertension (LHTD) of the diuretic.

[0308] Embodiment 108. The pharmaceutical composition according to Embodiment 103, wherein the dosage of the calcium channel blocker is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for calcium channel blockers.

[0309] Embodiment 109. The pharmaceutical composition according to Embodiment 108, wherein the dosage of the calcium channel blocker is replaced by approximately 200% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker.

[0310] Embodiment 110. A pharmaceutical composition according to any one of Embodiments 1 to 91, wherein the dosages of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are substituted with approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0311] Embodiment 111. The pharmaceutical composition according to Embodiment 110, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 80% to approximately 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0312] Embodiment 112. The pharmaceutical composition according to Embodiment 110, wherein the dosage of the diuretic is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose for hypertension (LHTD) of the diuretic.

[0313] Embodiment 113. The pharmaceutical composition according to Embodiment 110, wherein the dosage of the calcium channel blocker is replaced by approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for calcium channel blockers.

[0314] Embodiment 114. The pharmaceutical composition according to any one of Embodiments 110 to 113, wherein the dosages of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker are replaced by approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for the angiotensin II receptor blocker, diuretic, or calcium channel blocker.

[0315] Embodiment 115. The pharmaceutical composition according to Embodiment 114, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 80% to approximately 150% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

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

[0317] Embodiment 117. The pharmaceutical composition according to Embodiment 114, wherein the dosage of the diuretic is replaced by approximately 80% to approximately 150% of the minimum therapeutic dose for hypertension (LHTD) of the diuretic.

[0318] Embodiment 118. The pharmaceutical composition according to Embodiment 117, wherein the dosage of the diuretic is replaced by approximately 100% of the minimum hypertension-treating dose (LHTD) of the diuretic.

[0319] Embodiment 119. The pharmaceutical composition according to Embodiment 114, wherein the dosage of the calcium channel blocker is replaced by approximately 80% to approximately 150% of the minimum therapeutic dose (LHTD) for calcium channel blockers.

[0320] Embodiment 120. The pharmaceutical composition according to Embodiment 119, wherein the dosage of the calcium channel blocker is replaced by approximately 100% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker.

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

[0322] Embodiment 122. The pharmaceutical composition according to Embodiment 121, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 150% to approximately 250% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0323] Embodiment 123. The pharmaceutical composition according to Embodiment 122, wherein the dose of the angiotensin II receptor blocker is replaced by approximately 200% of the minimum hypertension therapeutic dose (LHTD) for the angiotensin II receptor blocker.

[0324] Embodiment 124. The pharmaceutical composition according to Embodiment 121, wherein the dosage of the diuretic is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for the diuretic.

[0325] Embodiment 125. The pharmaceutical composition according to Embodiment 124, wherein the dosage of the diuretic is replaced by approximately 200% of the minimum hypertension-treating dose (LHTD) of the diuretic.

[0326] Embodiment 126. The pharmaceutical composition according to Embodiment 121, wherein the dosage of the calcium channel blocker is replaced by approximately 150% to approximately 250% of the minimum therapeutic dose (LHTD) for calcium channel blockers.

[0327] Embodiment 127. The pharmaceutical composition according to Embodiment 126, wherein the dosage of the calcium channel blocker is replaced by approximately 200% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker.

[0328] Embodiment 128: A pharmaceutical composition, (a) Telmisartan; (b) Thiazide diuretics; and (c) Calcium channel blockers Includes, Herein, the dosage of (a), (b), and (c) is approximately 80% to approximately 150% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c), in a pharmaceutical composition.

[0329] Embodiment 129: The pharmaceutical composition according to Embodiment 128, wherein the pharmaceutical composition essentially does not contain an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a β-blocker or a pharmaceutically acceptable salt thereof, a lipid modifier, a platelet function modifier, a serum homocysteine ​​lowering agent, or a combination thereof.

[0330] Embodiment 130: The pharmaceutical composition according to Embodiment 128 or 129, wherein the thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof.

[0331] Embodiment 131: The pharmaceutical composition according to Embodiment 130, wherein the thiazide-like diuretic is indapamide or its hydrate.

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

[0333] Embodiment 133: The pharmaceutical composition according to any one of Embodiments 128 to 132, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clebidipine, dihydropyridine, relcanidipine, nitrendipine, cilnidipine, manidipine, mibeflazil, bepridil, barnidipine, nilvadipine, garopamil, lidoflazine, aranidipine, dotaridine, diproteverine, or a pharmaceutically acceptable salt or hydrate thereof.

[0334] Embodiment 134: The pharmaceutical composition according to Embodiment 133, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

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

[0336] Embodiment 136: The pharmaceutical composition according to any one of Embodiments 128 to 135, wherein the respective doses of (a), (b), and (c) are approximately 80% to approximately 120% of the minimum hypertension therapeutic dose (LHTD) for each of (a), (b), and (c).

[0337] Embodiment 137: The pharmaceutical composition according to Embodiment 136, wherein the dose of the thiazide-like diuretic is approximately 100% of the minimum hypertension-treating dose (LHTD) for the thiazide-like diuretic.

[0338] Embodiment 138: The pharmaceutical composition according to Embodiment 137, wherein the thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 1.25 mg.

[0339] Embodiment 139: The pharmaceutical composition according to any one of Embodiments 136 to 138, wherein the dose of the calcium channel blocker is approximately 100% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker.

[0340] Embodiment 140: The pharmaceutical composition according to Embodiment 139, wherein the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is approximately 2.5 mg.

[0341] Embodiment 141: The pharmaceutical composition according to any one of Embodiments 136 to 140, wherein the dose of telmisartan is approximately 100% of the minimum hypertension-treating dose (LHTD) for telmisartan.

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

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

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

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

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

[0347] Embodiment 147.(a), (b), and (c) are pharmaceutical compositions according to any one of Embodiments 1 to 145, each provided in a separate formulation.

[0348] Embodiment 148. Two of (a), (b), and (c) are pharmaceutical compositions according to any one of Embodiments 1 to 145, provided in a single formulation.

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

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

[0351] Embodiment 151: A method for treating a subject's hypertension as needed, comprising the step of administering any one of the pharmaceutical compositions of Embodiments 1 to 150.

[0352] Embodiment 152. The method according to Embodiment 151, wherein the procedure results in a systolic blood pressure (SBP) of less than approximately 140 mmHg.

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

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

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

[0356] Embodiment 156. The method according to any one of Embodiments 150 to 155, wherein the treatment results in a reduction of systolic blood pressure (SBP) greater than the reduction obtained by any one of (a), (b), and (c) of the pharmaceutical composition for complete minimum hypertension treatment.

[0357] Embodiment 157. The method according to any one of Embodiments 150 to 156, wherein the treatment results in a reduction of diastolic blood pressure (DBP) greater than the reduction obtained by any one of (a), (b), and (c) of the pharmaceutical composition for complete minimum hypertension treatment.

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

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

[0360] Embodiment 160. The method according to any one of Embodiments 150 to 159, wherein the subject does not receive the aforementioned hypertension treatment before the procedure.

[0361] While preferred embodiments of the Disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided only as examples. Numerous variations, alterations, and substitutions are now conceivable by those skilled in the art without departing from the Disclosure. It should be understood that various alternatives to the embodiments of the Disclosure described herein may be used in the practice of the Disclosure. The following claims define the scope of the Disclosure, and the methods and structures within the scope of these claims and their equivalents are intended to be encompassed thereby.

Claims

1. A pharmaceutical composition for use in treating hypertension, (a) Telmisartan, (b) Indapamide, and (c) Amlodipine besylate Includes, Here, the daily dose of telmisartan is approximately 8 mg to approximately 12 mg, the daily dose of indapamide is approximately 0.5 mg to approximately 0.75 mg, and the daily dose of amlodipine besylate is approximately 1 mg to approximately 1.5 mg. Herein, the pharmaceutical composition is a pharmaceutical composition for use in treating the hypertension that does not contain an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta-blocker or a pharmaceutically acceptable salt thereof, a lipid modifier, a platelet function modifier, a serum homocysteine ​​lowering agent, or a combination thereof.

2. The pharmaceutical composition for use according to claim 1, wherein the daily dose of indapamide is approximately 0.625 mg.

3. The pharmaceutical composition for use according to claim 1, wherein the daily dose of amlodipine besylate is approximately 1.25 mg.

4. The pharmaceutical composition for use according to claim 1, wherein the daily dose of telmisartan is approximately 10 mg.

5. The pharmaceutical composition for use according to claim 1, wherein the daily dose of telmisartan is approximately 10 mg, the daily dose of indapamide is approximately 0.625 mg, and the daily dose of amlodipine besylate is approximately 1.25 mg.

6. A pharmaceutical composition for use according to claim 1, suitable for oral administration.

7. A pharmaceutical composition for use according to claim 1, which is in the form of a pill, tablet, or capsule.

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