Composition for the treatment of hypertension

Abstract

To provide compositions for the treatment of hypertension. [Solution] This specification provides pharmaceutical compositions useful for the treatment of hypertension, comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. These compositions are administered at 40% to 80% of the minimum hypertension therapeutic dose (LHTD) for each agent. This application also relates to compositions comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker, administered at 80% to 150% of the LHTD for each agent.

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 content of which is hereby incorporated by reference in its 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 treatments that lower blood pressure (BP) are beneficial. However, despite the availability of medications that lower blood pressure, many patients continue to have poor blood pressure control, as demonstrated by numerous large population studies. Poor blood pressure control is attributed to factors such as poor adherence, complex guidelines that recommend 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 reduced durability. Therefore, there is a need for new treatments that are effective and durable in lowering blood pressure.

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 hypertensive treatment dose (LHTD) for each of (a), (b), and (c). ​

[0004] In some embodiments, the pharmaceutical composition is an angiotensin-converting enzyme inhibitor or the Pharmacologically acceptable salts, beta-blockers or pharmaceutically acceptable salts thereof, lipid regulators, platelet enzymes Platelet function-altering agent, serum It essentially does not contain homocysteine-lowering agents or combinations thereof.

[0005] In some embodiments, the diuretic is a thiazide-like diuretic. Thiazide-like diuretics include kinesazone, clopamide, chlorthalidone, mefluside, and closalidone. Lofenamide, Metrazone, Meticran, Xypamide, Indapamide, Chlorexolone, Fenquizone, or a pharmaceutically acceptable salt or hydrate thereof. Several implementation forms In this embodiment, the thiazide-like diuretic is indapamide or its hydrate. Several embodiments In this context, 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, mibefurazil, bepridil, barnidipine, nilvadipine , garopamil, lidoflazine, aranidipine, dotarizine, diproteverine, or These are pharmaceutically acceptable salts or hydrates of the same substance. In some embodiments, calcium thiosulfate The channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments... In this context, the calcium channel blocker is amlodipine besylate.

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

[0008] In some embodiments, the respective doses of (a), (b), and (c) are (a), (b) and (c) for each of the minimum hypertension treatment doses (LHTD) is approximately 40% to 60% It is %. In some embodiments, the diuretic is a thiazide-like diuretic, and thiazide-like The dosage of urinary medications is approximately 50% of the minimum therapeutic dose (LHTD) for thiazide-like diuretics. Yes. In some embodiments, the thiazide-like diuretic is indapamide, and indapamide The dosage is approximately 0.625 mg. In some embodiments, calcium channels The dosage of the blocker is the minimum therapeutic dose (LHTD) for calcium channel blockers. It is about 50% of the total. In some embodiments, the calcium channel blocker is besylate. It is mulodipine, and the dosage of amlodipine besylate is approximately 1.25 mg. In terms of administration methods, the dosage of angiotensin II receptor blockers is as follows: This is approximately 50% of the minimum therapeutic dose (LHTD) for receptor blockers. Several implementations In terms of morphology, the angiotensin II receptor blocker is telmisartan, and telmisartan The dosage of tan is approximately 10 mg. In some embodiments, angiotensin II receptor The blocker is telmisartan, the diuretic is indapamide, and the calcium channel The blocking agent is amlodipine besylate. In some embodiments, the dosage of telmisartan is from about 8 mg to about 12 mg, the dosage of indapamide is from about 0.5 mg to about 0.75 mg, and the dosage of amlodipine besylate is from about 1 mg to about 1.5 mg. In some embodiments, the dosage of telmisartan is about 10 mg, the dosage of indapamide is about 0.625 mg, and the dosage of amlodipine besylate is about 1.25 mg.

[0009] In another aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising: (a) telmisartan; (b) a thiazide-like diuretic; and (c) a calcium channel blocker wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the lowest hypertensive treatment dose (LHTD) for each of (a), (b), and (c).

[0010] In some embodiments, the pharmaceutical composition does not essentially contain an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a β-blocker or a pharmaceutically acceptable salt thereof, a lipid-regulating agent, a platelet function modifier, a serum homocysteine-lowering agent, or a combination thereof.

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

[0012] In some embodiments, the calcium channel blocker is amlodipine, nifedipine Diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine Nisoldipine, clebidipine, dihydropyridine, relcanidipine, nitrendipine , cilnidipine, manidipine, mibefurazil, bepridil, barnidipine, nilvadipine , garopamil, lidoflazine, aranidipine, dotarizine, diproteverine, or These are pharmaceutically acceptable salts or hydrates of the same substance. In some embodiments, calcium thiosulfate The channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments... In this context, the calcium channel blocker is amlodipine besylate.

[0013] In some embodiments, the respective doses of (a), (b), and (c) are (a), (b) and (c) for each of the following: approximately 80% to approximately 12% of the minimum hypertension treatment dose (LHTD) It is 0%. In some embodiments, the dosage of the thiazide-like diuretic is thiazide-like diuretic This is approximately 100% of the minimum therapeutic dose (LHTD) for the drug. In some embodiments... The thiazide-like diuretic is indapamide, and the dosage of indapamide is approximately 1.25 mg. In some embodiments, the dosage of the calcium channel blocker is such that the calcium This is approximately 100% of the minimum therapeutic dose (LHTD) for channel blockers. In one embodiment, the calcium channel blocker is amlodipine besylate, and besylate The dose of amlodipine is approximately 2.5 mg. In some embodiments, telmisalta The dosage of n is approximately 100% of the minimum hypertension-treating dose (LHTD) for telmisartan. Yes. In some embodiments, the dose of telmisartan is approximately 20 mg. In one embodiment, the thiazide-like diuretic is indapamide, and the calcium channel blocker It is amlodipine besylate. In some embodiments, the dose of telmisartan is The dosage is approximately 16 mg to 24 mg, and the indapamide dosage is approximately 1 mg to 1.5 mg. The dosage of amlodipine besylate is approximately 2 mg to 3 mg. In some embodiments, The dosage of telmisartan is approximately 20 mg, and the dosage of indapamide is approximately 1.25 mg. The amount is g, 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) is provided in one formulation. In some embodiments, (a), (b), (a) and (c) are each provided in separate formulations. In some embodiments, (a) Two of (b), and (c) are provided in a single formulation. Several embodiments In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. Therefore, it is suitable for oral administration of the pharmaceutical composition.

[0015] This specification also includes a step of administering any one of the pharmaceutical compositions disclosed herein. A method for treating hypertension in subjects requiring treatment is provided. In some embodiments, The treatment results in a systolic blood pressure (SBP) of less than approximately 140 mmHg. In this embodiment, the treatment results in a reduction of systolic blood pressure (SBP) of approximately 10 mmHg or more. This results in a diastolic blood pressure of less than approximately 90 mmHg. In some embodiments, the treatment brings about a diastolic blood pressure of less than approximately 90 mmHg. (DBP) results in a result. In some embodiments, the treatment is performed to reduce blood pressure to approximately 5 mmHg. This results in a decrease in the diastolic blood pressure (DBP). In some embodiments, The setting is a complete minimum hypertension in any one of (a), (b), and (c) in a pharmaceutical composition. This results in a greater reduction in systolic blood pressure (SBP) than would be achieved with symptomatic treatment. In some embodiments, the treatment is (a), (b), and (c) in the pharmaceutical composition. A reduction in diastolic blood pressure () greater than the reduction obtained with any one of the minimum effective doses for treating hypertension. This results in a reduction of DBP. In some embodiments, the treatment is performed on the pharmaceutical composition Treatment in any one of the following cases: (a), (b), and (c) with the minimum effective dose for treating hypertension. Compared to other methods, this results in greater long-term tolerance and a reduced risk of side effects. In some embodiments, the treatment is an initial or primary treatment for hypertension. Morphologically, the subjects did not receive the aforementioned treatment for hypertension prior to the procedure.

[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 (a), (b), and (c) This is approximately 40% to 80% of the minimum hypertension treatment dose (LHTD) for each individual.

[0017] This specification provides a pharmaceutical composition in another embodiment, the pharmaceutical composition comprising (a) tel (b) Angiotensin II receptor blockers such as misartan; (b) Thiazide-like diuretics; and ( c) substantially consisting of calcium channel blockers, where (a), (b), and (c) Each dose of (a), (b), and (c) is the minimum hypertension treatment dose (L It is approximately 80% to 150% of HTD. In some embodiments, (a), (b), The respective doses of (a), (b), and (c) are the minimum doses for each of (a), (b), and (c). This is approximately 80% to 120% of the therapeutic dose (LHTD). In some embodiments, (a) The respective doses of (a), (b), and (c) are the most appropriate for each of (a), (b), and (c). This is approximately 90% to 110% of the dosage used for treating low hypertension (LHTD).

[0018] Embedding by citation All published applications, patents, and patent applications referred to herein are treated as if they were individual published applications. Specifically and individually instructed that patents or patent applications be incorporated by reference, respectively. It is incorporated herein by reference to the same extent as so. [Brief explanation of the drawing]

[0019] Novel features of this disclosure are described in particular in the appended claims. Features and advantages of this disclosure For a better understanding of this, see the illustrative embodiments and accompanying figures in which the principles of this disclosure are applied. This can be obtained by referring to the following detailed description of the surface: [Figure 1] This shows the average systolic blood pressure (mmHg) over a time period following the treatment. [Figure 2] This shows the average diastolic blood pressure (mmHg) over a time period following the treatment. [Figure 3] This shows the average heart rate over a time period following the treatment. [Modes for carrying out the invention]

[0020] This specification includes angiotensin II receptor blockers, diuretics, and calcium channels. A pharmaceutical composition for the treatment of hypertension, comprising an antiblocker, is provided. In several embodiments... Furthermore, the dosage of each component is below the minimum dosage approved for the treatment of hypertension. The disclosure acknowledges the technical efficacy of the low-dose combination therapies described herein, and this This includes, but is not limited to, low-intensity treatments aimed at avoiding or improving side effects while maintaining or improving benefits. Dosage, synergistic therapeutic effects of specific drug combinations, and combination therapies that improve therapeutic effects. This includes the initial introduction of [a specific term]. In one embodiment, this specification describes the initial or primary treatment of hypertension. A combination of low-dose compositions for the treatment of hypertension, including the treatment of [specific treatment], is described.

[0021] Specific terms As used herein and in the appended claims, the singular forms "a", "an", and "the" Unless otherwise specified in the context, "medicine" includes multiple referents. Therefore, for example, "drug" A reference to "agent" includes multiple such agents, while a reference to "composition" includes one or more sets. This includes references to products (or multiple compositions) and equivalents known to those skilled in the art, such as molecular weight. The scope of the physical properties or chemical properties such as chemical formulas used herein is as follows: The scope and specific combinations of embodiments within it, as well as subordinate combinations, all encompass. It is intended to be. The term "about" is used when referring to a number or range of numbers. "This means that the numerical value or range of values ​​mentioned is within the range of experimental variability (or within statistical experimental error) ) is an approximation of and therefore in some embodiments, the numerical value or numerical range is not described. This means that the value or range of the value fluctuates between 1% and 10%. The term "includes" comprising) (and, including (comprise) or including (comp "rises"), or "having" or "includes" Related terms such as "ding") are used in other specific embodiments, for example, as described herein. Any embodiment of a compound, composition, method, or process described herein is a characteristic of the " This is intended to exclude cases where something "consists of" or "substantially consists of" it. isn't it.

[0022] definition The following terms, as used in the specification and attached claims, unless otherwise specified to have the opposite meaning: The following meanings apply:

[0023] "Pharmacologically acceptable salt" as used herein refers to acid addition salts and base addition salts. Both are included. In some embodiments, any one of the compounds described herein is used as a drug. Scientifically acceptable salts are those approved for use by the U.S. Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described are pharmaceutically acceptable acid addition salts and It is a pharmaceutically acceptable base addition salt.

[0024] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effects and properties of a free base. Furthermore, this is not biologically or otherwise undesirable, and hydrochloric acid, hydrobromic acid Formed by inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. It is done. Aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydr Loxyalkanoic acid, alkanedioic acid, aromatic acid, aliphatic acid This also includes salts formed from organic acids such as aromatic sulfonic acids, 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, methanesulfone Examples include acids, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, Typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, and phosphorus. Acid salts, monohydrogen phosphates, dihydrogen phosphates Salts (dihydrogenphosphates), metaphosphates, pyrophosphates, salts Salts, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates Isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fuma Salts, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates Salt, dinitrobenzoates, phthalates, benzene Sulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malic acid Examples include salts, tartrates, and methanesulfonates. Similarly, alginates and glucons. Salts of amino acids, such as acid salts and galacturonic acid salts, are also intended (for example, as a whole). The following is incorporated herein by reference: “Berge S.M. et al., “Pharm aceutical salts,” Journal ofPharmaceutica See "Science, 66:1-19 (1997)". Acid addition salts of basic compounds The free base form is brought into contact with a sufficient amount of the desired acid, in accordance with methods and techniques familiar to those skilled in the art. It can be prepared by allowing it to produce a salt.

[0025] A "pharmaceutically acceptable base addition salt" is a salt that retains the biological effects and properties of a free acid. This refers to something that is not biologically or otherwise undesirable. These salts are inorganic salts. Prepared by adding a group or organic base to a free acid. Pharmaceutically acceptable base addition. Salts are formed by metals or amines, such as alkalis and alkaline earth metals or organic amines. This can also occur. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, and lynx. Thium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum This includes salts of um, etc. Salts derived from organic bases are, but are not limited to, primary, secondary, and tertiary. cyclic amines, substituted amines including naturally occurring substituted amines, cyclic amines and salts Ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, Triethylamine, tripropylamine, ethanolamine, diethanolamine, 2- Dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, Lysine, arginine, histidine, caffeine, procaine, N,N-dibenzyle Ethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, Ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobium Romine, purines, piperazines, piperidines, N-ethylpiperidines, polyamine resins, etc. Contains salts of . See Berge et al. above.

[0026] As used herein, “hydrate” contains stoichiometric or non-stoichiometric amounts of water. In some embodiments, the compound is formed during the crystallization process in water. Hydrates are compounds described herein that are approved for use by the U.S. Food and Drug Administration. This means that it contains any one of the hydrates.

[0027] As used herein, the term "acceptable" is used with respect to formulations, compositions, or components. This means that the treatment will not have any lasting adverse effects on the overall health of the subject receiving the treatment. It tastes good.

[0028] Terms used herein such as "administer" and "administer" "administering," "administration" These are used to enable the delivery of compounds or compositions to the desired site of biological action. This refers to possible methods. These methods include, but are not limited to, oral routes, intraduodenal routes, and non- Oral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or intravenous infusion), local administration, and This includes rectal administration. Those skilled in the art may use the compounds and methods described herein. They are proficient in administration techniques. In several embodiments, the compounds described herein and The composition is administered orally.

[0029] The terms "subject" or "patient" include mammals. Examples of mammals are not limited to those mentioned above. However, this includes members of the following mammalian classes: humans, chimpanzees, and other non-human spirits. Longnids and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; rabbits Pet animals such as dogs and cats; rodents such as rats, mice and guinea pigs. Includes experimental animals. In one embodiment, mammals are humans.

[0030] As used herein, “treatment” or “to treat” or “to alleviate” The terms "to improve" or "to improve" are used interchangeably herein. These terms are not limited to... However, it is not possible to obtain beneficial or desirable results, including therapeutic and / or preventive effects. It refers to the law. "Therapeutic effect" means the eradication or remission of the underlying disease being treated. The therapeutic effect is that the patient may still be affected by the underlying disease. To observe improvement, one or more physiological symptoms associated with the underlying disease are eliminated or remitted. This is achieved by the composition. Regarding the preventive effect, the composition is effective even without a diagnosis of the disease. Patients at risk of disease progression, or patients reporting one or more physiological symptoms of the disease. It may be administered to the person.

[0031] Triple Compositions This specification describes a pharmaceutical composition comprising (a) angiotensin II receptor (a) a pharmacotrope; (b) a diuretic; and (c) a calcium channel blocker; where (a The respective doses of (a), (b), and (c) are equal to the respective doses of (a), (b), and (c). This is approximately 40% to 80% of the minimum hypertension treatment dose (LHTD). In some embodiments, The respective dosages of (a), (b), and (c) are as follows: This is approximately 40% to 60% of the minimum therapeutic dose for hypertension (LHTD). Several implementations In this state, the respective doses of (a), (b), and (c) are (a), (b), and (c This is approximately 50% of the minimum hypertension treatment dose (LHTD) for each of the following embodiments. In this case, the respective doses of (a), (b), and (c) are (a), (b), and (c) This is approximately 60% to 80% of the minimum hypertension treatment dose (LHTD) for each of the following: In the embodiment, the respective doses of (a), (b), and (c) are (a), (b), and This is approximately 66% of the minimum hypertension treatment dose (LHTD) for each of (c).

[0032] In some embodiments, the pharmaceutical composition contains an active ingredient that lowers blood pressure. This combination includes, where the active ingredient that lowers blood pressure is angiotensin II receptor It consists of a blocker, a diuretic, and a calcium channel blocker.

[0033] In another embodiment, a pharmaceutical composition is described, the pharmaceutical composition comprising (a) telmisartan Which angiotensin II receptor blockers; (b) thiazide-like diuretics; and (c) calcium The drug contains a mucochannel blocker; where the respective doses of (a), (b), and (c) are (a Approximately 80% of the minimum hypertension treatment dose (LHTD) for each of (b), (c), and (c) It is 150%. In some embodiments, the respective doses of (a), (b), and (c) The amount is approximately the minimum therapeutic dose for hypertension (LHTD) for each of (a), (b), and (c). It is 80% to approximately 120%. In some embodiments, (a), (b), and (c) Each dose is the minimum therapeutic dose for hypertension (LH) for each of (a), (b), and (c). It is approximately 90% to 110% of TD. In some embodiments, (a), (b), and The respective dosages of (a), (b), and (c) are the minimum therapeutic doses for hypertension for each of (a), (b), and (c). This is approximately 95% to 105% of the therapeutic dose (LHTD). In some embodiments, (a), The respective doses of (b) and (c) are the minimum doses of (a), (b), and (c) respectively. This is approximately 100% of the long-acting hypertension (LHTD) treatment dose.

[0034] In some embodiments, the pharmaceutical compositions disclosed herein modify angiotensin Essentially free of ACE inhibitors or their pharmaceutically acceptable salts. In that embodiment, the angiotensin-converting enzyme inhibitor is, but is not limited to, benazep Lil, Captopril, Enalapril, Fosinopril, Lysinopril, Moexipril, Perindopril, quinapril, ramipril, trandolapril, or their pharmacy Contains acceptable salts or hydrates.

[0035] This specification also describes pharmaceutical compositions, which include (a) angiotensin I (b) a receptor blocker; (c) a diuretic; and (c) a calcium channel blocker. Here, the respective doses of (a), (b), and (c) are (a), (b), and (c) This is approximately 40% to 80% of the minimum hypertension treatment dose (LHTD) for each of the following: In the embodiment, the respective doses of (a), (b), and (c) are (a), (b), and This is approximately 40% to 60% of the minimum hypertension treatment dose (LHTD) for each of (c). In some embodiments, the respective doses of (a), (b), and (c) are (a), ( b) and (c) are approximately 50% of the minimum hypertension treatment dose (LHTD) for each of these. In several embodiments, the respective doses of (a), (b), and (c) are (a), (b (c) and (c) are approximately 60% to 80% of the minimum therapeutic dose for hypertension (LHTD). Yes. In some embodiments, the respective doses of (a), (b), and (c) are (a (b) (c) is approximately 66% of the minimum hypertension treatment dose (LHTD) for each of the above. ru.

[0036] This specification also describes pharmaceutical compositions, which include (a) telmisartan, etc. (b) angiotensin II receptor blockers; (c) thiazide-like diuretics; and calcium It consists substantially of channel blockers; where the respective doses of (a), (b), and (c) This is approximately 8% of the minimum hypertension treatment dose (LHTD) for each of (a), (b), and (c). It ranges from 0% to approximately 150%. In some embodiments, each of (a), (b), and (c) The dosages are the minimum therapeutic dose for hypertension (LHT) for each of (a), (b), and (c). It is approximately 80% to 120% of D). In some embodiments, (a), (b), and Each dose of (c) is the minimum hypertension treatment for each of (a), (b), and (c). This is approximately 90% to 110% of the amount (LHTD). In some embodiments, (a), ( The respective doses of (a), (b), and (c) are the lowest doses for each of (a), (b), and (c). This is approximately 95% to 105% of the long-acting hypertension (LHTD) dose. In some embodiments, The respective doses of (a), (b), and (c) are as follows: This is approximately 100% of the minimum hypertension treatment dose (LHTD).

[0037] In some embodiments, the pharmaceutical compositions disclosed herein cause a moderate increase in blood pressure. A significant reduction in blood pressure is achieved in the subjects. In some embodiments, the following is described herein. The pharmaceutical composition shown achieves a significant reduction in blood pressure in subjects with moderately elevated blood pressure. Side effects are minimal, slight, or nonexistent.

[0038] Beta-blockers In some embodiments, the pharmaceutical compositions disclosed herein are beta-blockers or their pharmaceuticals Essentially contains no salts that are generally acceptable. In some embodiments, beta-blockers affect the sympathetic nervous system. The system, on the adrenergic β receptor, endogenous catecholamine epinephrine (adre It inhibits the receptor sites for narin and norepinephrine (noradrenaline), It is a compound. In some embodiments, the β-blocker is, but is not limited to, β-adrenaline. Blockers, β-antagonists, β-adrenergic antagonists, β-adrenergic receptor antagonists This includes a tagonist or a β-adrenergic receptor blocker. In some embodiments, the β-blocker is used. Drug withdrawal inhibits the activation of all types of β-adrenergic receptors. In some embodiments... In other words, beta-blockers inhibit both beta-adrenergic receptors and alpha-adrenergic receptors. In some embodiments, the beta-blocker is selective for one of the following beta-receptors. β1, β2, and β3 receptors.

[0039] In some embodiments, beta-blockers are non-selective β-adrenergic receptor antagonists. It is a gonist. Examples of non-selective β-adrenergic receptor antagonists are limited. However, pindolol, propranolol, oxprenolol, sotalol, timol The formula includes carteolol, pemblotrol, and nadolol. In some embodiments, In other words, beta-blockers block the action of pairs of beta-adrenergic and alpha-adrenergic receptors. These are compounds that have a compounding relationship. Appropriate examples, but are not limited to, include carvedilol and busine. Includes dolol and labetalol. In some embodiments, the β-blocker is β1 selective. It is an adrenergic receptor antagonist. β1 selective adrenergic receptor antagonist. Examples of [the substance] include, but are not limited to, atenolol, bisoprolol, betaxolol, and methoprolol. Includes roll, seriprolol, esmolol, nebibolol, and acebutolol. In some embodiments, the β-blocker is a β2-selective adrenergic receptor such as butoxamine. He is an antagonist.

[0040] In some embodiments, the beta-blocker is acebutolol, atenolol, betaxolol L, bisoprolol, carteolol, esmolol, pembutrol, metoprolol Nadolol, Nebibolol, Pindolol, Sotalol, Propranolol, Carveggie Roll, Labetaroll, Timolol, Esmolol, Ceriproroll, Oxprenoroll Lu, Lebobunolol, Practol, Metipranolol, Landiolol, Bobindro Pronetol, Butoxamine, Bevantrol, Tertatrol, Arotinolol Levobetaxolol, Befnolol, Amosuralol, Chilisolol, or those It is a pharmaceutically acceptable salt or hydrate of . In some embodiments, the β-blocker is acetaminophen. Butrol, atenolol, betaxolol, bisoprolol, carteolol, esmo Roll, pemblotrol, metoprolol, nadolol, nebivolol, pindolol, Sotalol, propranolol, carvedilol, labetalol, or their pharmaceutical It is an acceptable salt or hydrate. In some embodiments, the β-blocker is acebutol L, atenolol, betaxolol, bisoprolol, ceriprolol, oxprenolol Metoprolol, Nadolol, Nebivolol, Pindolol, Propranolol, Carvedilol, labetalol, timolol, or pharmaceutically acceptable salts thereof It is a hydrate. In some embodiments, the β-blocker is atenolol. In terms of form, the beta-blocker is bisoprolol or a pharmaceutically acceptable salt.

[0041] Lipid-regulating drugs In some embodiments, the pharmaceutical compositions disclosed herein include lipid modifiers and platelets. It essentially does not contain functional modifiers, serum homocysteine ​​lowering agents, or combinations thereof.

[0042] In some embodiments, the pharmaceutical compositions disclosed herein essentially provide lipid modifiers. It is not included. In some embodiments, the lipid modifier is a 3-H2N2, also known as a statin. Droxy-3-methylglutarylcoenzyme A (HMGCoA) reductase inhibitor In some embodiments, the lipid modulating agent is atorvastatin, simvastatin, Cerivastatin, fluvastatin, or pravastatin. In some embodiments... The lipid-modulating agent is atorvastatin or simvastatin. In some embodiments, The lipid modulating agent is atorvastatin. In some embodiments, the lipid modulating agent is It's mvastatin.

[0043] Platelet function modifiers In some embodiments, the pharmaceutical compositions disclosed herein are platelet function modifiers. Essentially does not contain. In some embodiments, the platelet function modifier is aspirin, cyclamate. These are pidine, dipyridamole, and clopidogrel. In some embodiments, platelet machines The drug that modifies function is a glycoprotein IIb / IIIa receptor inhibitor, such as absiximab. In some embodiments, the platelet function modifier is a nonsteroidal anti-steroidal anti-inflammatory drug such as ibuprofen. It is an anti-inflammatory drug. In some embodiments, the platelet function modifier is aspirin, cyclamate. These are pidine, 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 are serum homocysteine It essentially does not contain a hypoglycemic agent. In some embodiments, the serum homocysteine-lowering agent is Folic acid, vitamin B6, or vitamin B12, or a combination thereof. In terms of administration, the serum homocysteine-lowering agent is folic acid.

[0045] Angiotensin II receptor blockers / blockers As used herein, angiotensin II receptor blockers or blockers (ARBs) ) is when angiotensin II binds to angiotensin II receptors in the muscles surrounding blood vessels. It is a compound that modulates the function of angiotensin II by preventing its synthesis. In several embodiments, the angiotensin II receptor blocker is losartan, valsal Tan, candesartan, eprosartan, irbesartan, telmisartan, or that These are pharmaceutically acceptable salts or hydrates of the same. In some embodiments, angioten The syn-II receptor blocker is losartan. In some embodiments, angiotensin An angiotensin II receptor blocker is valsartan. In some embodiments, angiotensin The γ-II receptor blocker is candesartan. In some embodiments, angioten The synth II receptor blocker is eprosartan. In some embodiments, angiotherapy is used. The erythrocyte II receptor blocker is irbesartan. In some embodiments, angio Telmisartan is a tensin II receptor blocker.

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

[0047] In some embodiments, the pharmaceutical compositions disclosed herein include thiazide diuretics. Includes. In some embodiments, the pharmaceutical compositions disclosed herein are thiazide-like diuretics. Contains a drug. In some embodiments, the pharmaceutical compositions disclosed herein are loop diuretics. Contains medicine. In some embodiments, the pharmaceutical compositions disclosed herein have osmotic properties. Contains urinary drugs. In some embodiments, the pharmaceutical compositions disclosed herein are carbonic anhydride. Contains enzyme inhibitors. In some embodiments, the pharmaceutical compositions disclosed herein are Contains a sulfate-retaining diuretic.

[0048] Thiazide diuretics As used herein, thiazide diuretics contain a benzothiadiazine molecular structure. This refers to compounds that are present. In some embodiments, thiazide diuretics result in Sodium and salts in the distal tubules of the kidneys result in increased urinary excretion of thorium and water. It inhibits the reabsorption of toxic substances. Examples of thiazide diuretics include, but are not limited to, artizide and benzide. Droflumesiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, Epitizide, hydrochlorothiazide, hydroflumethiazide, mebutizide, meticulothia The present invention includes zide, polythiazide, and trichlormethiazide. In some embodiments, Azide diuretics include artizide, bendroflumesiazide, chlorothiazide, and cyanomethiazide. Clopenthiazide, cyclothiazide, epithizide, hydrochlorothiazide, hydroflumethicone Thiazide, mebutizide, mecyclothiazide, polythiazide, trichlormethiazide, or These are pharmaceutically acceptable salts or hydrates. In some embodiments, thiadi Thiazide diuretics are artizides. In some embodiments, thiazide diuretics are bend It is roflumesiazide. In some embodiments, the thiazide diuretic is chloromethiazide. It is an iazide. 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, Thiazide diuretics include hydrochlorothiazide. In some embodiments, thiazide The thiazide diuretic is hydroflumethiazide. In some embodiments, thiazide diuretics are used. The drug is mebutizide. In some embodiments, the thiazide diuretic is meticlothiazide. It is. In some embodiments, the thiazide diuretic is a polythiazide. In this embodiment, the thiazide diuretic is trichlormethiazide.

[0049] Thiazide-like diuretics As used herein, thiazide-like diuretics have similar physiological properties to thiazide diuretics. It has certain properties, but does not have the chemical properties of a thiazide compound (i.e., benzothiazide compound). It is a sulfonamide diuretic (without a diazine core). An example of a thiazide-like diuretic is , but not limited to, kinesazone, clopamide, chlorthalidon, mephruside, clofenadine Mid, Metrazone, Meticran, Xypamide, Indapamide, Chlorexolone, and Fe Includes NKIZON.

[0050] In some embodiments, the thiazide-like diuretic is kinesazone, clopamide, chlorsa Lidon, Mephruside, Clofenamide, Methrazone, Meticran, Xypamide, Indapa Mid, chlorexolone, fenquizone, or pharmaceutically acceptable salts or hydrates thereof In some embodiments, the thiazide-like diuretic is kinesazone. In the application form, the thiazide-like diuretic is clopamide. In some embodiments, A azid-like diuretic is chlorthalidone. In some embodiments, thiazide-like diuretics It is mefluside. In some embodiments, the thiazide-like diuretic is clofenamide. Yes. In some embodiments, the thiazide-like diuretic is metrazone. Morphologically, thiazide-like diuretics include meticran. In some embodiments, thia The thiazide-like diuretic is xipamide. In some embodiments, the thiazide-like diuretic is in It is dapamide or its hydrate. In some embodiments, the thiazide-like diuretic is ind It is pamid. 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 sodium, chloride, and potassium To inhibit reabsorption, the thick ascending leg of the loop of Henle Compounds that act on the Na+ / K+ / 2Cl- cotransporter in the oop of Henle Yes. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, and ethacrine. Contains etozolin, muzolimin, ozolinone, pyretanide, thienilic acid, and torasemide. In some embodiments, the loop diuretic is furosemide, bumetanide, or ethacric acid. , etozolin, muzolimin, ozolinone, pyretanide, thienilic acid, torasemide, or These are pharmaceutically acceptable salts or hydrates.

[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. To increase flow. Examples include, but are not limited to, mannitol and glycerol. .

[0053] Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors are inhibitors of carbonic anhydrase, as used herein. It is a compound. In some embodiments, carbonic anhydrase inhibitors result in alkalinity. The excretion of bicarbonates, including the accompanying sodium, potassium, and water, leads to increased urine flow. Increases leakage. In some embodiments, carbonic anhydrase inhibitors are used with small amounts of sodium However, it does not reabsorb, and there is a greater loss of sodium, bicarbonate, and water in the urine. It inhibits the transport of bicarbonate from the proximal tubular flexure to the interstitium. Examples of such compounds This includes, but is not limited to, acetazolamide, dichlorphenamide, and metazolamides. .

[0054] potassium-sparing diuretics Potassium-sparing diuretics compete with aldosterone for intracellular cytoplasmic receptor sites. or, sodium channels, specifically epithelial tissue sodium channels (ENaC) It is a compound that directly blocks potassium. Examples of potassium-sparing diuretics are not limited to, but include amylose. Contains lysate, spironolactone, eplerenone, triamterene, and potassium canrenoate. .

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

[0056] In some embodiments, the diuretic is dichlorphenamide, amiloride, or pamabro. Mu, mannitol, acetazolamide, metazolamide, spironolactone, triamtele These are ions, or pharmaceutically acceptable salts or hydrates thereof. In some embodiments, The diuretic is dichlorphenamide. In some embodiments, the diuretic is amylose. In some embodiments, the diuretic is pamabrom. In some embodiments, the diuretic is mannitol. It is mid. In some embodiments, the diuretic is metazolamide. In terms of form, the diuretic is spironolactone. In some embodiments, the diuretic is It is triamterene.

[0057] Calcium channel blockers As used herein, calcium channel blockers are used to block calcium from vascular smooth muscle cells. This compound promotes vasodilatory activity by reducing sodium influx. Several implementations In terms of form, calcium channel blockers include amlodipine, nifedipine, and diltiazepam. Mu, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine n, clebidipine, dihydropyridine, relcanidipine, nitrendipine, cilnidipine Manidipine, mibefradil, bepridil, barnidipine, nilvadipine, garopamil, Lidoflazine, alanidipine, dotarizine, diproteverine, or any of the following pharmaceutically acceptable substances It is a tolerable salt or hydrate. In some embodiments, the calcium channel blocker is Amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine , felodipine, nicardipine, nisoldipine, crebidipine, or their pharmacy It is an acceptable salt or hydrate. In some embodiments, it is a calcium channel blocker. amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, The calcium channel blocker is amlodipine silate. In some embodiments, calcium The calcium channel blocker is nifedipine. In some embodiments, calcium channel blockers are used. The Nell-blocking agent is diltiazem. In some embodiments, calcium channel blockade is used. The drug is nimodipine. In some embodiments, the calcium channel blocker is verapa It is a mill. In some embodiments, the calcium channel blocker is isradipine. In some embodiments, the calcium channel blocker is felodipine. In one embodiment, the calcium channel blocker is nicardipine. In terms of form, the calcium channel blocker is nisoldipine. In some embodiments... And the calcium channel blocker is clebidipine.

[0058] Minimum dose for treating hypertension As used herein, the minimum therapeutic dose for hypertension (LHTD) is defined by the U.S. Food and Drug Administration. This refers to the lowest dose of a single drug approved for hypertension, as defined in this application. As of the application date, Orange Book database (http: / / www.acce "Cancelled" by ssdata.fda.gov / scripts / cder / ob / It is not marked to indicate that it is the minimum dose for treating hypertension. It does not include the lowest manufactured dosage for cases that are not the same as the manufactured dosage. Furthermore, it does not include the lowest hypertension. The treatment dose refers to cases where the minimum treatment dose for hypertension is not the same as the dose recommended by the physician. Furthermore, it does not contain the dosage recommended by a physician. Lowest level of hypertension with otensin II receptor blockers, diuretics, or calcium channel blockers. The dosage is the same as that of an angiotensin II receptor blocker approved for use by the U.S. Food and Drug Administration. This refers to the dosage in the form of diuretics or calcium channel blockers, which is free base, Contains pharmaceutically acceptable salts or hydrates.

[0059] In some embodiments, the dose of angiotensin II receptor blockers is the lowest possible dose for hypertension. This accounts for approximately 40% to 80% of the total amount used to treat hypertension. In some embodiments, angiotensin The dosage of II receptor blockers is approximately 40% to 70% of the minimum dose for treating hypertension. In this embodiment, the dose of the angiotensin II receptor blocker is the minimum dose for treating hypertension. This is approximately 40% to 60% of the total amount. In some embodiments, angiotensin II receptors The dosage of corticosteroids is approximately 40% to 50% of the minimum dose for treating hypertension. Several implementations In this state, the dosage of angiotensin II receptor blockers is approximately 4 times the minimum dose for treating hypertension. The percentage ranges from 5% to approximately 55%. In some embodiments, angiotensin II receptor blockers The dosage is approximately 50% to 80% of the minimum dose for treating hypertension. In some embodiments, Therefore, the dosage of angiotensin II receptor blockers is approximately 50% to approximately the minimum dose for treating hypertension. It is 70%. In some embodiments, the dosage of angiotensin II receptor blockers This is approximately 50% to 60% of the minimum dose for treating hypertension. In some embodiments, The dosage of geotensin II receptor blockers is approximately 60% to 80% of the minimum dose for treating hypertension. Yes. In some embodiments, the dose of angiotensin II receptor blocker is at least This accounts for approximately 60% to 70% of the total amount used to treat hypertension. In some embodiments, angioten The dosage of syn-II receptor blockers is approximately 70% to 80% of the minimum dose used to treat hypertension.

[0060] In some embodiments, the dose of angiotensin II receptor blockers is the lowest possible dose for hypertension. Approximately 40%, 41%, 42%, 43%, 44%, 45%, and 46% of the total amount of treatment for hypertension. Approximately 47%, 48%, 49%, 50%, 51%, 52%, 53%, and 54%. Approximately 55%, 56%, 57%, 58%, 59%, 60%, 61%, and 62%. Approximately 63%, 64%, 65%, 66%, 67%, 68%, 69%, and 70% Approximately 71%, 72%, 73%, 74%, 75%, 76%, 77%, and 78%. The percentage is approximately 79%, or approximately 80%. In some embodiments, angiotensin II receptor The dosage of antihypertensive agents was approximately 40%, 41%, 42%, and 43% of the minimum dose for treating hypertension. Approximately 44%, 45%, 46%, 47%, 48%, 49%, 50%, and 51%. Approximately 52%, 53%, 54%, 55%, 56%, 57%, 58%, and 59%. , or about 60%. In some embodiments, angiotensin II receptor blockers The dosage is approximately 45%, 46%, 47%, 48%, and 49% of the minimum dose for treating hypertension. These are approximately 50%, 51%, 52%, 53%, 54%, or 55%. In one embodiment, the dose of the angiotensin II receptor blocker is the minimum dose for treating hypertension. It is about 50% of the total. In some embodiments, the administration of angiotensin II receptor blockers The dosage is approximately 60%, 61%, 62%, 63%, 64%, and 60% of the minimum dose for treating hypertension. 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80% In some embodiments, the dosage of the angiotensin II receptor blocker is the most Approximately 61%, 62%, 63%, 64%, 65%, 66%, and 6% of the total amount of treatment for hypotension. These are 67%, approximately 68%, approximately 69%, approximately 70%, or approximately 71%. Therefore, the dosage of angiotensin II receptor blockers is approximately 66% of the minimum dose for treating hypertension. ru.

[0061] In some embodiments, the dose of diuretic is approximately 40% to approximately 8% of the minimum dose for treating hypertension. It is 0%. In some embodiments, the dose of the diuretic is about 4 times the minimum dose for treating hypertension. The percentage ranges from 0% to approximately 70%. In some embodiments, the dosage of the diuretic is the minimum effective dose for treating hypertension. This is approximately 40% to 60% of the therapeutic dose. In some embodiments, the diuretic dose is at least This accounts for approximately 40% to 50% of the total amount used to treat hypertension. In some embodiments, diuretics are administered. The amount is approximately 45% to 55% of the minimum dose for treating hypertension. In some embodiments, The dosage of urinary medication is approximately 50% to 80% of the minimum dose for treating hypertension. In some embodiments... In some cases, the dosage of diuretics is approximately 50% to 70% of the minimum dose for treating hypertension. In the embodiment, the dose of the diuretic is approximately 50% to 60% of the minimum dose for treating hypertension. In some embodiments, the dose of diuretic is about 60% to about 8% of the minimum dose for treating hypertension. It is 0%. In some embodiments, the dose of the diuretic is about 6 times the minimum dose for treating hypertension. The percentage ranges from 0% to approximately 70%. In some embodiments, the dosage of the diuretic is the minimum effective dose for treating hypertension. This is approximately 70% to 80% of the total therapeutic dose.

[0062] In some embodiments, the dose of the diuretic is about 40% of the minimum dose for treating hypertension, about 4 1%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 4 9%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 5 7%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 6 5%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 7 3%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80% Yes. In some embodiments, the dose of the diuretic is about 40% of the minimum dose for treating hypertension. Approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, Approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, The percentages are approximately 57%, 58%, 59%, or 60%. In some embodiments, diuretic. The drug dosage is approximately 45%, 46%, 47%, 48%, and 49% of the minimum dose for treating hypertension. %, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, or approximately 55%. In one embodiment, the dose of the diuretic is approximately 50% of the minimum dose for treating hypertension. In the embodiment, the dose of the diuretic is approximately 60%, approximately 61%, and approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately The percentage is 78%, approximately 79%, or approximately 80%. In some embodiments, the dosage of the diuretic is Approximately 61%, 62%, 63%, 64%, 65%, and 66% of the minimum hypertension treatment dose. These are approximately 67%, 68%, 69%, 70%, or 71%. In some embodiments, In this case, the dosage of diuretics is approximately 66% of the minimum dose for treating hypertension.

[0063] In some embodiments, the dose of thiazide diuretics is approximately 4 times the minimum dose for treating hypertension. It ranges from 0% to approximately 80%. In some embodiments, the dose of thiazide diuretics is at least This accounts for approximately 40% to 70% of the total amount used to treat hypertension. In some embodiments, thiazide diuretics are used. The dosage of urinary drugs is approximately 40% to 60% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of thiazide diuretics is approximately 40% to 50% of the minimum dose for treating hypertension. In some embodiments, the dose of thiazide diuretics is about 4 times the minimum dose for treating hypertension. It ranges from 5% to approximately 55%. In some embodiments, the dose of thiazide diuretics is at least This accounts for approximately 50% to 80% of the total amount used to treat hypertension. In some embodiments, thiazide diuretics are used. The dosage of urinary medication is approximately 50% to 70% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage 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 6 times the minimum dose for treating hypertension. It ranges from 0% to approximately 80%. In some embodiments, the dose of thiazide diuretics is at least This accounts for approximately 60% to 70% of the total amount used to treat hypertension. In some embodiments, thiazide diuretics are used. The dosage of urinary medication is approximately 70% to 80% of the minimum dose used to treat hypertension.

[0064] In some embodiments, the dose of thiazide diuretics is approximately 4 times the minimum dose for treating hypertension. 0%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 4 8%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 5 6%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64% %, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72% %, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately It is 80%. In some embodiments, the dose of thiazide diuretics is the minimum for hypertension. Approximately 40%, 41%, 42%, 43%, 44%, 45%, 46%, and 4 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately The percentages are 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, or approximately 60%. In terms of morphology, the dosage of thiazide diuretics is approximately 45% and 46% of the minimum dose for treating hypertension. Approximately 47%, 48%, 49%, 50%, 51%, 52%, 53%, and 54%. , or about 55%. In some embodiments, the dose of thiazide diuretics is at least This accounts for approximately 50% of the total amount used to treat hypertension. In some embodiments, thiazide diuretics are administered. The dosages were approximately 60%, 61%, 62%, 63%, 64%, and 6% of the minimum dose for treating hypertension. 5%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 7 3%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80% Yes. In some embodiments, the dose of thiazide diuretics is the minimum dose for treating hypertension. Approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, The percentages are approximately 69%, 70%, or 71%. In some embodiments, thiazide diuretics are used. The dosage of the medication is approximately 66% of the minimum dose used to treat hypertension.

[0065] In some embodiments, the dose of a thiazide-like diuretic is approximately 4 times the minimum dose for treating hypertension. The percentage ranges from 0% to approximately 80%. In some embodiments, the dose of thiazide-like diuretics is at least This accounts for approximately 40% to 70% of the total amount used to treat hypertension. In some embodiments, thiazide-like benefits are available. The dosage of urinary drugs is approximately 40% to 60% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of thiazide-like diuretics is approximately 40% to 50% of the minimum dose for treating hypertension. In some embodiments, the dose of the thiazide-like diuretic is about 4 times the minimum dose for treating hypertension. The percentage ranges from 5% to approximately 55%. In some embodiments, the dose of thiazide-like diuretics is at least This accounts for approximately 50% to 80% of the total amount used to treat hypertension. In some embodiments, thiazide-like benefits are available. The dosage of urinary medication is approximately 50% to 70% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage 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 about 6 times the minimum dose for treating hypertension. The percentage ranges from 0% to approximately 80%. In some embodiments, the dose of thiazide-like diuretics is at least This accounts for approximately 60% to 70% of the total amount used to treat hypertension. In some embodiments, thiazide-like benefits are available. The dosage of urinary medication is approximately 70% to 80% of the minimum dose used to treat hypertension.

[0066] In some embodiments, the dose of a thiazide-like diuretic is approximately 4 times the minimum dose for treating hypertension. 0%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 4 8%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 5 6%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64% %, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72% %, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately It is 80%. In some embodiments, the dose of thiazide-like diuretics is the minimum dose for hypertension. Approximately 40%, 41%, 42%, 43%, 44%, 45%, 46%, and 4 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately The percentages are 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, or approximately 60%. In terms of morphology, the dosage of thiazide-like diuretics is approximately 45% and 46% of the minimum dose for treating hypertension. Approximately 47%, 48%, 49%, 50%, 51%, 52%, 53%, and 54%. , or approximately 55%. In some embodiments, the dose of thiazide-like diuretics is at least This accounts for approximately 50% of the total amount used to treat hypertension. In some embodiments, thiazide-like diuretics are administered. The dosages were approximately 60%, 61%, 62%, 63%, 64%, and 6% of the minimum dose for treating hypertension. 5%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 7 3%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80% Yes. In some embodiments, the dose of a thiazide-like diuretic is the minimum dose for treating hypertension. Approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, The percentages are approximately 69%, 70%, or 71%. In some embodiments, thiazide-like diuretics are used. The dosage of the medication is approximately 66% of the minimum dose used to treat hypertension.

[0067] In some embodiments, the dose of loop diuretic is approximately 40% of the minimum dose for treating hypertension. ~Approximately 80%. In some embodiments, the dosage of loop diuretics is the minimum hypertension dose. This is approximately 40% to 70% of the therapeutic dose. In some embodiments, the dosage of loop diuretics This is approximately 40% to 60% of the minimum dose for treating hypertension. In some embodiments, The dosage of diuretics is approximately 40% to 50% of the minimum dose for treating hypertension. In this context, the dosage of loop diuretics is approximately 45% to 55% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is approximately 50% of the minimum dose for treating hypertension. ~Approximately 80%. In some embodiments, the dosage of loop diuretics is the minimum hypertension dose. This is approximately 50% to 70% of the therapeutic dose. In some embodiments, the dosage of loop diuretics This is approximately 50% to 60% of the minimum dose for treating hypertension. In some embodiments, The dosage of diuretics is approximately 60% to 80% of the minimum dose for treating hypertension. Several implementations In this context, the dosage of loop diuretics is approximately 60% to 70% of the minimum dose for treating hypertension. In some embodiments, the dose of loop diuretic is approximately 70% of the minimum dose for treating hypertension. It's approximately 80%.

[0068] In some embodiments, the dose of loop diuretic is approximately 40% of the minimum dose for treating hypertension. Approximately 41%, 42%, 43%, 44%, 45%, 46%, 47%, and 48%. Approximately 49%, 50%, 51%, 52%, 53%, 54%, 55%, and 56%. Approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, Approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, Approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80% It is %. In some embodiments, the dose of loop diuretic is the minimum dose for treating hypertension. Approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, Approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, These are approximately 56%, 57%, 58%, 59%, or 60%. In some embodiments... The dosage of loop diuretics was approximately 45%, 46%, and 47% of the minimum dose for treating hypertension. Approximately 48%, 49%, 50%, 51%, 52%, 53%, 54%, or 55% It is %. In some embodiments, the dose of loop diuretic is the minimum dose for treating hypertension. It is approximately 50%. In some embodiments, the dosage of loop diuretics is the minimum effective dose for hypertension. Approximately 60%, 61%, 62%, 63%, 64%, 65%, 66%, and 6% of the total amount of treatment. 7%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 7 These are 5%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80%. In this state, the dosage of loop diuretics is approximately 61%, 62%, and 6% of the minimum dose for treating hypertension. 3%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, or It is approximately 71%. In some embodiments, the dosage of loop diuretics is the minimum effective dose for hypertension. This accounts for approximately 66% of the total medical treatment.

[0069] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. This is approximately 40% to 80% of the amount. In some embodiments, calcium channel blockers The dosage is approximately 40% to 70% of the minimum dose for treating hypertension. In some embodiments, Therefore, the dosage of calcium channel blockers is approximately 40% to 60% of the minimum dose for treating hypertension. Yes. In some embodiments, the dosage of a calcium channel blocker is the minimum amount for hypertension. This is approximately 40% to 50% of the therapeutic dose. In some embodiments, calcium channel blockade is used. The dose for discontinuation is approximately 45% to 55% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of calcium channel blockers is approximately 50% to 80% of the minimum dose for treating hypertension. It is %. In some embodiments, the dose of a calcium channel blocker is the lowest possible dose for hypertension. This accounts for approximately 50% to 70% of the therapeutic dose for hypertension. In some embodiments, calcium channels The dosage of antihypertensive drugs is approximately 50% to 60% of the minimum dose used for treating hypertension. Several implementations In this condition, the dosage of calcium channel blockers is approximately 60% to approximately the minimum dose for treating hypertension. It is 80%. In some embodiments, the dose of the calcium channel blocker is at least This accounts for approximately 60% to 70% of the amount used to treat hypertension. In some embodiments, calcium The dosage of channel blockers is approximately 70% to 80% of the minimum dose used to treat hypertension.

[0070] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. Approximately 40%, 41%, 42%, 43%, 44%, 45%, 46%, and 47% of the amount. %, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55 %, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63% %, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71% %, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79% %, or about 80%. In some embodiments, the administration of a calcium channel blocker. The amounts were approximately 40%, 41%, 42%, 43%, 44%, and 4% of the minimum dose for treating hypertension. 5%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 5 3%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, or approximately 60% Yes. In some embodiments, the dosage of a calcium channel blocker is the minimum amount for hypertension. Approximately 45%, 46%, 47%, 48%, 49%, 50%, 51%, and 50% of the treatment amount. It is 52%, approximately 53%, approximately 54%, or approximately 55%. In some embodiments, calcium The dosage of um channel blockers is approximately 50% of the minimum dose for treating hypertension. Several implementations In this state, the dosage of calcium channel blockers is approximately 60% of the minimum dose for treating hypertension, 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%. In some embodiments, the dosage of the calcium channel blocker is about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, or about 71 %. In some embodiments, the dosage of the calcium channel blocker is about 66% of the minimum antihypertensive treatment dose.

[0071] In some embodiments, for the following compounds, the minimum antihypertensive treatment dose (LHTD) , and the corresponding recommended dosages and dosage ranges are as set forth in the following table: :

[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 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. In some embodiments, the dosage of irbesartan is about 3 7.5 mg, the dosage of hydrochlorothiazide is about 6.25 mg, and the dosage of amlodipine besylate is about 1.25 mg.

[0074] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Telmisartan as a thiazide diuretic; and (c) Contains amlodipine besylate as a calcium channel blocker. Several implementations In this state, the dosage of telmisartan is approximately 8 mg to 12 mg, and hydrochlorothia The dosage of Zid is approximately 5 mg to 7.5 mg, while the dosage of amlodipine besylate is approximately 1 mg. g is approximately 1.5 mg. In some embodiments, the dose of telmisartan is approximately 10 The dose of hydrochlorothiazide is approximately 6.25 mg, and amlodiamine besylate is also present. The dosage of the pin is approximately 1.25 mg.

[0075] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Irbesartan as a thiazide-like diuretic; (c) It contains amlodipine besylate as a lucium channel blocker. In some embodiments, The dosage of irbesartan is approximately 30 mg to 45 mg, and the dosage of indapamide is The dosage is approximately 0.5 mg to approximately 0.75 mg, and the dose of amlodipine besylate is approximately 1 mg to approximately 1 The dose is 0.5 mg. In some embodiments, the dose of irbesartan is approximately 37.5 mg. The dosage of indapamide is approximately 0.625 mg, and the administration of amlodipine besylate is... The amount is approximately 1.25 mg.

[0076] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Telmisartan as a thiazide-like diuretic; (c) C It contains amlodipine besylate as a lucium channel blocker. In some embodiments, The dosage of telmisartan is approximately 8 mg to 12 mg, and the dosage of indapamide is approximately The dosage ranges from 0.5 mg to approximately 0.75 mg, and the administration of amlodipine besylate is approximately 1 mg to approximately 1. It is 5 mg. In some embodiments, the dose of telmisartan is approximately 10 mg. The dosage of indapamide is approximately 0.625 mg, and the dosage of amlodipine besylate is approximately It is 1.25 mg.

[0077] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Telmisartan as a thiazide-like diuretic; (c) It contains amlodipine besylate as a calcium channel blocker. In some embodiments... The dosage of telmisartan is approximately 8 mg to 12 mg, and the dosage of chlorthalidone is The recommended dosage is approximately 10 mg to 15 mg, while the recommended dosage of amlodipine besylate is approximately 1 mg to 1.5 mg. The dose is mg. In some embodiments, the dose of telmisartan is approximately 10 mg. The dosage of chlorthalidone is approximately 12.5 mg, and the dosage of amlodipine besylate is approximately 1 It is 0.25 mg.

[0078] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Irbesartan as a thiazide-like diuretic; (c) It contains amlodipine besylate as a calcium channel blocker. In some embodiments... The dosage of irbesartan is approximately 30 mg to 45 mg, and the dosage of chlorthalidone is also used. The dosage is approximately 10 mg to 15 mg, and the administration of amlodipine besylate is approximately 1 mg to 1 mg. The dose is 5 mg. In some embodiments, the dose of irbesartan is approximately 37.5 mg. Yes, the dosage of chlorthalidone is about 12.5 mg, and the dosage of amlodipine besylate is about 1.25 mg.

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

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

[0081] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Irbesartan as a thiazide-like diuretic; (c) It contains amlodipine besylate as a lucium channel blocker. In some embodiments, The dosage of irbesartan is approximately 45 mg to 60 mg, and the dosage of indapamide is The dosage is approximately 0.75 mg to 1.0 mg, and the dose of amlodipine besylate is approximately 1.5 mg. The dose is approximately 2 mg. In some embodiments, the dose of irbesartan is approximately 49.5 mg. The dosage of indapamide is approximately 0.825 mg, and the administration of amlodipine besylate is... The amount is approximately 1.65 mg.

[0082] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Telmisartan as a thiazide-like diuretic; (c) C It contains amlodipine besylate as a lucium channel blocker. In some embodiments, The dosage of telmisartan is approximately 12 mg to 16 mg, and the dosage of indapamide is The dosage is approximately 0.75 mg to 1.0 mg, and the dose of amlodipine besylate is approximately 1.5 mg. The dose is approximately 2 mg. In some embodiments, the dose of telmisartan is approximately 13.2 mg. The dosage of indapamide is approximately 0.825 mg, and the administration of amlodipine besylate is... The amount is approximately 1.65 mg.

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

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

[0085] In some embodiments, angiotensin II receptor blockers such as telmisartan The dosage is approximately 80% to 150% of the minimum dose for treating hypertension. In some embodiments... Furthermore, the dosage of angiotensin II receptor blockers is approximately 80% of the minimum dose for treating hypertension. It is approximately 140%. In some embodiments, the administration of angiotensin II receptor blockers The dosage is approximately 80% to 130% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin II receptor blockers is approximately 80% to 1% of the minimum dose for treating hypertension. It is 20%. In some embodiments, the dosage of angiotensin II receptor blockers This is approximately 80% to 110% of the minimum dose for treating hypertension.

[0086] In some embodiments, angiotensin II receptor blockers such as telmisartan The dosage is approximately 85% to 145% of the minimum dose for treating hypertension. In some embodiments... Furthermore, the dosage of angiotensin II receptor blockers is approximately 85% of the minimum dose for treating hypertension. It is approximately 135%. In some embodiments, the administration of angiotensin II receptor blockers The dosage is approximately 85% to 125% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin II receptor blockers is approximately 85% to 1% of the minimum dose for treating hypertension. It is 15%. In some embodiments, the dosage of angiotensin II receptor blockers This is approximately 85% to 105% of the minimum dose for treating hypertension.

[0087] In some embodiments, angiotensin II receptor blockers such as telmisartan The dosage is approximately 90% to 140% of the minimum dose for treating hypertension. In some embodiments... Furthermore, the dosage of angiotensin II receptor blockers is approximately 90% of the minimum dose for treating hypertension. It is approximately 130%. In some embodiments, the administration of angiotensin II receptor blockers The dosage is approximately 90% to 120% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin II receptor blockers is approximately 90% to 1% of the minimum dose for treating hypertension. It is 10%.

[0088] In some embodiments, angiotensin II receptor blockers such as telmisartan The dosage is approximately 95% to 135% of the minimum dose for treating hypertension. In some embodiments... Furthermore, the dosage of angiotensin II receptor blockers is approximately 95% of the minimum dose for treating hypertension. It is approximately 125%. In some embodiments, the administration of angiotensin II receptor blockers The dosage is approximately 95% to 115% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin II receptor blockers is approximately 95% to approximately 1% of the minimum dose for treating hypertension. It is 0.5%.

[0089] In some embodiments, the dose of angiotensin II receptor blockers is the lowest possible dose for hypertension. Approximately 80%, 81%, 82%, 83%, 84%, 85%, and 86% of the total amount used for treating hypertension. Approximately 87%, 88%, 89%, 90%, 91%, 92%, 93%, and 94% Approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 1 0.2%, 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 this embodiment, the dose of the angiotensin II receptor blocker is the minimum dose for treating hypertension. Approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, and 97% of the amount. %, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104% In percentages of 105%, 106%, 107%, 108%, 109%, or 110%. Yes. In some embodiments, the dose of angiotensin II receptor blocker is at least Approximately 95%, 96%, 97%, 98%, 99%, 100%, and 100% of the amount of hypertension treatment. It is 101%, approximately 102%, approximately 103%, approximately 104%, or approximately 105%. In terms of morphology, the dosage of angiotensin II receptor blockers is approximately the minimum dose for treating hypertension. It's 100%.

[0090] In some embodiments, the dose of a thiazide-like diuretic is approximately 8 times the minimum dose for treating hypertension. The range is 0% to approximately 150%. In some embodiments, the dosage of the thiazide-like diuretic is the most This is approximately 80% to 140% of the dosage used to treat hypotension. In some embodiments, thiazide The dosage of diuretics is approximately 80% to 130% of the minimum dose for treating hypertension. In terms of morphology, the dosage of thiazide-like diuretics is approximately 80% to 120% of the minimum dose for treating hypertension. It is %. In some embodiments, the dosage of thiazide-like diuretics is the minimum required for the treatment of hypertension. This is approximately 80% to 110% of the total amount.

[0091] In some embodiments, the dose of a thiazide-like diuretic is approximately 8 times the minimum dose for treating hypertension. The percentage ranges from 5% to approximately 145%. In some embodiments, the dosage of the thiazide-like diuretic is the most This is approximately 85% to 135% of the dosage used to treat hypotension. In some embodiments, thiazide The dosage of diuretics is approximately 85% to 125% of the minimum dose for treating hypertension. In terms of morphology, the dosage of thiazide-like diuretics is approximately 85% to 115% of the minimum dose for treating hypertension. It is %. In some embodiments, the dosage of thiazide-like diuretics is the minimum required for the treatment of hypertension. This is approximately 85% to 105% of the amount.

[0092] In some embodiments, the dose of a thiazide-like diuretic is approximately 9 times the minimum dose for treating hypertension. The range is 0% to approximately 140%. In some embodiments, the dosage of the thiazide-like diuretic is the most This is approximately 90% to 130% of the dosage used to treat hypotension. In some embodiments, thiazide The dosage of diuretics is approximately 90% to 120% of the minimum dose for treating hypertension. In terms of morphology, the dosage of thiazide-like diuretics is approximately 90% to 110% of the minimum dose for treating hypertension. It is a percentage.

[0093] In some embodiments, the dose of a thiazide-like diuretic is approximately 9 times the minimum dose for treating hypertension. It ranges from 5% to approximately 135%. In some embodiments, the dosage of the thiazide-like diuretic is the most This is approximately 95% to 125% of the dosage used to treat hypotension. In some embodiments, thiazide The dosage of diuretics is approximately 95% to 115% of the minimum dose for treating hypertension. In terms of morphology, the dosage of thiazide-like diuretics is approximately 95% to 105% of the minimum dose for treating hypertension. It is a percentage.

[0094] In some embodiments, the dose of a thiazide-like diuretic is approximately 8 times the minimum dose for treating hypertension. 0%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 8 8%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 9 6%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103% %, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 1 10%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, It is approximately 117%, approximately 118%, approximately 119%, or approximately 120%. Therefore, the dosage of thiazide-like diuretics was approximately 90%, 91%, and 92% of the minimum dose for treating hypertension. Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. %, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 1 These are approximately 0.7%, 10.8%, 10.9%, or 11.0%. In some embodiments, The dosage of thiazide-like diuretics was approximately 95%, 96%, 97%, and 97% of the minimum dose for treating hypertension. 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, or It is approximately 105%. In some embodiments, the dose of the thiazide-like diuretic is the minimum high This accounts for approximately 100% of the amount used to treat hypertension.

[0095] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. This is approximately 80% to 150% of the amount. In some embodiments, calcium channel blockade occurs. The drug dosage is approximately 80% to 140% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of calcium channel blockers is approximately 80% to 13% of the minimum dose for treating hypertension. It is 0%. In some embodiments, the dose of the calcium channel blocker is the lowest high This is approximately 80% to 120% of the dose used to treat hypertension. In some embodiments, calcium thrombocytopenia is used. The dosage of channel blockers is approximately 80% to 110% of the minimum dose used to treat hypertension.

[0096] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. This is approximately 85% to 145% of the amount. In some embodiments, calcium channel blockade is performed. The drug dosage is approximately 85% to 135% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of calcium channel blockers is approximately 85% to 12% of the minimum dose for treating hypertension. It is 5%. In some embodiments, the dose of the calcium channel blocker is the minimum high This is approximately 85% to 115% of the amount used to treat hypertension. In some embodiments, calcium The dosage of channel blockers is approximately 85% to 105% of the minimum dose used to treat hypertension.

[0097] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. This is approximately 90% to 140% of the amount. In some embodiments, calcium channel blockade occurs. The drug dosage is approximately 90% to 130% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of calcium channel blockers is approximately 90% to 12% of the minimum dose for treating hypertension. It is 0%. In some embodiments, the dose of the calcium channel blocker is the lowest high This represents approximately 90% to 110% of the total amount used to treat hypertension.

[0098] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. The amount is approximately 95% to 135%. In some embodiments, calcium channel blockade occurs. The drug dosage is approximately 95% to 125% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of calcium channel blockers is approximately 95% to 11% of the minimum dose for treating hypertension. It is 5%. In some embodiments, the dose of the calcium channel blocker is the minimum high This is approximately 95% to 105% of the amount used to treat hypertension.

[0099] In some embodiments, the dosage of a calcium channel blocker is the minimum required for the treatment of hypertension. Approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, and 87% of the amount. %, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95% %, approximately 96%, approximately 97%, approximately 98%, approximately 99%, 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 1 These are 16%, approximately 117%, approximately 118%, approximately 119%, or approximately 120%. In this state, the dosage of calcium channel blockers is approximately 90% of the minimum dose for treating hypertension, 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, It is approximately 106%, approximately 107%, approximately 108%, approximately 109%, or approximately 110%. In terms of administration, the dosage of calcium channel blockers is approximately 95% of the minimum dose for treating hypertension. Approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately It is 103%, approximately 104%, or approximately 105%. In some embodiments, calcium The dosage of channel blockers is approximately 100% of the minimum dose used to treat hypertension.

[0100] In some embodiments, the minimum therapeutic dose (LHTD) for the following compounds The corresponding recommended dosages and dosage ranges are as shown in the table below. ru:

[0101] [Table 2-1]

[0102] [Table 2-2]

[0103] In some embodiments, angiotensin II receptor blockers, diuretics, and calcium The dosage of any one of the um channel blockers is equivalent to that of an angiotensin II receptor blocker or diuretic. Approximately 80% of the minimum therapeutic dose (LHTD) for drugs or calcium channel blockers. It is replaced by approximately 250%. In some embodiments, it blocks the angiotensin II receptor. The dosage for discontinuing the medication is the minimum therapeutic dose for hypertension (LH) for angiotensin II receptor blockers. Approximately 80% to 250% of TD is replaced. In some embodiments, diuretics are administered. The amount replaced is approximately 80% to 250% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dosage of the calcium channel blocker is such that the calcium channel blocker It replaces channel blockers at approximately 80% to 250% of the minimum therapeutic dose (LHTD) for hypertension. In some embodiments, angiotensin II receptor blockers, diuretics, and The dosage of any one of the lucium channel blockers is equivalent to that of an angiotensin II receptor blocker. Approximately 8 times the minimum therapeutic dose (LHTD) for diuretics or calcium channel blockers. The substitution rate ranges from 0% to approximately 150%. In some embodiments, angiotensin II receptors are replaced. The dosage of angiotensin II receptor blockers is the minimum therapeutic dose for hypertension compared to angiotensin II receptor blockers. It replaces approximately 80% to 150% of LHTD. In some embodiments, angio The dosage of tensin II receptor blockers is the minimum dosage for angiotensin II receptor blockers. It replaces approximately 100% of the long hypertension treatment dose (LHTD). In some embodiments, The dosage of urinary medications is approximately 80% to 150% of the minimum therapeutic dose for hypertension (LHTD) for diuretics. It is replaced by a percentage. In some embodiments, the dose of the diuretic is the lowest high of the diuretic. It replaces approximately 100% of the long-hypertension-treating dose (LHTD). In some embodiments, The dosage of calcium channel blockers is the minimum treatment for hypertension compared to calcium channel blockers. It is replaced by approximately 80% to 150% of the amount (LHTD). In some embodiments, The dosage of calcium channel blockers is the minimum treatment for hypertension compared to calcium channel blockers. It is replaced by approximately 100% of the amount (LHTD). In some embodiments, angiotensin The dosage of any one of the following: ₂ receptor blockers, diuretics, and calcium channel blockers is: The most effective treatment for angiotensin II receptor blockers, diuretics, or calcium channel blockers. It replaces the low hypertension treatment dose (LHTD) at approximately 150% to 250%. Several implementations In this state, the dosage of angiotensin II receptor blockers is determined by the angiotensin II receptor It replaces the minimum therapeutic dose (LHTD) for body blockers at approximately 150% to 250%. In some embodiments, the dosage of an angiotensin II receptor blocker is... The minimum therapeutic dose (LHTD) for otensin II receptor blockers is set at approximately 200%. It is replaced. In some embodiments, the dosage of the diuretic is the minimum amount for hypertension with respect to the diuretic. It is replaced at approximately 150% to 250% of the therapeutic dose (LHTD). In some embodiments The dosage of diuretics should be set at approximately 200% of the minimum therapeutic dose for hypertension (LHTD) for diuretics. It is replaced. In some embodiments, the dosage of the calcium channel blocker is calcium Approximately 150% to 250% of the minimum therapeutic dose (LHTD) for mucochannel blockers. It is replaced. In some embodiments, the dosage of the calcium channel blocker is such that the calcium It replaces um-channel blockers at approximately 200% of the minimum therapeutic dose (LHTD) for hypertension. .

[0104] In some embodiments, angiotensin II receptor blockers, diuretics, and calcium Any two doses of um channel blockers are angiotensin II receptor blockers and diuretics. Approximately 80% of the minimum therapeutic dose (LHTD) for drugs or calcium channel blockers. It is replaced by approximately 250%. In some embodiments, it blocks the angiotensin II receptor. The dosage for discontinuing the medication is the minimum therapeutic dose for hypertension (LH) for angiotensin II receptor blockers. Approximately 80% to 250% of TD is replaced. In some embodiments, diuretics are administered. The amount replaced is approximately 80% to 250% of the minimum therapeutic dose (LHTD) for diuretics. In some embodiments, the dosage of the calcium channel blocker is such that the calcium channel blocker It replaces channel blockers at approximately 80% to 250% of the minimum therapeutic dose (LHTD) for hypertension. In some embodiments, angiotensin II receptor blockers, diuretics, and Any two doses of lucium channel blockers are angiotensin II receptor blockers. Approximately 8 times the minimum therapeutic dose (LHTD) for diuretics or calcium channel blockers. The substitution rate ranges from 0% to approximately 150%. In some embodiments, angiotensin II receptors are replaced. The dosage of angiotensin II receptor blockers is the minimum therapeutic dose for hypertension compared to angiotensin II receptor blockers. It replaces approximately 80% to 150% of LHTD. In some embodiments, angio The dosage of tensin II receptor blockers is the minimum dosage for angiotensin II receptor blockers. It replaces approximately 100% of the long hypertension treatment dose (LHTD). In some embodiments, The dosage of urinary medications is approximately 80% to 150% of the minimum therapeutic dose for hypertension (LHTD) for diuretics. It is replaced by a percentage. In some embodiments, the dose of the diuretic is the lowest high of the diuretic. It replaces approximately 100% of the long-hypertension-treating dose (LHTD). In some embodiments, The dosage of calcium channel blockers is the minimum treatment for hypertension compared to calcium channel blockers. It is replaced by approximately 80% to 150% of the amount (LHTD). In some embodiments, The dosage of calcium channel blockers is the minimum treatment for hypertension compared to calcium channel blockers. It is replaced by approximately 100% of the amount (LHTD). In some embodiments, angiotensin Any two of the following dosages of γ-II receptor blockers, diuretics, and calcium channel blockers: The most effective treatment for angiotensin II receptor blockers, diuretics, or calcium channel blockers. It replaces the low hypertension treatment dose (LHTD) at approximately 150% to 250%. Several implementations In this state, the dosage of angiotensin II receptor blockers is determined by the angiotensin II receptor It replaces the minimum therapeutic dose (LHTD) for body blockers at approximately 150% to 250%. In some embodiments, the dosage of an angiotensin II receptor blocker is... The minimum therapeutic dose (LHTD) for otensin II receptor blockers is set at approximately 200%. It is replaced. In some embodiments, the dosage of the diuretic is the minimum amount for hypertension with respect to the diuretic. It is replaced at approximately 150% to 250% of the therapeutic dose (LHTD). In some embodiments The dosage of diuretics should be set at approximately 200% of the minimum therapeutic dose for hypertension (LHTD) for diuretics. It is replaced. In some embodiments, the dosage of the calcium channel blocker is calcium Approximately 150% to 250% of the minimum therapeutic dose (LHTD) for mucochannel blockers. It is replaced. In some embodiments, the dosage of the calcium channel blocker is such that the calcium It replaces um-channel blockers at approximately 200% of the minimum therapeutic dose (LHTD) for hypertension. .

[0105] In some embodiments, angiotensin II receptor blockers, diuretics (e.g., thi The dosage of azide diuretics (or thiazide-like diuretics) and calcium channel blockers is as follows: Each of these independently involves angiotensin II receptor blockers, diuretics, or calcium channel blockers. It replaces antihypertensive drugs (LHTDs) at approximately 80% to 150% of the minimum therapeutic dose (LHTD) compared to antihypertensive drugs. In some embodiments, the dose of an angiotensin II receptor blocker is Approximately 80% to 15% of the minimum therapeutic dose (LHTD) for tensin II receptor blockers. It is replaced with 0%. In some embodiments, the diuretic dose is the minimum of the diuretic dose. It replaces approximately 80% to 150% of the hypertension treatment dose. In some embodiments, The dosage of calcium channel blockers is the minimum treatment for hypertension compared to calcium channel blockers. It is replaced by approximately 80% to 150% of the amount (LHTD). In some embodiments, The dosage of geotensin II receptor blockers, diuretics, and calcium channel blockers is Independently, angiotensin II receptor blockers, diuretics, or calcium channels It is replaced by antihypertensive drugs at approximately 80% to 120% of the minimum therapeutic dose (LHTD) for antihypertensive drugs. In some embodiments, the dosage of an angiotensin II receptor blocker is such that the angiotensin II receptor blocker is administered. Approximately 80% to 120% of the minimum therapeutic dose (LHTD) for methionine II receptor blockers. It is replaced by %. In some embodiments, an angiotensin II receptor blocker is administered. The amount is approximately the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. It is 100%. In some embodiments, the dose of the diuretic is the lowest high of the diuretic. It replaces approximately 80% to 120% of the blood pressure treatment dose. In some embodiments, diuretics The dosage is replaced by approximately 100% of the minimum antihypertensive dose for diuretics. In terms of administration methods, the dosage of the calcium channel blocker is relative to the calcium channel blocker. It is replaced at approximately 80% to 120% of the minimum therapeutic dose for hypertension (LHTD). In terms of administration methods, the dosage of the calcium channel blocker is relative to the calcium channel blocker. This is approximately 100% of the minimum therapeutic dose for hypertension (LHTD). In some embodiments, The dosage of angiotensin II receptor blockers, diuretics, and calcium channel blockers Each of these can be used independently: angiotensin II receptor blockers, diuretics, or calcium saturates. It replaces nel-blockers at approximately 90% to 110% of the minimum therapeutic dose (LHTD) for hypertension. In some embodiments, the dosage of an angiotensin II receptor blocker is... Approximately 90% to approximately 1% of the minimum therapeutic dose (LHTD) for otensin II receptor blockers It is replaced by 10%. In some embodiments, an angiotensin II receptor blocker The dosage is the minimum therapeutic dose (LHTD) for angiotensin II receptor blockers. It is approximately 100% of the diuretic dose. In some embodiments, the diuretic dose is the most effective relative to the diuretic. It replaces approximately 90% to 110% of the low hypertension treatment dose (LHTD). Several embodiments In this case, the dosage of diuretics was approximately 10 times the minimum therapeutic dose for hypertension (LHTD) for diuretics. It is replaced with 0%. In some embodiments, the dosage of the calcium channel blocker is Approximately 90% to 11% of the minimum therapeutic dose (LHTD) for calcium channel blockers It is replaced with 0%. In some embodiments, the dosage of the calcium channel blocker is This is approximately 100% of the minimum therapeutic dose (LHTD) for calcium channel blockers. .

[0106] In some embodiments, the pharmaceutical composition is (a) an angiotensin II receptor blocker (b) Telmisartan as a thiazide-like diuretic; (c) C It contains amlodipine besylate as a lucium channel blocker. In some embodiments, The dosage of telmisartan is approximately 16 mg to 30 mg, and the dosage of indapamide is The dosage ranges from approximately 1 mg to approximately 1.875 mg, and the administration of amlodipine besylate is approximately 2 mg to approximately 3 mg. It is 75 mg.

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

[0108] In some embodiments, the dose of telmisartan is approximately 18 mg to approximately 22 mg. The dosage of indapamide is approximately 1.125 mg to 1.375 mg, and amlo besylate is also used. The dosage of dipine is approximately 2.25 mg to 2.75 mg.

[0109] In some embodiments, the dose of telmisartan is approximately 20 mg, and indapam The dosage of [drug name] is approximately 1.25 mg, and the dosage of amlodipine besylate is approximately 2.5 mg. ru.

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

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

[0112] In some embodiments, the dose of telmisartan is approximately 18 mg to approximately 22 mg. The dosage of chlorthalidone is approximately 22.5 mg to 27.5 mg, and amlodiamine besylate is also used. The dosage of the pin is approximately 2.25 mg to 2.75 mg.

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

[0114] formulation In some embodiments, angiotensin II receptor blockers, diuretics, and calcium A um channel blocker is provided in one formulation. In some embodiments, Ggiotensin II receptor blockers, diuretics, and calcium channel blockers are each treated separately. Provided in a formulation of the angiotensin II receptor blocker. In some embodiments, angiotensin II receptor blocker Two of the following are provided in a single formulation: a drug-free agent, a diuretic, and a calcium channel blocker. In some embodiments, angiotensin II receptors and diuretics are used in a single formulation. Provided in several embodiments, angiotensin II receptor blockers and A calcium channel blocker is provided in one formulation. In several embodiments, Therefore, diuretics and calcium channel blockers are provided in a single formulation. In terms of administration, angiotensin II receptor blockers, diuretics, and calcium channels are used. The blocking agent is provided in one formulation. In some embodiments, the pharmaceutical composition is The form is a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is a pill. This is the form. In some embodiments, the pharmaceutical composition is in the form of a tablet. In terms of administration, the pharmaceutical composition is in the form of a capsule. In some embodiments, The drug composition is suitable for oral administration.

[0115] Other suitable formulations include, but are not limited to, rectal, topical, buccal, and parenteral (e.g., subcutaneous, intramuscular) formulations. This includes those suitable for internal, intradermal, or intravenous administration, rectal, vaginal, or aerosol administration, but The most appropriate form of administration in any given case is the degree and severity of the disease being treated. and the properties of the special compounds used. For example, the disclosed composition is a unit It may also be formulated as a dosage.

[0116] Typical pharmaceutical compositions are available in the form of pharmaceutical formulations, for example, in the form of solids, semi-solids, or liquids. It may be used, and this is an organic or inorganic substance suitable for external, intestinal, or parenteral use. When mixed with a carrier or excipient, it contains one or more of the disclosed compounds as an active ingredient. The active ingredient is present in various forms, such as tablets, pellets, capsules, suppositories, solutions, and emulsions. It is available in the form of a suspension and other forms suitable for use, usually with a non-toxic and pharmaceutically acceptable carrier. It may be synthesized. The active target compound exerts the desired effect on the disease process or state. It is contained in a sufficient amount of the pharmaceutical composition to exert its effect.

[0117] To prepare solid compositions such as tablets, the main active ingredient is the disclosed compound or To form a solid preliminary formulation composition containing a homogeneous mixture of non-toxic, pharmaceutically acceptable salts. For this purpose, pharmaceutical carriers, such as corn starch, lactose, sucrose, sorbitol, and lubricants, are used. Stone, stearic acid, magnesium stearate, dicalcium phosphate, or rubber, etc. The original tableting component and other pharmaceutical diluents, such as water, may be mixed. When a composition is referred to as homogeneous, it means that the composition is equally effective as tablets, pills, and capsules. This means that the active ingredient is uniformly dispersed throughout the composition so that it can be easily subdivided into different dosage forms. do.

[0118] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) In this case, the target composition is one or more such as sodium citrate or dicalcium phosphate. A pharmaceutically acceptable carrier and / or can be mixed with any of the following: (1) starch, ra Fillers or additives such as sucrose, glucose, mannitol, and / or silicate. (2) For example, carboxymethylcellulose, alginate, gelatin, polyvinyl (3) A binder such as lupyrolidone, sucrose, and / or acacia; (4) Glycerin, etc. Diluents; (4) Agar, calcium carbonate, potato or tapioca starch, alginic acid, (5) Disintegrants such as certain silicates and sodium carbonate; (6) Solution-releasing agents such as paraffin (6) Absorption-enhancing substances such as quaternary ammonium compounds; (7) For example, acetylalco (8) Wetting agents such as kaolin and glycerol monostearate; (8) Kaolin and bentonite adhesives Absorbent materials such as soil (bentonite clay); (9) Talc, calcium stearate Cium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Lubricants such as lium and mixtures thereof; and (10) colorants. Capsules, tablets, and In the case of pills, the composition may also include a buffering agent. Similar types of solid compositions are high in Similar to polyethylene glycol, an excipient such as lactose or lactose is used. It may be used as a filler in soft or hard-filled gelatin capsules.

[0119] Tablets may be manufactured by compression or molding, along with one or more auxiliary components as desired. The compressed tablets contain a binder (e.g., gelatin or hydroxypropyl methylcellulose) and a lubricant. inert diluents, preservatives, and disintegrants (e.g., sodium starch glycolate or crosslinking agents). Using sodium carboxymethylcellulose, surfactants, or dispersants It may be prepared. The molded tablets are moistened with an inert liquid diluent in a suitable machine. It may be produced by molding a mixture of the target composition. In some embodiments, Capsules are made by enclosing tablets in hard gelatin capsules (for example, overcapsules). Prepared by capsule formation. Tablets, dragees, capsules, pills, and granules, etc. Other solid dosage forms include enteric coatings and other coatings well known in the field of pharmaceutical formulation. The coating and shell may be optionally scored or prepared. .

[0120] In some embodiments, the pharmaceutical composition described herein contains angiotensin II Receptor blockers can be replaced by angiotensin-converting enzyme inhibitors (ACE inhibitors). Examples of appropriate angiotensin-converting enzyme inhibitors include, but are not limited to, benazepril, capsulphil. Topril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril Lil, quinapril, ramipril, trandolapril, or any of the pharmaceutically acceptable ones Contains salt or hydrate. In some embodiments, an angiotensin-converting enzyme inhibitor is administered. The dosage is approximately 80% to 150% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin-converting enzyme inhibitors is approximately 80% to 12% of the minimum dose for treating hypertension. It is 0%. In some embodiments, the dose of angiotensin-converting enzyme inhibitor is This is approximately 90% to 110% of the minimum dose for treating hypertension. In some embodiments, the angi The dosage of otensin-converting enzyme inhibitors is approximately 100% of the minimum dose for treating hypertension. In this embodiment, the dose of the angiotensin-converting enzyme inhibitor is the minimum dose for treating hypertension. This is approximately 40% to 80%. In some embodiments, angiotensin-converting enzyme inhibitors The dosage of the harmful drug is approximately 40% to 70% of the minimum dose for treating hypertension. In some embodiments... In this context, the dosage of angiotensin-converting enzyme inhibitors is approximately 40% of the minimum dose for treating hypertension. It is approximately 60%. In some embodiments, the dosage of angiotensin-converting enzyme inhibitors This is approximately 40% to 50% of the minimum dose for treating hypertension. In some embodiments, The dosage of geotensin-converting enzyme inhibitors is approximately 45% to 55% of the minimum dose for treating hypertension. In some embodiments, the dosage of angiotensin-converting enzyme inhibitors is the minimum amount required for hypertension. This accounts for approximately 50% to 80% of the amount used to treat hypertension. In some embodiments, angiotensin The dosage of converting enzyme inhibitors is approximately 50% to 70% of the minimum dose for treating hypertension. In one embodiment, the dose of angiotensin-converting enzyme inhibitor is the minimum dose for treating hypertension. The percentage is approximately 50% to 60%. In some embodiments, angiotensin-converting enzyme inhibition is used. The dosage of the drug is approximately 60% to 80% of the minimum dose for treating hypertension. In some embodiments... The dosage of angiotensin-converting enzyme inhibitors is approximately 60% to approximately the minimum dose for treating hypertension. It is 70%. In some embodiments, the dose of angiotensin-converting enzyme inhibitors This is approximately 70% to 80% of the minimum dose for treating hypertension. In some embodiments, The dosage of otensin-converting enzyme inhibitors is approximately 40%, 41%, and 4% of the minimum dose for treating hypertension. 2%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 5 0%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 5 8%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 6 6%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 7 It is 4%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, or approximately 80%. In that embodiment, the dose of the angiotensin-converting enzyme inhibitor is the minimum dose for treating hypertension. Approximately 40%, 41%, 42%, 43%, 44%, 45%, 46%, and 47% of the amount. %, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55 These are approximately 56%, 57%, 58%, 59%, or 60%. In this case, the dosage of angiotensin-converting enzyme inhibitors was approximately 45% of the minimum dose for treating hypertension. Approximately 46%, 47%, 48%, 49%, 50%, 51%, 52%, and 53% The percentage is approximately 54%, or approximately 55%. In some embodiments, angiotensin-converting yeast The dose of the hypertension inhibitor is approximately 50% of the minimum dose for treating hypertension. In some embodiments, The dosage of angiotensin-converting enzyme inhibitors is approximately 60% of the minimum dose for treating hypertension, approximately 61%. %, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69% %, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77% This is approximately 78%, 79%, or 80%. In some embodiments, angio The dosage of glycan-converting enzyme inhibitors is approximately 61%, 62%, and 63% of the minimum dose for treating hypertension. , approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, or approximately 7 It is 1%. In some embodiments, the dose of the angiotensin-converting enzyme inhibitor is This represents approximately 66% of the minimum amount of medication used to treat hypertension.

[0121] Treatment method The pharmaceutical compositions described herein are for treating hypertension in subjects requiring treatment. It is useful for the following: In some embodiments, the treatment is for systolic blood pressure less than about 140 mmHg. (SBP) results in this. In some embodiments, the procedure is performed at approximately 135 mmH This results in a systolic blood pressure (SBP) of less than g. In some embodiments, the treatment This results in a decrease in systolic blood pressure (SBP) of approximately 10 mmHg or more. In this embodiment, the procedure is performed when the systolic blood pressure (SBP) is approximately 10 mmHg to approximately 20 mmHg. This results in a reduction. In some embodiments, the treatment is performed from about 10 mmHg to about 3 This results in a reduction of systolic blood pressure (SBP) to 0 mmHg. In some embodiments... The treatment is performed at approximately 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, and approximately 14mmHg, approximately 15mmHg, approximately 16mmHg, approximately 17mmHg, approximately 18mmHg, approximately This results in a decrease in systolic blood pressure (SBP) of 19 mmHg, or approximately 20 mmHg. In some embodiments, the treatment is performed at approximately 10 mmHg, approximately 11 mmHg, and approximately 12 mmHg. g, approx. 13mmHg, approx. 14mmHg, approx. 15mmHg, approx. 16mmHg, approx. 17mmH g, approx. 18mmHg, approx. 19mmHg, approx. 20mmHg, approx. 21mmHg, approx. 22mmH g, approx. 23mmHg, approx. 24mmHg, approx. 25mmHg, approx. 26mmHg, approx. 27mmH A reduction in systolic blood pressure (SBP) of approximately 28 mmHg, 29 mmHg, or 30 mmHg. This results in a small increase. In some embodiments, the treatment expands the blood pressure to less than about 90 mmHg. This results in a tensile blood pressure (DBP). In some embodiments, the procedure is approximately 85 This results in a diastolic blood pressure (DBP) of less than mmHg in some embodiments. The treatment results in a reduction of approximately 5 mmHg or more in diastolic blood pressure (DBP). In that embodiment, the treatment involves adjusting the diastolic blood pressure (DBP) to approximately 5 mmHg to approximately 10 mmHg. This results in a reduction of approximately 5 mmHg to approximately 1 This results in a 5 mmHg reduction in diastolic blood pressure (DBP). In some embodiments... The treatment involves approximately 5mmHg, 6mmHg, 7mmHg, 8mmHg, and 9mmHg. This results in a decrease in diastolic blood pressure (DBP) of several grams, or approximately 10 mmHg. In this embodiment, the treatment is performed at approximately 5 mmHg, approximately 6 mmHg, approximately 7 mmHg, and approximately 8 mmHg. Approximately 9mmHg, approximately 10mmHg, approximately 11mmHg, approximately 12mmHg, approximately 13mmHg, This results in a reduction of approximately 14 mmHg or 15 mmHg in diastolic blood pressure (DBP). vinegar.

[0122] In some embodiments, the treatment involves angiotensin II receptors in a pharmaceutical composition. Complete minimal hypertension treatment with one of the following: a blocker, a diuretic, or a calcium channel blocker. This results in a greater reduction in systolic blood pressure (SBP) than the reduction achieved by the amount of medication. In several embodiments, the treatment involves blocking the angiotensin II receptor in the pharmaceutical composition. A reduction in systolic blood pressure (SBP) greater than the reduction achieved with the complete minimum dose of medication for treating hypertension. This results in a small amount. In some embodiments, the treatment is diuretic in the pharmaceutical composition. A reduction in systolic blood pressure (SBP) greater than the reduction achieved with the complete minimum dose of medication for treating hypertension. This results in a small amount. In some embodiments, the treatment is performed on the pharmaceutical composition. More than the reduction achieved with the complete minimum dose of sodium channel blockers for hypertension, systolic This results in a decrease in blood pressure (SBP).

[0123] In some embodiments, the treatment involves angiotensin II receptors in a pharmaceutical composition. Complete minimal hypertension treatment with one of the following: a blocker, a diuretic, or a calcium channel blocker. This results in a greater reduction in diastolic blood pressure (DBP) than the reduction achieved by the amount of medication. In several embodiments, the treatment involves blocking the angiotensin II receptor in the pharmaceutical composition. A reduction in diastolic blood pressure (DBP) greater than the reduction achieved with the complete minimum dose of medication for treating hypertension. This results in a small amount. In some embodiments, the treatment is diuretic in the pharmaceutical composition. A reduction in diastolic blood pressure (DBP) greater than the reduction achieved with the complete minimum dose of medication for treating hypertension. This results in a small amount. In some embodiments, the treatment is performed on the pharmaceutical composition. More diastolic reduction than that achieved with the complete minimum dose of sodium channel blockers for treating hypertension. This results in a decrease in blood pressure (DBP).

[0124] In some embodiments, the treatment involves angiotensin II receptors in a pharmaceutical composition. Complete minimal hypertension treatment with one of the following: a blocker, a diuretic, or a calcium channel blocker. Compared to treatment with a larger dose, this also results in greater long-term tolerance and a reduced risk of side effects. To add. In some embodiments, the treatment involves adding angiotensin II to the pharmaceutical composition. Compared to treatment with receptor blockers at the minimum effective dose for hypertension, it offers greater long-term tolerance and This results in a reduction in the risk of side effects. In some embodiments, the procedure is performed by a medical Compared to treatment with the complete minimum dose of diuretics in drug compositions for hypertension, more long This results in improved tolerance and reduced risk of side effects. In some embodiments, The treatment involves the complete minimum therapeutic dose of calcium channel blockers in pharmaceutical compositions for hypertension. Compared to other treatments, this results in greater long-term tolerance and a reduced risk of side effects. .

[0125] In some embodiments, the treatment involves angiotensin II receptors in a pharmaceutical composition. The reduction obtained by any two combination of blockers, diuretics, and calcium channel blockers If it is less than or equal to a small amount, it results in a decrease in systolic blood pressure (SBP), and here, angio The dosages for each of the following drugs are: This is approximately 50% of the minimum dose for treating hypertension. In some embodiments, the treatment is a pharmaceutical composition. Angiotensin II receptor blockers, diuretics, and calcium channel blockers in A reduction in diastolic blood pressure (DBP) greater than the reduction obtained by any combination of two of the above results in a positive outcome. This is brought about by angiotensin II receptor blockers, diuretics, and calcium The dosage of each channel blocker is approximately 50% of the minimum dose for treating hypertension. In terms of administration, the treatment involves an angiotensin II receptor blocker and a diuretic in the pharmaceutical composition. Compared to treatment with any two combinations of drugs and calcium channel blockers, This results in increased long-term tolerance and a reduced risk of side effects, and here, angiotherapy The dosages for each of the following drugs are: This is approximately 50% of the minimum dose required 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 slightly elevated before the procedure. In this case, the subject had not received the aforementioned treatment for hypertension before the procedure. In several embodiments The subject's blood pressure was very slightly elevated before the procedure, and the subject had the aforementioned hypertension before the procedure. I am not receiving medical treatment.

[0127] This disclosure relates to angiotensin II receptor blockers in the pharmaceutical compositions disclosed herein. In some embodiments, its use resulted in a significant decrease in blood pressure, or a slight increase in blood pressure between subjects. This includes a significant reduction in blood pressure, greater long-term tolerance, and a reduced risk of side effects. We recognize that beneficial therapeutic effects are not limited to these. Lipid modifiers, platelet function modifiers, serum homocysteine ​​lowering agents, or in the indicated pharmaceutical composition By removing those combinations, in some embodiments, a considerable reduction in blood pressure is achieved. Significant reduction in blood pressure among subjects with mildly elevated blood pressure, greater long-term tolerance, and side effects. Beneficial therapeutic effects are brought about, including but not limited to, a reduction in the risk of use. To recognize.

[0128] Furthermore, in several embodiments, each component is provided in a minimum therapeutic dose of approximately 40% for hypertension. Approximately 80% of these are angiotensin II receptor blockers, diuretics, and calcium saturates. The triple combination described herein, including a nel-blocker, is one in which each component is the minimum treatment for hypertension. Angiotensin II receptor blockers (such as losartan) and diuretics, which make up 100% of the therapeutic dose. (e.g., hydrochlorothiazide), and calcium channel blockers (e.g., amlodipine besylate) A significantly greater number of blood pressure (systolic blood pressure, diastolic blood pressure, or so) than the triple combination including ) It is recognized that this results in a decrease of both (and so on). In some embodiments, each component Angiotensin II receptor blockers, which account for approximately 40% to 60% of the minimum dose for treating hypertension. A triple combination as described herein, comprising a diuretic and a calcium channel blocker. This is because each component is 100% of the minimum therapeutic dose for hypertension, and it blocks angiotensin II receptors. Drugs (such as losartan), diuretics (such as hydrochlorothiazide), and calcium channels Significantly more blood pressure (concentration) than the triple combination including a blocking agent (amlodipine besylate). This results in a decrease in systolic blood pressure, diastolic blood pressure, or both.

[0129] Furthermore, in several embodiments, this specification describes how each component is used in a minimum therapeutic dose of approximately 80% to approximately 1 It contains 50% telmisartan, thiazide-like diuretics, and calcium channel blockers. The triple combination described in the specification is an angiotensin II receptor blocker. Losartan, thiazide diuretics (such as hydrochlorothiazide), and calcium channels Significantly more blood pressure than a triple combination including a blood-blocker (amlodipine besylate) It is recognized that this can result in a decrease in systolic blood pressure, diastolic blood pressure, or both. In several embodiments, each component is present in an amount of approximately 80% to 120% of the minimum therapeutic dose. The following are described herein, including rutan, thiazide-like diuretics, and calcium channel blockers. The triple combination involves losartan as an angiotensin II receptor blocker, thiadione Diuretics (such as hydrochlorothiazide) and calcium channel blockers (such as besylate) Significantly more blood pressure (systolic blood pressure, diastolic blood pressure) than the triple combination including mulodipine. It results in a decrease in pressure (or both). [Examples]

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

[0131] overview The purpose of this study is to identify angiotensin II receptor blockers, calcium channel blockers, and blood pressure in three different combinations of diuretics (thiazide diuretics or thiazide-like diuretics) The objective was to evaluate the relative effects on different drugs from the same class. The differences in the effects of combinations using these methods, and very low doses (i.e., minimum doses for treating hypertension) Different dosages, including 50% of LHTDs (doses below the approved and manufactured minimum dosage), The objective was to evaluate whether there were differences among combinations of drugs using the same dosage.

[0132] The specific combinations studied were as follows: • Combination 1: Telmisartan, amlodipine besylate, and indapamide, all at minimum levels. 50% of the long hypertension treatment dose (LHTD), or 4 / 4 of the usual maintenance dose recommended by the FDA. 1 (Telmisartan 10 mg, Amlodipine besylate 1.25 mg, and Indapamide 0 Equivalent to 0.625 mg; • Combination 2: Telmisartan, amlodipine, and indapamide, all for diastolic hypertension. 100% of the therapeutic dose (LHTD), or half of the usual maintenance dose recommended by the FDA. Lumisartan 20 mg, amlodipine besylate 2.5 mg, and indapamide 1.25 mg (equivalent to g); and • Combination 3: Losartan, amlodipine besylate, and hydrochlorothiazide, all 100% of the minimum hypertension treatment dose (LHTD), or the usual maintenance dose recommended by the FDA. Half (Losartan 25 mg, Amlodipine besylate 2.5 mg, and Hydrochloroth Equivalent to 12.5 mg of azide;

[0133] The study is most commonly conducted using spontaneously hypertensive rats (SHRs), i.e., in the study of hypertension. This was done in animal models (Pinto YM, Paul M, Ganten D .“Lessons from rat models of hypertension: from Goldblatt to genetic engineering”.Car See Diovascular Research. 39(1):77-88. Drug administration The dosage was determined from the Cmax and AUC values ​​of each of the six antihypertensive drugs based on published literature. The calculations were performed using relative scaling and data. Each animal was arranged in a Latin square. The patient was exposed to a single dose of the compound drug.

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

[0135] The following animals were used in the study: spontaneously hypertensive rats (SHR / NCrl). arles River Laboratories, Inc., Kingston, Ne. Rats were obtained from York. Their age at the start of treatment was approximately 12 weeks. (13 rats) Eight male rats were used for adaptation. Eight male rats were used in the study. The animals were cascaded. Identified by a card and tattoo.

[0136] Telemetry Embedding: DataSci for collecting blood pressure and heart rate data in animals. An ence International transmitter (HD-S10) was implanted. Postoperatively, At least until the 10th, the animals were not administered the drug.

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

[0138] Diet: Unless otherwise specified, Teklad GlobalDiet-Rodent Envigo RMS, Inc. 2014 was provided as appropriate. In some cases, health Where indicated by the condition, this diet was given to the animals in the form of a meal.

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

[0140] Impurities: Known impurities, in levels that interfere with this study, are present in the food, water, or bedding (applicable). (If possible) it did not exist.

[0141] Environment: Environmental control for the animal housing room was set up to maintain the following indoor conditions: 2 A temperature range of 0-26°C, relative humidity of 30-70%, and a 12-hour light / 12-hour dark cycle. Ikuru.

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

[0143] Environmental and food enrichment: Various cage enrichment devices for animals (that do not require statistical analysis) And they provided a rich diet.

[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] Medication procedure: For combinations 1, 2, and 3, each test combination formulation is newly administered on each day of administration. It was prepared by adding a portion (approximately 80%) of the vehicle to the test combination formulation, and the preparation was Mix until homogeneous. If a homogeneous suspension or solution is not obtained, use 1NNaOH and Add the vehicle / or 1N HCl to adjust the pH to 9+0.2. Add the remaining vehicle and stir. The mixture was mixed using a bar. The test combination formulations were continuously stirred at room temperature for approximately 30 minutes before administration. The test combination formulations were protected from light for minutes and throughout the entire administration. It was stored in a refrigerator set, stirred, and maintained at 2-8°C.

[0150] Medication Procedure: Regarding pre-administration, the test combination formulation should be administered at least 30 times before administration. The temperature was adjusted to approximately room temperature for several minutes. The animals were administered a volume of 10 mL / kg, and the actual dose was measured in units of 10 mL / kg. The product was based on recent body weight. The dose was administered using oral gastric tube feeding. The dose interval was: The medication was administered once daily on days 1, 8, 15, and 22. After administration, the remaining test combination formulations were administered. It was disposed of according to the standard processing procedure.

[0151] Telemetry collection: Animals should not be exposed to telemetry data collection without prior consent, and During this time, it was not interrupted or was handled skillfully. Such interruptions are not limited to, but include, For collecting telemetry data on changes in body temperature, bedding, swabbing, public health, or cardiovascular conditions. This includes anything that disturbs the important natural, tranquil environment.

[0152] Animal observation: Each rat was observed once a day, every morning. Any abnormal findings were recorded. We observed mortality, abnormalities, and signs of pain or distress. During unscheduled observation periods, We also paid attention to any unusual findings that were noticed.

[0153] Body weight: Body weight was measured at least once during the pre-administration phase and before each scheduled dose. Where appropriate, additional weight was recorded to monitor the animal's health. A transmitter was attached to the animal. Equipped with typical transmitters and leads, for dosage calculations, The balance was checked before the weight was collected.

[0154] Telemetry data acquisition: Raw arterial pressure signals are counted at a sampling rate of 500 Hz. The parameters derived at the pre-administration and administration stages were the same. Regarding data acquisition, all embedded telemetry devices are used for signal consistency and Furthermore, we verified that the telemetry signal was acceptable for analysis. Signal verification This consists of at least one telemetry record obtained from each rat being studied. Telemetry data was recorded continuously for approximately 24 hours. The telemetry data was examined. Then, we determined whether the rats were qualified for research. We saved the data in the research records and used this. The nominal 24-hour mean intermediate arterial pressure was calculated to support randomized animal selection. For staged data collection, continuous telemetry data should be collected at least 90 minutes before administration. Starting from there, data was collected during the administration phase, over a period of approximately 48 hours after administration.

[0155] Nominal medication time: Telemetry time points are single nominal medication times for all animals. Based on the calculation, the nominal administration time per day for each administration stage is calculated for each animal. The end of the first half of the administration for animals that were administered on the day recorded on the computer. Ta.

[0156] Telemetry data evaluation: heart rate (pulse / min), systolic blood pressure (mmHg), diastolic blood pressure Telemetry including mean arterial pressure (mmHg), and arterial pressure (mmHg). The parameters were analyzed and reported. Telemetry generated by Ponemah during the administration phase. The tree data was analyzed using a 1-minute sample. The data was processed using a 15-minute average. Provided for data analysis. The average data over 15 minutes was binned into the following analysis period: Further averaging was achieved by binning: • 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 is performed using all available data points, and the timing of measurements is not uniform. Weight was measured to reflect the results. The effectiveness of treatment was evaluated using the direct product autoregressive correlation structure (di rect product autoregressivecorrelation st Models combined with `structure` (SAS 9.4, SAS Institute, Calculated using the evaluated differences between treatments using Cary,NC), and within the individual over time. The repeated measurements are described below.

[0159] result The study began with eight animals; however, the telemetry transmitter did not work with 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 time periods following the treatment. Figure 2 shows, Figure 3 shows the average diastolic blood pressure (mmHg) over time periods following the treatment. This shows the average heart rate over a time period.

[0163] In this non-restrictive example, the result is that combination 1 is considerably larger than combination 3. This results in a decrease in systolic blood pressure, and combination 2 yields a significantly greater effect than combination 3 or 1. This demonstrated a decrease in systolic blood pressure. These differences were observed over a full 44-hour period. This continued over time. The result was that both combination 1 and combination 2 were better than combination 3. This demonstrated that it resulted in a considerably larger decrease in systolic blood pressure. These differences were observed to be This continued for a full 44-hour period. In the decrease of DPB, the three combinations Similar differences existed, and there was no difference in heart rate between these combinations.

[0164] In this non-limiting example, these results are for telmisartan and amlodipine besylate. , a combination of indapamide, losartan, amlodipine besylate, hydrochlorothia To demonstrate unexpected differences with zide combinations. Specifically, with equivalent or low doses In this context, the combination of telmisartan, amlodipine besylate, and indapamide is This is considerably better than the combination of sartan, amlodipine besylate, and hydrochlorothiazide. This resulted in a significant reduction in blood pressure. The dosage of amlodipine besylate was in combination 2 and 3. Since the results were the same, the results were as follows when provided in parallel with amlodipine besylate. Certain angiotensin II receptor blockers and certain diuretics (thiazide diuretics vs. thiazide diuretics) To demonstrate previously unknown differences in the effectiveness of diuretics (such as iodine-type diuretics).

[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. It is divided into two stages. During the first stage (4 weeks), participants are given a triple combination composition. Participants will be randomized (1:1) to receive either the treatment or a placebo. This will be followed by a 2-week period. A washout (placebo) is conducted, after which participants switch to the opposite group and undergo a different treatment for four weeks. Participants will be from the community, mainly from the West Sydney (Australia) community. It will be recruited through the general practice of tea.

[0166] participants Participants are eligible if they meet the following inclusion criteria: 1) Adults aged 18 or older, 2) Separate Office SBP > 140 mmHg and / or DBP > for two readings on the same day 90 mmHg; and baseline ambulatory SBP > 135 and / or DBP > 85; 3) Not receiving medical treatment for hypertension. Exclusion criteria include: triple combination. No clear contraindications for one or more component drugs in the compound composition; a reliable clinician However, they feel that changes in current treatments are putting patients at risk; severe or advanced hypertension; pregnancy Pregnancy; inability to provide informed consent; and expected pregnancy of less than 3 months A medical disease that affects the average life expectancy.

[0167] intervention For these studies, three components were used at 50% of the lowest therapeutic dose for hypertension (LHTD). A combination of different components, or a triple dose containing each component at 100% of the minimum therapeutic dose for hypertension (LHTD). Test one of the following combinations.

[0168] The study involved a triple combination of each component at 50% of the lowest hypertension treatment dose (LHTD). When testing, the test composition is as follows. The triple combination composition is specific It is a single encapsulated pill containing the following three ingredients in this amount: telmisartan 10 mg, Amlodipine besylate 1.25 mg and indapamide 0.625 mg. Placebo capsule. The tablets appeared identical, and in the triple combination composition, placebo tablets of the same weight as those tablets appeared. It includes.

[0169] The study involved a triple combination of each component at 100% of the lowest hypertension treatment dose (LHTD). When testing the combination, the test composition is as follows. The triple combination composition is special It is a single, enclosed pill containing the following three ingredients in a fixed amount: Telmisartan 20 mg 2.5 mg of amlodipine besylate and 1.25 mg of indapamide. Placebo capsule. The agents appear identically, and in the triple combination composition, placebo tablets of the same weight as them are present. It contains.

[0170] Participants received either a single pill, a triple combination composition, or a placebo throughout the trial. The medication is administered. The patient is instructed to take the tablets simultaneously every day, and to take them in the morning. It is encouraged, but the time of day (morning or evening) is up to the patient's preference.

[0171] All test reagents comply with TGA-cGMP (Therapeutic Goods Aust ralia-certificate of Good ManufacturingPr Prepared in a manufacturing facility licensed by ACTICE. Low strength where appropriate. The dosage was divided by half using a pill splitting device without crushing to achieve half the dosage of half the strength. Obtain the amount, weigh it, and ensure accuracy in halving the dosage. Then administer a low-intensity dose. The quantity is encapsulated using gelatin capsules (DBCaps-Capsugel). Store the capsules in a cool, dry place until dispensing, and monitor the temperature using a temperature logger. Ring it.

[0172] Treatment assignments will be blinded to both research staff and participants. In addition to the investigational drug, all Participants were expected to maintain a healthy lifestyle as recommended by guidelines for managing hypertension. Education on the options will be provided.

[0173] Randomization Computer-assisted randomized sequencing was created by statisticians, and the pharmaceutical packaging society... The data will be provided to the company. Research assistants, supplementary teams, and researchers will be blinded to this sequence. For each patient, i.e., the randomly assigned number of patients, the pill was administered in a three-stage study. Packaged in three child-safe packs. All packs are blindfolded for patients and research staff. They have the same appearance to ensure inspection. Next, the drug packs are arranged in the sequence. Prescribe.

[0174] Results and Data Collection The primary endpoint was the mean 2 over 4 weeks using ambulatory blood pressure monitoring (ABP). The 4-hour reduction in systolic blood pressure is the secondary endpoint, which includes: a. Average 24-hour diastolic blood pressure, and reductions in daytime and nighttime SBP and DBP over 4 weeks. b. Office SBP and DBP measured by a standardized automated blood measurement cuff. decrease c. 24-hour BP <135 / 85 mmHg and Office B <140 / 90 mmHg P is defined as the ratio of controlled blood pressure over 4 weeks. d. Adverse events and adverse events identified in advance by laboratory parameters: 3% above the upper limit of normal More than double, or double when the baseline level is known to have risen, Elevated aminase (ALT / AST); estimated, as assessed from serum creatinine. >20% decrease in glomerular filtration rate; sodium, potassium, and uric acid levels e. Evaluation of acceptability and tolerance

[0175] Patients receive four 24-hour ABP monitoring cycles - baseline (investigational drug discontinuation), 4 weeks (stage 1 drug), 6 weeks (placebo), and 10 weeks (stage 3 drug). Inconvenience To minimize this, patients are referred to the laboratory for ABP. The ABP unit is sent to the manufacturer. Calibration is performed at equal intervals by the laboratory according to standards. To minimize variability, tracking readings are used. This is repeated from the same collection center using the same brand of equipment. Participants are responsible for transportation costs and Participants will receive a refund of the face value, including parking fees. Research drugs and surveys will be provided to participants free of charge. The office BP is used with OMRON T9P (HEM-759-C1) at each visit. Record three times. Average the second and third readings for research analysis. In addition, 4 In weeks 1 and 10, patients undergo blood tests to assess biochemical side effects and clinically. Participants were asked to complete a questionnaire regarding side effects, and compliance was evaluated based on self-reporting and the number of pills taken. Worthy. Upon completing this questionnaire, patients will be blinded to their treatment assignments. It will remain as it is.

[0176] Drug acceptance and tolerance will also be evaluated at the end of the study. All adverse events will be recorded. In addition... Clinical adverse events likely associated with blood pressure lowering medications include: dizziness, visual disturbances, and loss of consciousness. Loss / collapse, chest pain / angina, shortness of breath, cough, wheeze, pediatric edema, rash, Ask about the itchiness in more detail.

[0177] The trial involved two core members with expertise in clinical medicine, testing, and statistics, and a simplified approach. The safety and management of the collected data are ensured. Ten patients were randomly selected to participate in the trial to assess safety. Once this is done, a meeting will be convened, and the research will be advised to continue.

[0178] Statistical considerations We planned a sample size of 50 patients and used 90% power (p=0.05). r) was obtained, and a 12 mmHg SBP difference was detected between the intervention and the control, and the patient with 12 mmHg Assuming standard deviation within individual differences, a 10% loss is taken into account for tracking purposes.

[0179] Statistical methods Statistical analysis is performed with the intention of addressing the underlying principles. All tests are two-sided and have a nominal alpha. The level is 5%. All statistical analyses are unadjusted for prognostic covariates. Using data on pill size (dosage) and dose lost over time, we analyze the patient's response to the investigational drug. I reported adherence to my medication.

[0180] Kenward and Roger's method (KenwardMG, Roger JH) .The use of baseline covariatesin crossove (r studies. Biostatistics 2010;11(1):1-17) Therefore, a linear mixed model was used to measure the change in blood pressure from baseline for each treatment period. Evaluate the effectiveness of the treatment. Baseline data collected at the beginning of each treatment period (week 0, week 6) To properly adjust to the level, this method results in all measurements (both periods) It uses baseline and tracking measurements between individuals, but accounts for the covariance between measurements. Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate dependent variable inanalysis of change from baseli ne in clinical trials? StatMed 2009;28(20) :2509-30). Period (1st / 2nd), type of measurement (baseline / final), and The linear contrast between variations, which represents the treatment received (placebo / triple combination composition), is shown as follows: An unbiased estimate of the effect of the triple combination composition on blood pressure changes compared to sebum was obtained. All available data is included in the model, and no data loss is attributed to the patient. If data is lost over a period of time, use the data from the validity period. A sensitivity analysis was performed including only patients for whom data was available from the period, and the effect of the treatment was modified. Check if it worked. Kenward and Ro are best suited for smaller sample sizes. There is also a method for adjusting the denominator degrees of freedom, as described by ger (2009) (KenwardMG, Roger). JH.An improved approximation to the precis ion of fixed effects from restricted maximum m likelihood.ComputationalStatistics & Da ta Analysis 2009;53(7):2583-95).

[0181] The trial for carryover is the main result that has order as an effect. We will use an unpaired t-test. We will examine the time effect by comparing the main results of period 1 with the main results of period 2 from the same patient. The test is performed using a paired t-test to compare the results. Sensitivity analysis is also performed using the same patient over different periods. A standard paired t-test was used to compare the primary endpoint between different treatments. The baseline levels for each period are ignored.

[0182] Continuous secondary values ​​at baseline (e.g., daytime / nighttime free-roaming SBP / DBP) The endpoints are similarly analyzed against the primary endpoint. The baseline for each period Analyze other continuous variables without in-values ​​using a paired t-test. The number and percentage of all adverse events... Report the stage. For sensitivity analysis, use complete cases (i.e., complete data for each measurement period). Then, we repeat the analysis.

[0183] Age (<=60 vs >60 years), gender, and BMI (<=30 vs <30 kg / m²) 2 ) A study on the interaction of therapeutic effects. Subgroup analysis will also be performed for each variation. The analysis 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 main objective of this study is to evaluate the effectiveness of triple combination therapy in a double-blind, randomized, controlled trial. Initiating treatment in patients with hypertension is in accordance with current guidelines and standard treatment Compared to starting with monotherapy, it more effectively lowers blood pressure and reduces side effects. The first objective is to investigate whether this method is safe and standard. The goal is to evaluate whether it reduces side effects compared to care.

[0185] research design This was a 12-week double-blind study involving 650 patients with grade 1 and 2 essential hypertension. This is a randomized controlled trial (1:1) of the eye. The subjects are current Australian patients with hypertension According to the idline, randomization is performed via a central computer-based randomization service. Initial treatment with a triple combination composition, or angiotensin receptor blockers (ARBs). Treatment is initiated with ), and calcium channel blockers (CCBs) are added as an option if necessary. This included the following: The primary endpoint was the standardized automated BP cuff over 12 weeks. The secondary endpoint is the reduction in the mean systolic blood pressure used. The secondary endpoint is control over 6 and 12 weeks. This includes the ratio to the measured blood pressure, ambulatory blood pressure (ABP) measurement, and tolerance / occurrence of adverse events. .

[0186] Eligibility Criteria The inclusion criteria are as follows: - Adults (≥18 years old) - Treatment naive, or not currently receiving treatment (i.e., not taken within the last 4 weeks), or one BP-lowering drug (Angioten) Syn-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers (Discontinued medication, taking aldosterone antagonists, alpha-blockers) - SBP 140-179 mmHg and / or in two separate cases of more than one week, documented separately. or DBP 90-109 mmHg -At least one of the measurements must be documented by the research staff, and the research itself The dynamic BP device OR monitors daytime average SBP ≥ 13 during 24-hour ambulatory BP monitoring. Recorded as 5 mmHg and / or DBP ≥ 85 mmHg -At least one of these measurements must be recent (within the last 12 weeks) of) -24-hour outpatient BP monitoring showed a daytime mean SBP ≥ 135 mmHg and / or DBP A blood glucose level of ≥85 mmHg is documented within 12 weeks of randomization.

[0187] The exclusion criteria are as follows: - Contraindications for telmisartan, amlodipine, or indapamide - Hypertension, e.g., renal artery stenosis; severe renal dysfunction (eGRF < 50), serum potassium Secondary causes of the rise in lumens (above the normal limit of the laboratory) evidence -Pregnant, breastfeeding, and / or potentially pregnant, and regarding the medical contraception of the study as a whole Women who do not use acceptable pharmacokinetics (pharmaceutical or barrier methods) - From the perspective of the research team / primary care physicians, the implementation of the study, including the evaluation of the results, Any accompanying illnesses, physical impairments, or mental conditions that may interfere - Participation in concurrent interventional medical studies or clinical trials. Observational natural studies that do not involve intervention. The patient in the / or epidemiological investigation is eligible. - The participant's trusted primary care provider or other trusted physician should discontinue the current monotherapy. We believe that replacing it would not be appropriate for the participants. - 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, three components were used at 50% of the lowest therapeutic dose for hypertension (LHTD). A combination of different components, or a triple dose containing each component at 100% of the minimum therapeutic dose for hypertension (LHTD). Test one of the following combinations.

[0189] The study found that a triple combination containing each component at 50% of the minimum therapeutic dose for hypertension (LHTD) When conducting the test, the test composition is as follows. Patients who meet the inclusion criteria are subject to the following: The following three components are artificially created: 1) Telmisartan 10 mg, Amlodipine besylate 1 1) A combination pill containing 0.25 mg of indapamide and 0.625 mg of indapamide; or 2) Telmisa Rutan 40mg

[0190] The study involved a triple combination of each component at 100% of the minimum therapeutic dose for hypertension (LHTD). When testing, the test composition is as follows. Patients who meet the inclusion criteria are as follows: Randomization will be performed on: 1) the following three components - telmisartan 20 mg, amlodipine besylate. 2) A combination pill containing 2.5 mg of indapamide and 1.25 mg of indapamide; or 2) Telmisal 40mg of tannin

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

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

[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, mean over 12 weeks Differences between groups in SBP and DBP at night d. Differences between groups in daytime, nighttime, and 24-hour BP load (NHFA Guide) In accordance with the management of hypertension2008, on normal days, (Percentage of area under the blood pressure curve above nighttime and 24-hour values) e. Percentage of cases where nighttime blood pressure does not decrease (nighttime BP is measured according to the NHFA Guide to management) According to the 2008 Eng. of Hypertension, more than the average daytime BP (both 10% lower), and the coefficient of variability of BP (O'Brien, E., G. Parathonbach) i,and G. Stergiou,Hypertension,2013.62(6) Differences between groups (pp. 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 (SBP < 140 mmHg and DBP < 90 mmHg) percentage in mHg 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. Possible related side effects (dizziness, visual impairment, loss / decreased consciousness, chest pain / narrowing) Psychosis, shortness of breath, cough, wheezing, ankle edema, rash, itching, gout, hyperkalemia (hyperkalemia) Differences between groups in rkalaemia, hypokalemia, hyponatremia, and other conditions. b. Average potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UAC Differences between groups in R (urinary albumin-creatinine ratio) and creatinine levels c. Differences between groups in participants who discontinued treatment.

[0194] statistical methods All statistical analyses of the research results will be performed according to the principle of comprehensive analysis. Systolic blood over 12 weeks. The main analysis of changes in pressure (SBP) included treatment group and baseline SBP as covariates. Perform the analysis using Analysis of Variance (ANCOVA). Analyze the sequential secondary outcome items in the same way. Additional analyses include treatment groups, visits, and visit interactions, as well as baseline measurements. Includes measurements at 6 and 12 weeks in the long-term model. Hmm. We model the correlation within patients using a general assessment equation. A similar method is used for linear Logarithmic-binomial regression is used instead of regression for two-variable endpoints (e.g., hypertension). Applies to the control group. Pre-defined parameters include baseline blood pressure, sex, age, and history of hypertension treatment. Subgroup analyses have also been conducted. Detailed analysis plans are developed before the analysis becomes blind.

[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, Here, the respective doses of (a), (b), and (c) are (a), (b), and (c) A pharmaceutical composition that is approximately 40% to 80% of the minimum therapeutic dose (LHTD) for each individual. .

[0202] Embodiment 2. The pharmaceutical composition comprises a combination of active ingredients that lower blood pressure. In addition, the active ingredients that lower blood pressure are angiotensin II receptor blockers and diuretics. The pharmaceutical composition according to Embodiment 1, comprising a calcium channel blocker.

[0203] Embodiment 3. The pharmaceutical composition is an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable thereof. A pharmaceutical composition according to Embodiment 1 or 2, which is essentially free of salts.

[0204] Embodiment 4. The pharmaceutical composition is essentially free of beta-blockers or pharmaceutically acceptable salts thereof. or the pharmaceutical composition according to any one of Embodiments 1 to 3.

[0205] Embodiment 5. The pharmaceutical composition is a lipid regulator, a platelet function modifier, and a serum homocysteine ​​reducer. Any one of Embodiments 1 to 4, which essentially does not contain drugs or combinations thereof. A pharmaceutical composition.

[0206] Embodiment 6. The pharmaceutical composition according to Embodiment 5, which essentially does not contain a lipid modifier. A finished product.

[0207] Embodiment 7. Lipid modulating agents include atorvastatin, simvastatin, cerivastatin, and flu The pharmaceutical composition according to Embodiment 6, wherein the composition is vastatin or pravastatin.

[0208] Embodiment 8. The lipid modulating agent is atorvastatin or simvastatin, Embodiment 6 or This is the pharmaceutical composition described in 7.

[0209] Embodiment 9. The pharmaceutical composition described in Embodiment 5, which essentially does not contain a platelet function modifier. Pharmaceutical composition.

[0210] Embodiment 10. The platelet function modifier is aspirin, ticlopidine, dipyridamole, chlorophenate. The pharmaceutical composition according to Embodiment 9, which is pyrogrel, absiximab, or ibuprofen. thing.

[0211] Embodiment 11. The platelet function modifier is aspirin, as described in Embodiment 9 or 10. A pharmaceutical composition.

[0212] Embodiment 12. A pharmaceutical composition that essentially does not contain a serum homocysteine-lowering agent. The pharmaceutical composition described in 5.

[0213] Embodiment 13. The serum homocysteine ​​lowering agent is folic acid, vitamin B6, vitamin B12, Alternatively, a combination thereof, as described in Embodiment 12.

[0214] Embodiment 14. The serum homocysteine-lowering agent is folic acid, as described in Embodiment 12 or 13. A pharmaceutical composition.

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

[0216] Embodiment 16. The thiazide diuretic is artizide, bendroflumesiazide, clo Rosiazide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide Zide, hydroflumethiazide, mebutizide, meticlothiazide, polythiazide, trichloro In Embodiment 15, lumethiazide, or a pharmaceutically acceptable salt or hydrate thereof, is used. The pharmaceutical composition described.

[0217] Embodiment 17. The thiazide diuretic is hydrochlorothiazide, as described in Embodiment 16. A pharmaceutical composition.

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

[0219] Embodiment 19. The thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, meph Lucid, Clofenamide, Metrazone, Meticran, Xypamide, Indapamide, Chloride Xolone, fenquizone, or pharmaceutically acceptable salts or hydrates thereof, implementation The pharmaceutical composition described in Form 18.

[0220] Embodiment 20. The thiazide-like diuretic is indapamide or its hydrate, Embodiment 19. The pharmaceutical composition described above.

[0221] Embodiment 21. The thiazide-like diuretic is indapamide, as described in Embodiment 20. A finished product.

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

[0223] Embodiment 23. The diuretic is a loop diuretic, as described in any one of Embodiments 1 to 14. A pharmaceutical composition.

[0224] Embodiment 24. Loop diuretics include furosemide, bumetanide, ethacrine, and etozolin. Muzolimin, ozolinone, pyretanide, thienilic acid, torasemide, or their pharmaceuticals The pharmaceutical composition according to Embodiment 23, which is a generally acceptable salt or hydrate.

[0225] Embodiment 25. The diuretic is dichlorfenamide, amiloride, pamabrom, mannitol Al, acetazolamide, metazolamide, spironolactone, triamterene, or so A pharmaceutically acceptable salt or hydrate of these is described in any one of Embodiments 1 to 14. A pharmaceutical composition.

[0226] Embodiment 26. The calcium channel blocker is amlodipine, nifedipine, dilthia Zem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldi Pin, clebidipine, dihydropyridine, relcanidipine, nitrendipine, cilnidipine Manidipine, Mibefradil, Bepridil, Barnidipine, Nilvadipine, Garopamil Lidoflazine, alanidipine, dotarizine, diproteverine, or their pharmacy A pharmaceutical composition according to any one of Embodiments 1 to 25, which is an acceptable salt or hydrate.

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

[0228] Embodiment 28. The calcium channel blocker is amlodipine besylate, Embodiment 2 The pharmaceutical composition described in 7.

[0229] Embodiment 29. The angiotensin II receptor blocker is irbesartan, telmisalta Valsartan, candesartan, eprosartan, olmesartan, azilsartan Embodiments 1 to 1000 are losartan, or pharmaceutically acceptable salts or hydrates thereof. A pharmaceutical composition as described in any one of the 28.

[0230] Embodiment 30. The angiotensin II receptor blocker is irbesartan, Embodiment The pharmaceutical composition described in 29.

[0231] Embodiment 31. The angiotensin II receptor blocker is telmisartan, Embodiment The pharmaceutical composition described in 29.

[0232] The respective dosages for Embodiment 32.(a), (b), and (c) are (a), (b), and (c) is approximately 40% to 60% of the minimum hypertension treatment dose (LHTD) for each of the above. A pharmaceutical composition according to any one of the application forms 1 to 31.

[0233] Embodiment 33. The urinary drug is a thiazide diuretic, and the dosage of the thiazide diuretic is thiazide This is approximately 50% of the minimum therapeutic dose (LHTD) for diuretics, as described in Embodiment 32. A listed pharmaceutical composition.

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

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

[0236] Embodiment 36. The thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 0 The pharmaceutical composition according to Embodiment 35, which is 0.625 mg.

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

[0238] Embodiment 38. The diuretic is a loop diuretic, and the dosage of the loop diuretic is The pharmaceutical combination described in Embodiment 32 is approximately 50% of the minimum hypertension treatment dose (LHTD). A finished product.

[0239] Embodiment 39. The dosage of the calcium channel blocker is Any of embodiments 32 to 38, which is approximately 50% of the minimum therapeutic dose for hypertension (LHTD). A pharmaceutical composition as described in one.

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

[0241] Embodiment 41. The dosage of the angiotensin II receptor blocker is Embodiment 32, which is approximately 50% of the minimum therapeutic dose (LHTD) for receptor blockers. A pharmaceutical composition as described in any one of the above (1) to (40).

[0242] Embodiment 42. The angiotensin II receptor blocker is irbesartan, and irbesa The pharmaceutical composition according to Embodiment 41, wherein the dose of rutan is approximately 37.5 mg.

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

[0244] Embodiment 44. The angiotensin II receptor blocker is irbesartan, and the diuretic is Hydrochlorothiazide is a calcium channel blocker, while amlodipine besylate is a calcium channel blocker. The pharmaceutical composition described in Embodiment 32.

[0245] Embodiment 45. The dosage of irbesartan is approximately 30 mg to approximately 45 mg, and hydrochloride The dosage of rothiazide is approximately 5 mg to 7.5 mg, and the dosage of amlodipine besylate is The pharmaceutical composition according to Embodiment 44, which is approximately 1 mg to approximately 1.5 mg.

[0246] Embodiment 46. The dose of irbesartan is approximately 37.5 mg, and hydrochlorothiaz The dosage of [drug name] is approximately 6.25 mg, and the dosage of amlodipine besylate is approximately 1.25 mg. A pharmaceutical composition according to one embodiment 45.

[0247] Embodiment 47. The angiotensin II receptor blocker is telmisartan, and the diuretic is Hydrochlorothiazide is a calcium channel blocker, while amlodipine besylate is a calcium channel blocker. The pharmaceutical composition described in Embodiment 32.

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

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

[0250] Embodiment 50. The angiotensin II receptor blocker is irbesartan, and the diuretic is Indapamide is used, and the calcium channel blocker is amlodipine besylate, in practice. The pharmaceutical composition described in Act 32.

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

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

[0253] Embodiment 53. The angiotensin II receptor blocker is telmisartan, and the diuretic is Indapamide is used, and the calcium channel blocker is amlodipine besylate, in practice. The pharmaceutical composition described in Act 32.

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

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

[0256] Embodiment 56. The angiotensin II receptor blocker is telmisartan, and the diuretic is Chlorthalidone is used, and the calcium channel blocker is amlodipine besylate. The pharmaceutical composition described in Form 32.

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

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

[0259] Embodiment 59. The angiotensin II receptor blocker is irbesartan, and the diuretic is Chlorthalidone is used, and the calcium channel blocker is amlodipine besylate. The pharmaceutical composition described in Form 32.

[0260] Embodiment 60. The dosage of irbesartan is approximately 30 mg to approximately 45 mg, and chlortari The dosage of Don is approximately 10mg to 15mg, and the dosage of amlodipine besylate is approximately 1mg. The pharmaceutical composition according to Embodiment 59, wherein the amount is approximately 1.5 mg (g).

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

[0262] The respective dosages for Embodiment 62.(a), (b), and (c) are (a), (b), and (c) is approximately 60% to 80% of the minimum hypertension treatment dose (LHTD) for each of the above. A pharmaceutical composition according to any one of the application forms 1 to 31.

[0263] Embodiment 63. The urinary drug is a thiazide diuretic, and the dosage of the thiazide diuretic is thiazide This is approximately 66% of the minimum therapeutic dose (LHTD) for diuretics, as described in Embodiment 62. A listed pharmaceutical composition.

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

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

[0266] Embodiment 66. The thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 0 The pharmaceutical composition according to Embodiment 65, wherein the amount is 0.825 mg.

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

[0268] Embodiment 68. The diuretic is a loop diuretic, and the dosage of the loop diuretic is The pharmaceutical compound described in Embodiment 62 is approximately 66% of the minimum hypertension treatment dose (LHTD). A finished product.

[0269] Embodiment 69. The dosage of the calcium channel blocker is Any of embodiments 62 to 68, which is approximately 66% of the minimum therapeutic dose for hypertension (LHTD). A pharmaceutical composition as described in one.

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

[0271] Embodiment 71. The dosage of the angiotensin II receptor blocker is Embodiment 62, which is approximately 66% of the minimum therapeutic dose (LHTD) for receptor blockers. A pharmaceutical composition as described in any one of the claims to 70.

[0272] Embodiment 72. The angiotensin II receptor blocker is irbesartan, and irbesa The pharmaceutical composition according to Embodiment 71, wherein the dose of rutan is approximately 49.5 mg.

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

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

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

[0276] Embodiment 76. The dose of irbesartan is approximately 49.5 mg, and hydrochlorothiaz The dosage of [drug name] is approximately 8.25 mg, and the dosage of amlodipine besylate is approximately 1.65 mg. A pharmaceutical composition according to one embodiment 75.

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

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

[0279] Embodiment 79. The dose of telmisartan is approximately 13.2 mg, and hydrochlorothiadione The dosage of [drug name] is approximately 8.25 mg, and the dosage of amlodipine besylate is approximately 1.65 mg. A pharmaceutical composition according to one embodiment 78.

[0280] Embodiment 80. The angiotensin II receptor blocker is irbesartan, and the diuretic is Indapamide is used, and the calcium channel blocker is amlodipine besylate, in practice. The pharmaceutical composition described in Form 62.

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

[0282] Embodiment 82. The dose of irbesartan was approximately 49.5 mg, and the dose of indapamide was administered. The quantity is approximately 0.825 mg, and the dose of amlodipine is approximately 1.65 mg, according to this embodiment. The pharmaceutical composition described in 81.

[0283] Embodiment 83. The angiotensin II receptor blocker is telmisartan, and the diuretic is Indapamide is used, and the calcium channel blocker is amlodipine besylate, in practice. The pharmaceutical composition described in Form 62.

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

[0285] Embodiment 85. The dose of telmisartan was approximately 13.2 mg, and the administration of indapamide was also performed. The amount is approximately 0.825 mg, and the dose of amlodipine besylate is approximately 1.65 mg. The pharmaceutical composition described in Embodiment 84.

[0286] Embodiment 86. The angiotensin II receptor blocker is telmisartan, and the diuretic is Chlorthalidone is used, and the calcium channel blocker is amlodipine besylate. The pharmaceutical composition described in Form 62.

[0287] Embodiment 87. The dosage of telmisartan is approximately 12 mg to approximately 16 mg, and chlortari The dosage of Don is approximately 15 mg to 20 mg, and the dosage of amlodipine besylate is approximately 1. The pharmaceutical composition according to Embodiment 86, wherein the amount is 5 mg to approximately 2 mg.

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

[0289] Embodiment 89. The angiotensin II receptor blocker is irbesartan, and the diuretic is Chlorthalidone is used, and the calcium channel blocker is amlodipine besylate. The pharmaceutical composition described in Form 62.

[0290] Embodiment 90. The dosage of irbesartan is approximately 45 mg to approximately 60 mg, and chlortari The dosage of Don is approximately 15 mg to 20 mg, and the dosage of amlodipine besylate is approximately 1. The pharmaceutical composition according to Embodiment 89, wherein the amount is 5 mg to approximately 2 mg.

[0291] Embodiment 91. The dose of irbesartan was approximately 49.5 mg, and the dose of chlorthalidone was The administered dose was approximately 16.5 mg, and the dose of amlodipine besylate was approximately 1.65 mg. The pharmaceutical composition described in Embodiment 90.

[0292] Embodiment 92. Angiotensin II receptor blocker, diuretic, and calcium channel The dosage of any one of the blocking agents is: angiotensin II receptor blockers, diuretics, or serotonin. Approximately 80% to 250% of the minimum therapeutic dose (LHTD) for sodium channel blockers A pharmaceutical composition according to any one of Embodiments 1 to 91, which is replaced by [the specified substance].

[0293] Embodiment 93. The dosage of the angiotensin II receptor blocker is It replaces receptor blockers at approximately 80% to 250% of the minimum therapeutic dose (LHTD) for hypertension. The pharmaceutical composition according to Embodiment 92.

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

[0295] Embodiment 95. The dosage of the calcium channel blocker is Embodiment 9, which replaces the minimum therapeutic dose for hypertension (LHTD) at approximately 80% to 250%. The pharmaceutical composition described in 2.

[0296] Embodiment 96. Angiotensin II receptor blocker, diuretic, and calcium channel The dosage of any one of the blocking agents is: angiotensin II receptor blockers, diuretics, or serotonin. Approximately 80% to 150% of the minimum therapeutic dose (LHTD) for sodium channel blockers A pharmaceutical composition according to any one of embodiments 92 to 95, which is replaced by [the specified component].

[0297] Embodiment 97. The dosage of the angiotensin II receptor blocker is It replaces receptor blockers at approximately 80% to 150% of the minimum therapeutic dose (LHTD) for hypertension. The pharmaceutical composition described in Embodiment 96.

[0298] Embodiment 98. The dosage of the angiotensin II receptor blocker is It replaces receptor blockers at approximately 100% of the minimum therapeutic dose for hypertension (LHTD). The pharmaceutical composition described in Form 97.

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

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

[0301] Embodiment 101. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In the embodiment, the drug is replaced by approximately 80% to 150% of the minimum hypertension treatment dose (LHTD). The pharmaceutical composition described in 96.

[0302] Embodiment 102. The dosage of the calcium channel blocker is determined by the calcium channel blocker. The corresponding dose is replaced by approximately 100% of the minimum hypertension treatment dose (LHTD), as described in Embodiment 101. A listed pharmaceutical composition.

[0303] Embodiment 103. Angiotensin II receptor blocker, diuretic, and calcium channel The dosage of any one of the angiotensin II receptor blockers is: an angiotensin II receptor blocker, a diuretic, or a cyanoacrylate. Approximately 150% to 25% of the minimum therapeutic dose (LHTD) for lucium channel blockers. A pharmaceutical composition according to any one of embodiments 92 to 95, which is replaced with 0%.

[0304] Embodiment 104. The dosage of the angiotensin II receptor blocker is The dosage for I receptor blockers is set at approximately 150% to 250% of the minimum therapeutic dose for hypertension (LHTD). The pharmaceutical composition described in Embodiment 103, which is replaced.

[0305] Embodiment 105. The dosage of the angiotensin II receptor blocker is It replaces I receptor blockers at approximately 200% of the minimum therapeutic dose (LHTD) for hypertension. The pharmaceutical composition described in application form 104.

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

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

[0308] Embodiment 108. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In practice, it is replaced by approximately 150% to 250% of the minimum hypertension treatment dose (LHTD). The pharmaceutical composition described in Form 103.

[0309] Embodiment 109. The dosage of the calcium channel blocker is determined by the calcium channel blocker. The equivalent is replaced with approximately 200% of the minimum hypertension treatment dose (LHTD), as described in Embodiment 108. A listed pharmaceutical composition.

[0310] Embodiment 110. Angiotensin II receptor blocker, diuretic, and calcium channel Any two doses of the angiotensin II receptor blockers may be an angiotensin II receptor blocker, a diuretic, or a cyanoacrylate drug. Approximately 80% to approximately 250% of the minimum therapeutic dose (LHTD) for lucium channel blockers. A pharmaceutical composition according to any one of Embodiments 1 to 91, which is substituted by %.

[0311] Embodiment 111. The dosage of the angiotensin II receptor blocker is Replaces I receptor blockers at approximately 80% to 250% of the minimum therapeutic dose (LHTD). The pharmaceutical composition described in Embodiment 110.

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

[0313] Embodiment 113. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In the embodiment, the drug is replaced by approximately 80% to 250% of the minimum hypertension treatment dose (LHTD). The pharmaceutical composition described in 110.

[0314] Embodiment 114. Angiotensin II receptor blocker, diuretic, and calcium channel Any two doses of the angiotensin II receptor blockers may be an angiotensin II receptor blocker, a diuretic, or a cyanoacrylate drug. Approximately 80% to 150% of the minimum therapeutic dose (LHTD) for lucium channel blockers. A pharmaceutical composition according to any one of embodiments 110 to 113, which is replaced by %.

[0315] Embodiment 115. The dosage of the angiotensin II receptor blocker is Replaces I receptor blockers at approximately 80% to 150% of the minimum therapeutic dose (LHTD). The pharmaceutical composition described in Embodiment 114.

[0316] Embodiment 116. The dosage of the angiotensin II receptor blocker is It replaces I receptor blockers at approximately 100% of the minimum therapeutic dose (LHTD) for hypertension. The pharmaceutical composition described in application form 115.

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

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

[0319] Embodiment 119. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In the embodiment, the drug is replaced by approximately 80% to 150% of the minimum hypertension treatment dose (LHTD). The pharmaceutical composition described in 114.

[0320] Embodiment 120. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In contrast, it is replaced with approximately 100% of the minimum hypertension treatment dose (LHTD), as described in Embodiment 119. A listed pharmaceutical composition.

[0321] Embodiment 121. Angiotensin II receptor blocker, diuretic, and calcium channel Any two doses of the angiotensin II receptor blockers may be an angiotensin II receptor blocker, a diuretic, or a cyanoacrylate drug. Approximately 150% to 25% of the minimum therapeutic dose (LHTD) for lucium channel blockers. A pharmaceutical composition according to any one of embodiments 110 to 113, which is replaced with 0%.

[0322] Embodiment 122. The dosage of the angiotensin II receptor blocker is The dosage for I receptor blockers is set at approximately 150% to 250% of the minimum therapeutic dose for hypertension (LHTD). The pharmaceutical composition described in Embodiment 121, which is replaced.

[0323] Embodiment 123. The dosage of the angiotensin II receptor blocker is It replaces I receptor blockers at approximately 200% of the minimum therapeutic dose (LHTD) for hypertension. The pharmaceutical composition described in application form 122.

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

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

[0326] Embodiment 126. The dosage of the calcium channel blocker is determined by the calcium channel blocker. In practice, it is replaced by approximately 150% to 250% of the minimum hypertension treatment dose (LHTD). The pharmaceutical composition described in Form 121.

[0327] Embodiment 127. The dosage of the calcium channel blocker is determined by the calcium channel blocker. The equivalent is replaced with approximately 200% of the minimum hypertension treatment dose (LHTD), as described in Embodiment 126. A listed pharmaceutical composition.

[0328] Embodiment 128: A pharmaceutical composition, (a) Telmisartan; (b) Thiazide diuretics; and (c) Calcium channel blockers Includes, Here, the respective doses of (a), (b), and (c) are (a), (b), and (c) The drug composition is approximately 80% to 150% of the minimum hypertension treatment dose (LHTD) for each individual. thing.

[0329] Embodiment 129: The pharmaceutical composition is an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable substance thereof. Acceptable salts, beta-blockers or pharmaceutically acceptable salts thereof, lipid regulators, platelet function modifiers, Embodiment 12, which essentially does not contain serum homocysteine ​​lowering agents or combinations thereof. The pharmaceutical composition described in 8.

[0330] Embodiment 130: The thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, me Fluside, clofenamide, metrazone, meticran, xypamide, indapamide, clo Lexolone, fenquizone, or their pharmaceutically acceptable salts or hydrates, The pharmaceutical composition described in application form 128 or 129.

[0331] Embodiment 131: The thiazide-like diuretic is indapamide or its hydrate, Embodiment 1 The pharmaceutical composition described in 30.

[0332] Embodiment 132: The thiazide-like diuretic is indapamide, as described in Embodiment 131. A pharmaceutical composition.

[0333] Embodiment 133: The calcium channel blocker is amlodipine, nifedipine, dilti Azem, nimodipine, verapamil, islazipine, felodipine, nicardipine, nisol Dipine, crebidipine, dihydropyridine, relcanidipine, nitrendipine, cilnidi Pin, manidipine, mibefurazil, bepridil, barnidipine, nilvadipine, garopami L, lidoflazine, alanidipine, dotarizine, diproteverine, or their pharmaceutical A pharmaceutically acceptable salt or hydrate as described in any one of Embodiments 128 to 132. composition.

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

[0335] Embodiment 135: The calcium channel blocker is amlodipine besylate, Embodiment The pharmaceutical composition described in 134.

[0336] Embodiment 136: The respective dosages of (a), (b), and (c) are (a), (b), and This is approximately 80% to 120% of the minimum hypertension treatment dose (LHTD) for each of (c). or the pharmaceutical composition according to any one of embodiments 128 to 135.

[0337] Embodiment 137: Dosage of thiazide-like diuretic is the minimum hypertension for thiazide-like diuretics. The pharmaceutical composition according to Embodiment 136, which is approximately 100% of the dose used for treatment of the disease (LHTD).

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

[0339] Embodiment 139: The dosage of the calcium channel blocker is determined by the calcium channel blocker. Embodiments 136 to 138 represent approximately 100% of the minimum hypertension treatment dose (LHTD). A pharmaceutical composition as described in any one of the following.

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

[0341] Embodiment 141: The dosage of telmisartan is the minimum therapeutic dose for hypertension with telmisartan. The therapeutic dose (LHTD) is approximately 100% of the amount described in any one of Embodiments 136 to 140. Pharmaceutical composition.

[0342] Embodiment 142: The dose of telmisartan is approximately 20 mg, as described in Embodiment 141. A pharmaceutical composition.

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

[0344] Embodiment 144: The dosage of telmisartan is approximately 16 mg to approximately 24 mg, and indapa The dosage of mid is approximately 1 mg to 1.5 mg, and the dosage of amlodipine besylate is approximately 2 mg. The pharmaceutical composition according to Embodiment 143, which is approximately 3 mg in a quantity of g.

[0345] Embodiment 145: The dose of telmisartan is approximately 20 mg, and the dose of indapamide is The dose is approximately 1.25 mg, and the dose of amlodipine besylate is approximately 2.5 mg, in practice The pharmaceutical composition described in Form 143.

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

[0347] Embodiments 147.(a), (b), and (c) are each provided in separate formulations. or the pharmaceutical composition according to any one of Embodiments 1 to 145.

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

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

[0350] Embodiment 150. Any of Embodiments 1 to 149, the pharmaceutical composition is suitable for oral administration. A pharmaceutical composition as described in one.

[0351] Embodiment 151: Includes the step of administering any one of the pharmaceutical compositions of Embodiments 1 to 150. Hmm, methods for treating the required subject hypertension.

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

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

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

[0355] Embodiment 155. The treatment results in a reduction of diastolic blood pressure (DBP) of approximately 5 mmHg or more. A method according to any one of embodiments 150 to 154, which brings about the present invention.

[0356] Embodiment 156. The treatment is any one of (a), (b), and (c) in the pharmaceutical composition. A reduction in systolic blood pressure (SBP) greater than the reduction achieved with one complete minimum hypertension treatment dose. A method according to any one of embodiments 150 to 155, which results in a small

[0357] Embodiment 157. The treatment is any one of (a), (b), and (c) in the pharmaceutical composition. A reduction in diastolic blood pressure (DBP) greater than the reduction achieved with one complete dose of diastolic blood pressure medication. A method according to any one of embodiments 150 to 156, which results in a small

[0358] Embodiment 158. The treatment is any one of (a), (b), and (c) in the pharmaceutical composition. Compared to treatment with one complete minimum dose for hypertension, it has more long-term tolerance and fewer side effects. The method described in any one of Embodiments 150 to 157, which results in a reduction of risk. Law.

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

[0360] Embodiment 160. The subject does not receive the aforementioned hypertension treatment before the procedure, Embodiment 150 The method described in any one of the methods in (1) through (159).

[0361] Preferred embodiments of this disclosure have been shown and described herein, but such embodiments are It is obvious to those skilled in the art that this is merely one example. The transformation, modification, and substitution of numbers may be conceived by those skilled in the art without departing from this disclosure. Various alternatives to the embodiments of the disclosure described herein may be used in practice. Please understand that this may be used in practice. The following claims are the basis of this disclosure. This defines the scope of these claims and the methods and structures within the scope of these claims and their equivalents. The construction is intended to be encompassed by it. The present invention provides, for example, the following items: (Item 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. (Item 2) The pharmaceutical composition described in item 1, which essentially 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. (Item 3) The diuretic is a thiazide-like diuretic, as described in item 1 of the pharmaceutical composition. (Item 4) The thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof, as described in item 3 of the pharmaceutical composition. (Item 5) The thiazide-like diuretic is indapamide or its hydrate, as described in item 4 of the pharmaceutical composition. (Item 6) The thiazide-like diuretic is indapamide, as described in item 5 of the pharmaceutical composition. (Item 7) 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, as described in item 1 of the pharmaceutical composition. (Item 8) The pharmaceutically acceptable composition described in item 7, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. (Item 9) The calcium channel blocker is amlodipine besylate, as described in item 8 of the pharmaceutical composition. (Item 10) The angiotensin II receptor blocker is irbesartan, telmisartan, valsartan, candesartan, eprosartan, olmesartan, azilsartan, losartan, or a pharmaceutically acceptable salt or hydrate thereof, as described in item 1 of the pharmaceutical composition. (Item 11) The angiotensin II receptor blocker is telmisartan, as described in item 10 of the pharmaceutical composition. (Item 12) The pharmaceutical composition described in item 1, wherein the respective doses of (a), (b), and (c) are approximately 40% to approximately 60% of the minimum hypertension-treating dose (LHTD) for each of (a), (b), and (c). (Item 13) 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, as described in item 12. (Item 14) The thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 0.625 mg, as described in item 13 of the pharmaceutical composition. (Item 15) The pharmaceutical composition described in item 12, wherein the dose of the calcium channel blocker is approximately 50% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker. (Item 16) The pharmaceutical composition described in item 15 is one in which the calcium channel blocker is amlodipine besylate, and the dose of amlodipine besylate is approximately 1.25 mg. (Item 17) The pharmaceutical composition described in item 12, wherein the dose of the angiotensin II receptor blocker is approximately 50% of the minimum hypertension-treating dose (LHTD) for the angiotensin II receptor blocker. (Item 18) The angiotensin II receptor blocker is telmisartan, and the dose of telmisartan is approximately 10 mg, as described in item 17 of the pharmaceutical composition. (Item 19) The pharmaceutical composition described in item 12, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate. (Item 20) The pharmaceutical composition described in item 19, wherein the dosage of telmisartan is approximately 8 mg to approximately 12 mg, the dosage of indapamide is approximately 0.5 mg to approximately 0.75 mg, and the dosage of amlodipine besylate is approximately 1 mg to approximately 1.5 mg. (Item 21) The pharmaceutical composition described in item 19, 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. (Item 22) 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. (Item 23) The pharmaceutical composition described in item 22, which essentially 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. (Item 24) The thiazide-like diuretic is kinesazone, clopamide, chlorthalidone, mefluside, clofenamide, metrazone, meticran, xipamide, indapamide, chlorexolone, fenquizone, or a pharmaceutically acceptable salt or hydrate thereof, as described in item 22 of the pharmaceutical composition. (Item 25) The thiazide-like diuretic is indapamide or its hydrate, as described in item 24 of the pharmaceutical composition. (Item 26) The thiazide-like diuretic is indapamide, as described in item 25 of the pharmaceutical composition. (Item 27) 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, as described in item 22 of the pharmaceutical composition. (Item 28) The pharmaceutically acceptable composition described in item 27, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. (Item 29) The calcium channel blocker is amlodipine besylate, as described in item 28 of the pharmaceutical composition. (Item 30) The pharmaceutical composition described in item 22, 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). (Item 31) The pharmaceutical composition described in item 30, wherein the dose of the thiazide-like diuretic is approximately 100% of the minimum hypertension-treating dose (LHTD) for the thiazide-like diuretic. (Item 32) The thiazide-like diuretic is indapamide, and the dose of indapamide is approximately 1.25 mg, as described in item 31 of the pharmaceutical composition. (Item 33) The pharmaceutical composition described in item 30, wherein the dose of the calcium channel blocker is approximately 100% of the minimum hypertension-treating dose (LHTD) for the calcium channel blocker. (Item 34) The calcium channel blocker is amlodipine besylate, and the dosage of amlodipine besylate is approximately 2.5 mg, as described in item 33 of the pharmaceutical composition. (Item 35) The pharmaceutical composition described in item 30, wherein the dose of telmisartan is approximately 100% of the minimum hypertension-treating dose (LHTD) for telmisartan. (Item 36) The pharmaceutical composition described in item 35 contains approximately 20 mg of telmisartan. (Item 37) The pharmaceutical composition described in item 30, wherein the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate. (Item 38) The pharmaceutical composition described in item 37, wherein the dosage of telmisartan is approximately 16 mg to approximately 24 mg, the dosage of indapamide is approximately 1 mg to approximately 1.5 mg, and the dosage of amlodipine besylate is approximately 2 mg to approximately 3 mg. (Item 39) The pharmaceutical composition described in item 37, wherein the dosage of telmisartan is approximately 20 mg, the dosage of indapamide is approximately 1.25 mg, and the dosage of amlodipine besylate is approximately 2.5 mg. (Item 40) A method for treating hypertension in a subject in need, comprising the step of administering the pharmaceutical composition described in item 1 to the subject. (Item 41) A method for treating hypertension in a subject in need, comprising the step of administering a pharmaceutical composition described in item 22 to the subject.

Claims

[Claim 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.

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