Composition for treating hypertension

文档序号：1785293 发布日期：2019-12-06 浏览：29次中文

阅读说明：本技术 用于治疗高血压的组合物 (Composition for treating hypertension ) 是由安东尼·罗杰斯史蒂芬·麦克马洪于 2018-01-23 设计创作，主要内容包括：本文提供了可用于治疗高血压的药物组合物,其包含血管紧张素II受体阻滞剂、利尿剂和钙通道阻滞剂。这些组合物以每种药剂的最低高血压治疗剂量(LHTD)的40-80％的剂量施用。本申请还涉及包含替米沙坦、噻嗪样利尿剂和钙通道阻滞剂的组合物,其以每种药剂的LHTD的80-150％的剂量施用。(Provided herein are pharmaceutical compositions useful for treating hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. These compositions are administered at a dose of 40-80% of the lowest therapeutic hypertension dose (LHTD) for each agent. The application also relates to compositions comprising telmisartan, thiazide-like diuretic and calcium channel blocker, administered at a dose of 80-150% of the LHTD of each agent.)

1. A pharmaceutical composition comprising

(a) An angiotensin II receptor blocker;

(b) A diuretic; and

Wherein the dosage of each of (a), (b), and (c) is from about 40% to about 80% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

2. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition is substantially free of angiotensin converting enzyme inhibitors or pharmaceutically acceptable salts thereof, beta blockers or pharmaceutically acceptable salts thereof, lipid modulators, platelet function modifiers, serum homocysteine lowering agents, or combinations thereof.

3. The pharmaceutical composition of claim 1, wherein the diuretic is a thiazide-like diuretic.

4. The pharmaceutical composition of claim 3, wherein the thiazide-like diuretic is quinethazone, chlorophamide, chlorthalidone, mefuside, clofenamide, metolazone, metteclman, xipamide, indapamide, chlorsulfuron, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof.

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

6. The pharmaceutical composition according to claim 5, wherein the thiazide-like diuretic is indapamide.

7. The pharmaceutical composition according to claim 1, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, imaradipine, imiradidil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, polytitarizine, dipropviraline, or a pharmaceutically acceptable salt or hydrate thereof.

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

9. The pharmaceutical composition of claim 8, wherein the calcium channel blocker is amlodipine besylate.

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

11. the pharmaceutical composition according to claim 10, wherein the angiotensin II receptor blocker is telmisartan.

12. The pharmaceutical composition of claim 1, wherein the dosage of each of (a), (b), and (c) is from about 40% to about 60% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

13. The pharmaceutical composition of claim 12, wherein the diuretic is a thiazide-like diuretic and the dose of the thiazide-like diuretic is about 50% of the minimum hypertension treatment dose (LHTD) of the thiazide-like diuretic.

14. The pharmaceutical composition according to claim 13, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 0.625 mg.

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

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

17. The pharmaceutical composition of claim 12, wherein the dose of the angiotensin II receptor blocker is about 50% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker.

18. the pharmaceutical composition according to claim 17, wherein the angiotensin II receptor blocker is telmisartan and the dose of telmisartan is about 10 mg.

19. The pharmaceutical composition according to claim 12, wherein the angiotensin II receptor blocker is telmisartan, the diuretic is indapamide, and the calcium channel blocker is amlodipine besylate.

20. The pharmaceutical composition according to claim 19, wherein the dose of telmisartan is from about 8mg to about 12mg, the dose of indapamide is from about 0.5mg to about 0.75mg, and the dose of amlodipine besylate is from about 1mg to about 1.5 mg.

21. The pharmaceutical composition according to claim 19, wherein the dose of telmisartan is about 10mg, the dose of indapamide is about 0.625mg, and the dose of amlodipine besylate is about 1.25 mg.

22. A pharmaceutical composition comprising

(a) Telmisartan;

(b) Thiazide-like diuretics; and

Wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is substantially free of angiotensin converting enzyme inhibitors or pharmaceutically acceptable salts thereof, beta blockers or pharmaceutically acceptable salts thereof, lipid modulators, platelet function modifiers, serum homocysteine lowering agents, or combinations thereof.

24. The pharmaceutical composition of claim 22, wherein the thiazide-like diuretic is quinethazone, chlorophamide, chlorthalidone, mefuside, clofenamide, metolazone, metteclman, xipamide, indapamide, chlorsulfuron, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof.

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

26. The pharmaceutical composition according to claim 25, wherein the thiazide-like diuretic is indapamide.

27. The pharmaceutical composition according to claim 22, wherein the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, imaradipine, imiradidil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, polytitarizine, dipropviraline, or a pharmaceutically acceptable salt or hydrate thereof.

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

29. The pharmaceutical composition of claim 28, wherein the calcium channel blocker is amlodipine besylate.

30. The pharmaceutical composition of claim 22, wherein the dosage of each of (a), (b), and (c) is from about 80% to about 120% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

31. The pharmaceutical composition of claim 30, wherein the dose of said thiazide-like diuretic is about 100% of the Lowest Hypertension Therapeutic Dose (LHTD) of said thiazide-like diuretic.

32. The pharmaceutical composition according to claim 31, wherein the thiazide-like diuretic is indapamide and the dose of indapamide is about 1.25 mg.

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

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

35. the pharmaceutical composition of claim 30, wherein the dose of telmisartan is about 100% of the Lowest Hypertensive Therapeutic Dose (LHTD) of telmisartan.

36. The pharmaceutical composition according to claim 35, wherein the dose of telmisartan is about 20 mg.

37. The pharmaceutical composition according to claim 30, wherein the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate.

38. The pharmaceutical composition according to claim 37, wherein the dose of telmisartan is from about 16mg to about 24mg, the dose of indapamide is from about 1mg to about 1.5mg, and the dose of amlodipine besylate is from about 2mg to about 3 mg.

39. The pharmaceutical composition according to claim 37, wherein the dose of telmisartan is about 20mg, the dose of indapamide is about 1.25mg, and the dose of amlodipine besylate is about 2.5 mg.

40. A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of claim 1.

41. A method of treating hypertension in a subject in need thereof, comprising administering the pharmaceutical composition of claim 22.

Background

High blood pressure (high blood pressure), also known as hypertension (hypertension), is a leading cause of preventable morbidity and mortality, and treatments to reduce Blood Pressure (BP) have been determined to be beneficial. However, despite the availability of a large number of hypotensive drugs, blood pressure control in many patients remains poor as evidenced by multiple large-scale population studies. Factors affecting poor blood pressure control include poor compliance, complex guidelines suggesting multiple up-titration steps, and treatment inertia. Furthermore, most patients receiving treatment receive only a monotherapy, which is limited in efficacy even at high doses with increased side effects and reduced tolerability. Thus, there is a need for new treatments for lowering hypertension that are effective and tolerable.

Disclosure of Invention

In one aspect, provided herein is a pharmaceutical composition comprising

(a) An angiotensin II receptor blocker;

(b) A diuretic; and

Wherein the dosage of each of (a), (b), and (c) is from about 40% to about 80% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

In some embodiments, the pharmaceutical composition is substantially free of an angiotensin converting enzyme inhibitor or a pharmaceutically acceptable salt thereof, a beta blocker or a pharmaceutically acceptable salt thereof, a lipid modulating agent, a platelet function altering agent, a serum homocysteine lowering agent, or a combination thereof.

In some embodiments, the diuretic is a thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is quinethazone, chloropapamide, chlorthalidone, mefuside, clofenamide, metolazone, metipran, xipamide, indapamide, chlorsulfuron, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide (indapamide) or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide.

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

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

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

In another aspect, a pharmaceutical composition is provided comprising

(a) telmisartan;

(b) Thiazide-like diuretics; and

Wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

In some embodiments, the dosage of each of (a), (b), and (c) is from about 80% to about 120% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dose of the thiazide-like diuretic is about 100% of the minimum hypertension treatment dose (LHTD) of the thiazide-like diuretic. In some embodiments, the thiazide-like diuretic is indapamide, and the dose of indapamide is about 1.25 mg. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest therapeutic hypertensive dose (LHTD) of the calcium channel blocker. In some embodiments, the calcium channel blocker is amlodipine besylate and the dose of amlodipine besylate is about 2.5 mg. In some embodiments, the dose of telmisartan is about 100% of the Lowest Hypertensive Therapeutic Dose (LHTD) of telmisartan. In some embodiments, the dose of telmisartan is about 20 mg. In some embodiments, the thiazide-like diuretic is indapamide and the calcium channel blocker is amlodipine besylate. In some embodiments, the dose of telmisartan is from about 16mg to about 24mg, the dose of indapamide is from about 1mg to about 1.5mg, and the dose of amlodipine besylate is from about 2mg to about 3 mg. In some embodiments, the dose of telmisartan is about 20mg, the dose of indapamide is about 1.25mg, and the dose of amlodipine besylate is about 2.5 mg.

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

also provided herein is a method of treating hypertension in a subject in need thereof comprising administering any one of the pharmaceutical compositions disclosed herein. In some embodiments, the treatment results in a Systolic Blood Pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg or more. In some embodiments, the treatment results in a diastolic pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a reduction in diastolic pressure (DBP) of about 5mmHg or more. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than the reduction obtained at the full minimum hypertensive therapeutic dose of any of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than the reduction obtained at the full minimum hypertensive therapeutic dose of any of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with the full minimum hypertensive therapeutic dose of any of (a), (b), and (c) in the pharmaceutical composition. In some embodiments, the treatment is an initial or first line treatment of hypertension. In some embodiments, the subject has not received any previous hypertension therapy prior to treatment.

In another aspect, provided herein is a pharmaceutical composition consisting essentially of

(a) An angiotensin II receptor blocker;

(b) A diuretic; and

Wherein the dosage of each of (a), (b), and (c) is from about 40% to about 80% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

In another aspect, provided herein is a pharmaceutical composition consisting essentially of

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

(b) Thiazide-like diuretics; and

Wherein the dosage of each of (a), (b), and (c) is from about 80% to about 150% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 80% to about 120% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 90% to about 110% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c).

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features believed characteristic of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

Figure 1 shows the mean systolic blood pressure (mmHg) over a period of time as treated.

Figure 2 shows mean diastolic pressure (mmHg) over a period of treatment.

Figure 3 shows the average heart rate over a period of time as a treatment.

Detailed Description

Provided herein are pharmaceutical compositions for treating hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker. In some embodiments, the dose of each component is lower than the lowest dose approved for the treatment of hypertension. The present disclosure recognizes the technical effects of the low dose combination therapies described herein, including, but not limited to, the use of low doses to avoid or reduce side effects while maintaining or improving benefits, synergistic therapeutic benefits of certain drug combinations, early introduction of combination therapies to improve therapeutic effects, and the like. In one aspect, described herein are low dose combination compositions for the treatment of hypertension, including initial or first line treatment of hypertension.

Certain terms

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

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

As used herein, "pharmaceutically acceptable salts" include acid addition salts and base addition salts. In some embodiments, any of the pharmaceutically acceptable salts of the compounds described herein are in a form approved for use by the U.S. food and drug administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, are biologically or otherwise desirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, and the like. Also included are salts with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and the organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, mesylate, and the like. Also contemplated are Salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge S.M. et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science,66:1-19(1997), which is incorporated by reference herein in its entirety). Acid addition salts of basic compounds can be prepared according to methods and techniques familiar to the skilled artisan by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

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

As used herein, a "hydrate" is a compound that contains a stoichiometric or non-stoichiometric amount of water, and in some embodiments, is formed during crystallization with water. Hydrates are intended to include hydrates of any of the compounds described herein that are approved for use by the U.S. food and drug administration.

As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that there is no lasting deleterious effect on the general health of the subject being treated.

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

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

As used herein, "treatment" or "treating" or "alleviating" are used interchangeably. These terms refer to a method for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or alleviation of the underlying disorder being treated. Furthermore, therapeutic benefits may also be realized as follows: eradication or alleviation of one or more physiological symptoms associated with the underlying disorder results in an improvement being observed in the patient, although the patient may still suffer from the underlying disorder. For prophylactic benefit, the composition can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

Triple combination

Described herein are pharmaceutical compositions comprising (a) an angiotensin II receptor blocker, (b) a diuretic, and (c) a calcium channel blocker; wherein the dosage of each of (a), (b), and (c) is from about 40% to about 80% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 40% to about 60% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 50% of the lowest therapeutic hypertension dose (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is from about 60% to about 80% of the Lowest Hypertensive Therapeutic Dosage (LHTD) of each of (a), (b), and (c). In some embodiments, the dosage of each of (a), (b), and (c) is about 66% of the lowest therapeutic hypertension dose (LHTD) of each of (a), (b), and (c).

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

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

In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of angiotensin converting enzyme inhibitors (ACE inhibitors) or pharmaceutically acceptable salts thereof. In some embodiments, the angiotensin converting enzyme inhibitor includes, but is not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

In some embodiments, the pharmaceutical compositions disclosed herein achieve a significant reduction in blood pressure in a subject with moderate elevated blood pressure. In some embodiments, the pharmaceutical compositions disclosed herein achieve significant blood pressure reduction with minimal, no, or no side effects in subjects with moderate elevated blood pressure.

beta receptor blockers

In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of a beta blocker or a pharmaceutically acceptable salt thereof. In some embodiments, the beta blocker is a compound that inhibits the receptor sites on the adrenergic beta receptors of the sympathetic nervous system for endogenous catecholaminephrine (epinephrine) and norepinephrine (norepinephrine). In some embodiments, the beta blocker includes, but is not limited to, a beta-adrenergic blocker, a beta receptor antagonist, a beta-adrenergic receptor antagonist, or a beta-adrenergic receptor antagonist. In some embodiments, the beta blocker inhibits activation of all types of beta-adrenergic receptors. In some embodiments, the beta blocker inhibits both the beta-adrenergic receptor and the alpha-adrenergic receptor. In some embodiments, the beta blocker is selective for one of the following beta receptors: β 1 receptors, β 2 receptors and β 3 receptors.

In some embodiments, the beta blocker is a non-selective beta-adrenoceptor antagonist. Examples of non-selective beta-adrenoceptor antagonists include, but are not limited to, pindolol, propranolol, oxprenolol, sotalol, timolol, carteolol, penbutolol, and nadolol. In some embodiments, the beta blocker is a compound having a combined beta-adrenoceptor and alpha-adrenoceptor blocking effect. Suitable examples include, but are not limited to, carvedilol, bucindolol, and labetalol. In some embodiments, the beta blocker is a beta 1 selective adrenoceptor antagonist. Examples of β 1 selective adrenoceptor antagonists include, but are not limited to, atenolol, bisoprolol, betaxolol, metoprolol, celiprolol, esmolol, nebivolol, and acebutolol. In some embodiments, the beta blocker is a beta 2 selective adrenoceptor antagonist, such as butaxamine.

In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, timolol, esmolol, celiprolol, oxprenolol, levobunolol, pranopolol, metiprolol, landiolol, bopindolol, propranolol, butazamine, bevantolol, etalol, arotinolol, levobetaxolol, phenfuralol, sulfametolol, tililol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, penbutolol, metoprolol, nadolol, nebivolol, pindolol, sotalol, propranolol, carvedilol, labetalol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, oxprenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, carvedilol, labetalol, timolol, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the beta blocker is atenolol. In some embodiments, the beta blocker is bisoprolol or a pharmaceutically acceptable salt thereof.

Lipid modulators

In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of lipid modulators, platelet function altering agents, serum homocysteine lowering agents, or combinations thereof.

In some embodiments, the pharmaceutical compositions disclosed herein are substantially free of lipid modulating agents. In some embodiments, the lipid modulating agent is a 3-hydroxy-3-methylglutaryl coenzyme a (hmg coa) reductase inhibitor, also known as a statin. 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 simvastatin.

Platelet function-modifying agent

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

Serum homocysteine lowering agents

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

Angiotensin II receptor antagonists/blockers

As used herein, an angiotensin II receptor antagonist or blocker (ARB) is a compound that modulates the action of angiotensin II by blocking angiotensin II binding to angiotensin II receptors on the perivascular muscles. In some embodiments, the angiotensin II receptor blocker is losartan, valsartan, candesartan, eprosartan, irbesartan, telmisartan, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the angiotensin II receptor blocker is losartan. In some embodiments, the angiotensin II receptor blocker is valsartan. In some embodiments, the angiotensin II receptor blocker is candesartan. In some embodiments, the angiotensin II receptor blocker is eprosartan. In some embodiments, the angiotensin II receptor blocker is irbesartan. In some embodiments, the angiotensin II receptor blocker is telmisartan.

Diuretic agents

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

In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a thiazide-like diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a loop diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a penetrating diuretic. In some embodiments, the pharmaceutical compositions disclosed herein comprise a carbonic anhydrase inhibitor. In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium sparing diuretic.

Thiazide diuretics

As used herein, thiazide diuretics refer to compounds that contain the molecular structure of benzothiadiazine. In some embodiments, the thiazide diuretic inhibits sodium and chloride reabsorption in the distal tubule of the kidney, which results in increased urinary excretion of sodium and water. Examples of thiazide diuretics include, but are not limited to, althiazide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epinasethiazide, hydrochlorothiazide, hydroflumethiazide, mebutazine, methyclothiazide, polythiazide, and trichlorthiazide.

In some embodiments, the thiazide diuretic is althiazide, bendroflumethiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epinasethiazide, hydrochlorothiazide, hydroflumethiazide, mebutazine, methyclothiazide, polythiazide, trichlormethiazide, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide diuretic is althiazide. In some embodiments, the thiazide diuretic is bendroflumethiazide. In some embodiments, the thiazide diuretic is chlorothiazide. In some embodiments, the thiazide diuretic is cyclopenthiazide. In some embodiments, the thiazide diuretic is cyclothiazide. In some embodiments, the thiazide diuretic is epinasethiazide. In some embodiments, the thiazide diuretic is hydrochlorothiazide. In some embodiments, the thiazide diuretic is hydrofluorothiazide. In some embodiments, the thiazide diuretic is mebutazine. In some embodiments, the thiazide diuretic is methyclothiazide. In some embodiments, the thiazide diuretic is polythiazide. In some embodiments, the thiazide diuretic is trichlorthiazine.

Thiazide diuretics

as used herein, a thiazide diuretic is a sulfonamide diuretic that has similar physiological properties to thiazide diuretics, but does not have the chemical properties of thiazines (i.e., does not have the benzothiadiazine core). Examples of thiazide-like diuretics include, but are not limited to, quinethazone, chlorophamide, chlorthalidone, mefuside, clofenamide, metolazone, metipran, xipamide, indapamide, chlorsulfuron, and fenquinazole.

In some embodiments, the thiazide-like diuretic is quinethazone, chloropapamide, chlorthalidone, mefuside, clofenamide, metolazone, metipran, xipamide, indapamide, chlorsulfuron, fenquinazole, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the thiazide-like diuretic is quinethazone. In some embodiments, the thiazide-like diuretic is chloramide. In some embodiments, the thiazide-like diuretic is chlorthalidone. In some embodiments, the thiazide-like diuretic is meffexist. In some embodiments, the thiazide-like diuretic is clofenamide. In some embodiments, the thiazide-like diuretic is metolazone. In some embodiments, the thiazide-like diuretic is melphalan. In some embodiments, the thiazide-like diuretic is xipamide. In some embodiments, the thiazide-like diuretic is indapamide or a hydrate thereof. In some embodiments, the thiazide-like diuretic is indapamide. In some embodiments, the thiazide-like diuretic is chlorsulfuron. In some embodiments, the thiazide-like diuretic is fenquinazole.

Loop diuretics

As used herein, a loop diuretic is a compound that acts on the Na +/K +/2 Cl-cotransporter in the loop of the sharehler loop to inhibit sodium, chloride and potassium reabsorption. Examples of loop diuretics include, but are not limited to, furosemide, bumetanide, ethacrynic acid, etozoline, famoxadine, olyzolinone, piretanide, tennic acid, and torasemide. In some embodiments, the loop diuretic is furosemide, bumetanide, ethacrynic acid, etozoline, famoxadine, ozolinone, piretanide, tennic acid, torasemide or a pharmaceutically acceptable salt or hydrate thereof.

Other diuretics

Osmotic diuretics are compounds that cause water to be retained within the proximal tubule and shared loop descending branch. In some embodiments, the osmotic diuretic expands fluid and plasma volume and increases blood flow to the kidney. Examples include, but are not limited to, mannitol and glycerol.

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors as used herein are compounds that are inhibitors of carbonic anhydrase. In some embodiments, the carbonic anhydrase inhibitor increases bicarbonate excretion with accompanying sodium, potassium, and water, which results in increased alkaline urine flow. In some embodiments, the carbonic anhydrase inhibitor inhibits the transport of bicarbonate from the proximal convoluted tubule into the interstitium, which results in less sodium being reabsorbed and provides greater sodium, bicarbonate, and water loss in the urine. Examples of such compounds include, but are not limited to, acetazolamide, dichlorofenamide, and methazolamide.

potassium-retained diuretic agents

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

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

In some embodiments, the diuretic is diclofenamide, amiloride, pamabrom, mannitol, acetazolamide, methazolamide, spironolactone, triamterene, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the diuretic is dichlorfenamide. In some embodiments, the diuretic is amiloride. In some embodiments, the diuretic is pamabrom. In some embodiments, the diuretic is mannitol. In some embodiments, the diuretic is acetazolamide. In some embodiments, the diuretic is methazolamide. In some embodiments, the diuretic is spironolactone. In some embodiments, the diuretic is triamterene.

Calcium channel blockers

As used herein, a calcium channel blocker is a compound that promotes vasodilatory activity by reducing calcium influx into vascular smooth muscle cells. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, dihydropyridine, lercanidipine, nitrendipine, cilnidipine, manidipine, imaradidil, bepridil, barnidipine, nilvadipine, gallopamil, lidoflazine, aranidipine, polytriazine, dipropyline, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine, nifedipine, diltiazem, nimodipine, verapamil, isradipine, felodipine, nicardipine, nisoldipine, clevidipine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. In some embodiments, the calcium channel blocker is amlodipine besylate. In some embodiments, the calcium channel blocker is nifedipine. In some embodiments, the calcium channel blocker is diltiazem. In some embodiments, the calcium channel blocker is nimodipine. In some embodiments, the calcium channel blocker is verapamil. In some embodiments, the calcium channel blocker is isradipine. In some embodiments, the calcium channel blocker is felodipine. In some embodiments, the calcium channel blocker is nicardipine. In some embodiments, the calcium channel blocker is nisoldipine. In some embodiments, the calcium channel blocker is clevidipine.

Minimum therapeutic dose for hypertension

http://www.accessdata.fda.gov/scripts/cder/ob/As used herein, the lowest therapeutic hypertensive dose (LHTD) refers to the lowest-strength dose of a single hypertensive agent approved by the united states food and drug administration and, as of the filing date of the present application, has not been marked as "off-use" by the Orange peel Book (Orange Book) database (http:// www.accessdata.fda.gov/scripts/cder/ob /). For the case where the lowest hypertensive dose is different from the lowest manufactured dose, the lowest hypertensive dose does not include the lowest manufactured dose. Further, for the case where the minimum hypertensive dose is different from the physician-suggested dose, the minimum hypertensive dose does not include the physician-suggested dose. Further, the minimum hypertensive dose of an angiotensin II receptor blocker, diuretic, or calcium channel blocker as described herein refers to a dose in the form of an angiotensin II receptor blocker, diuretic, or calcium channel blocker approved for use by the U.S. food and drug administration, including the free base, pharmaceutically acceptable salt, or hydrate thereof.

In some embodiments, the dosage of the angiotensin II receptor blocker is from about 40% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 40% to about 70% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 40% to about 60% of the lowest therapeutic hypertension dose. In some embodiments, the dose of angiotensin II receptor blocker is from about 40% to about 50% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 45% to about 55% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 50% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 50% to about 70% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 50% to about 60% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 60% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 60% to about 70% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 70% to about 80% of the lowest therapeutic hypertension dose.

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

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

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

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

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

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

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

In some embodiments, the loop diuretic dose is from about 40% to about 80% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic dose is from about 40% to about 70% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic dose is from about 40% to about 60% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic dose is from about 40% to about 50% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic dose is from about 45% to about 55% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic dose is from about 50% to about 80% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic is at a dose from about 50% to about 70% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic is at a dose from about 50% to about 60% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is from about 60% to about 80% of the minimum hypertension treatment dose. In some embodiments, the loop diuretic is at a dose from about 60% to about 70% of the minimum hypertension therapeutic dose. In some embodiments, the loop diuretic dose is from about 70% to about 80% of the minimum hypertension treatment dose.

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

In some embodiments, the dose of the calcium channel blocker is from about 40% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 40% to about 70% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 40% to about 60% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 40% to about 50% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 45% to about 55% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 50% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 50% to about 70% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 50% to about 60% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 60% to about 80% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 60% to about 70% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 70% to about 80% of the lowest therapeutic hypertension dose.

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

In some embodiments, the following compounds are given in the following table for the lowest therapeutic hypertension dose (LHTD) and corresponding recommended doses and recommended dose ranges:

Table 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, the dose of angiotensin II receptor blocker such as telmisartan is from about 90% to about 140% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 90% to about 130% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 90% to about 120% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 90% to about 110% of the lowest therapeutic hypertension dose.

in some embodiments, the dose of angiotensin II receptor blocker such as telmisartan is from about 95% to about 135% of the lowest therapeutic hypertension dose. In some embodiments, the dose of angiotensin II receptor blocker is from about 95% to about 125% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 95% to about 115% of the lowest therapeutic hypertension dose. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 95% to about 105% of the lowest therapeutic hypertension dose.

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

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

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

In some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 140% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 130% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 120% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 90% to about 110% of the minimum hypertension treatment dose.

In some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 135% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 125% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 115% of the minimum hypertension treatment dose. In some embodiments, the dose of the thiazide-like diuretic is from about 95% to about 105% of the minimum hypertension treatment dose.

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

In some embodiments, the dose of the calcium channel blocker is from about 80% to about 150% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 140% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 130% of the lowest hypertensive therapeutic dose. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 120% of the lowest hypertensive therapeutic dose. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 110% of the lowest therapeutic hypertensive dose.

In some embodiments, the dose of the calcium channel blocker is from about 85% to about 145% of the lowest hypertensive therapeutic dose. In some embodiments, the dose of the calcium channel blocker is from about 85% to about 135% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 85% to about 125% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 85% to about 115% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 85% to about 105% of the lowest therapeutic hypertensive dose.

in some embodiments, the dose of the calcium channel blocker is from about 90% to about 140% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 90% to about 130% of the lowest hypertensive therapeutic dose. In some embodiments, the dose of the calcium channel blocker is from about 90% to about 120% of the lowest hypertensive therapeutic dose. In some embodiments, the dose of the calcium channel blocker is from about 90% to about 110% of the lowest therapeutic hypertensive dose.

In some embodiments, the dose of the calcium channel blocker is from about 95% to about 135% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 95% to about 125% of the lowest therapeutic hypertension dose. In some embodiments, the dose of the calcium channel blocker is from about 95% to about 115% of the lowest therapeutic hypertensive dose. In some embodiments, the dose of the calcium channel blocker is from about 95% to about 105% of the lowest therapeutic hypertensive dose.

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

In some embodiments, the following compounds are given in the following table for the lowest therapeutic hypertension dose (LHTD) and corresponding recommended doses and recommended dose ranges:

Table 2.

In some embodiments, the dose of any one of the angiotensin II receptor blocker, diuretic and calcium channel blocker is replaced with about 80% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the Lowest Hypertension Therapeutic Dosage (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 80% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 80% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of any one of the angiotensin II receptor blocker, diuretic and calcium channel blocker is replaced with about 80% to about 150% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 100% of the lowest therapeutic hypertension dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 80% to about 150% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is replaced with about 100% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of calcium channel blocker. In some embodiments, the dose of calcium channel blocker is replaced with about 100% of the lowest therapeutic hypertension dose (LHTD) of calcium channel blocker. In some embodiments, the dose of any one of the angiotensin II receptor blocker, diuretic and calcium channel blocker is replaced with about 150% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 200% of the lowest therapeutic hypertension dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 150% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is replaced with about 200% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 150% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of calcium channel blocker is replaced with about 200% of the lowest therapeutic hypertension dose (LHTD) of calcium channel blocker.

in some embodiments, the dose of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced with about 80% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 250% of the Lowest Hypertension Therapeutic Dosage (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 80% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 80% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced with about 80% to about 150% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 100% of the lowest therapeutic hypertension dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 80% to about 150% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is replaced with about 100% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of calcium channel blocker. In some embodiments, the dose of calcium channel blocker is replaced with about 100% of the lowest therapeutic hypertension dose (LHTD) of calcium channel blocker. In some embodiments, the dose of any two of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is replaced with about 150% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is replaced by about 150% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of angiotensin II receptor blocker is replaced by about 200% of the lowest therapeutic hypertension dose (LHTD) of angiotensin II receptor blocker. In some embodiments, the dose of diuretic is replaced by about 150% to about 250% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is replaced with about 200% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of calcium channel blocker is replaced by about 150% to about 250% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of calcium channel blocker is replaced with about 200% of the lowest therapeutic hypertension dose (LHTD) of calcium channel blocker.

In some embodiments, the dosage of the angiotensin II receptor blocker, diuretic (e.g., thiazide diuretic or thiazide-like diuretic), and calcium channel blocker is each independently about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of diuretic is from about 80% to about 150% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 150% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is each independently about 80% to about 120% of the Lowest Hypertension Therapeutic Dosage (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 80% to about 120% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the lowest therapeutic hypertension dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of diuretic is from about 80% to about 120% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is about 100% of the lowest therapeutic hypertension dose (LHTD) of diuretic. In some embodiments, the dose of the calcium channel blocker is from about 80% to about 120% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest therapeutic hypertension dose (LHTD) of the calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker, diuretic, and calcium channel blocker is each independently about 90% to about 110% of the Lowest Hypertension Therapeutic Dosage (LHTD) of the angiotensin II receptor blocker, diuretic, or calcium channel blocker. In some embodiments, the dosage of the angiotensin II receptor blocker is from about 90% to about 110% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of the angiotensin II receptor blocker is about 100% of the lowest therapeutic hypertension dose (LHTD) of the angiotensin II receptor blocker. In some embodiments, the dose of diuretic is from about 90% to about 110% of the Lowest Hypertension Therapeutic Dose (LHTD) of diuretic. In some embodiments, the dose of diuretic is about 100% of the lowest therapeutic hypertension dose (LHTD) of diuretic. In some embodiments, the dose of the calcium channel blocker is from about 90% to about 110% of the Lowest Hypertensive Therapeutic Dose (LHTD) of the calcium channel blocker. In some embodiments, the dose of the calcium channel blocker is about 100% of the lowest therapeutic hypertension dose (LHTD) of the calcium channel blocker.

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

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

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

In some embodiments, the dose of telmisartan is about 20mg, the dose of indapamide is about 1.25mg, and the dose of amlodipine besylate is about 2.5 mg.

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

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

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

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

Preparation

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

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

Exemplary pharmaceutical compositions can be used in the form of a pharmaceutical preparation (e.g., in solid, semi-solid, or liquid form) comprising one or more of the disclosed compounds as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. For example, the active ingredient may be mixed with pharmaceutically acceptable carriers which are generally non-toxic and are employed in the form of tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

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

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agents, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents (retaring agents), such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as acetol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also employ excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as fillers in soft and hard-filled gelatin capsules.

Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active agents or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, the capsules are prepared by encapsulating (e.g., encapsulating) the tablets in hard gelatin capsules. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

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

Method of treatment

The pharmaceutical compositions described herein can be used to treat hypertension in a subject in need thereof. In some embodiments, the treatment results in a Systolic Blood Pressure (SBP) of less than about 140 mmHg. In some embodiments, the treatment results in a Systolic Blood Pressure (SBP) of less than about 135 mmHg. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg or more. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg to about 20 mmHg. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg to about 30 mmHg. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg, about 11mmHg, about 12mmHg, about 13mmHg, about 14mmHg, about 15mmHg, about 16mmHg, about 17mmHg, about 18mmHg, about 19mmHg, or about 20 mmHg. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) of about 10mmHg, about 11mmHg, about 12mmHg, about 13mmHg, about 14mmHg, about 15mmHg, about 16mmHg, about 17mmHg, about 18mmHg, about 19mmHg, about 20mmHg, about 21mmHg, about 22mmHg, about 23mmHg, about 24mmHg, about 25mmHg, about 26mmHg, about 27mmHg, about 28mmHg, about 29mmHg, or about 30 mmHg. In some embodiments, the treatment results in a diastolic pressure (DBP) of less than about 90 mmHg. In some embodiments, the treatment results in a Diastolic Blood Pressure (DBP) of less than about 85 mmHg. In some embodiments, the treatment results in a reduction in diastolic pressure (DBP) of about 5mmHg or more. In some embodiments, the treatment results in a reduction in diastolic pressure (DBP) of about 5mmHg to about 10 mmHg. In some embodiments, the treatment results in a reduction in diastolic pressure (DBP) of about 5mmHg to about 15 mmHg. In some embodiments, the treatment results in a reduction in diastolic pressure (DBP) of about 5mmHg, about 6mmHg, about 7mmHg, about 8mmHg, about 9mmHg, or about 10 mmHg. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) of about 5mmHg, about 6mmHg, about 7mmHg, about 8mmHg, about 9mmHg, about 10mmHg, about 11mmHg, about 12mmHg, about 13mmHg, about 14mmHg, or about 15 mmHg.

In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than the reduction obtained with the full minimum hypertensive therapeutic dose of any of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than the reduction obtained with the full minimum hypertensive therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than the reduction obtained with the full minimum hypertension therapeutic dose of a diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than the reduction obtained with the full minimum hypertensive therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than the reduction obtained with the full minimum hypertensive therapeutic dose of any of the angiotensin II receptor blocker, diuretic, and calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than that obtained with the full minimum hypertensive therapeutic dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than the reduction obtained with the full minimum hypertension therapeutic dose of a diuretic in the pharmaceutical composition. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than that obtained with the full minimum hypertensive therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with the full minimum hypertension therapeutic dose of any of the angiotensin II receptor blocker, diuretic and calcium channel blocker in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with the full minimum therapeutic hypertension dose of the angiotensin II receptor blocker in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with the full minimum hypertension therapeutic dose of the diuretic in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with the full minimum hypertensive therapeutic dose of the calcium channel blocker in the pharmaceutical composition.

In some embodiments, the treatment results in a reduction in Systolic Blood Pressure (SBP) that is greater than or equal to the reduction obtained with a combination of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition, wherein the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each at a dose that is about 50% of the minimum hypertension treatment dose. In some embodiments, the treatment results in a reduction in Diastolic Blood Pressure (DBP) that is greater than or equal to the reduction obtained with a combination of any two of the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker in the pharmaceutical composition, wherein the angiotensin II receptor blocker, the diuretic, and the calcium channel blocker are each at a dose that is about 50% of the minimum hypertension treatment dose. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to treatment with a combination of any two of an angiotensin II receptor blocker, a diuretic and a calcium channel blocker in the pharmaceutical composition, wherein the angiotensin II receptor blocker, the diuretic and the calcium channel blocker are each at a dose of about 50% of the lowest hypertensive therapeutic dose.

In some embodiments, the treatment is an initial or first line treatment of hypertension. In some embodiments, the subject has a very slight increase in blood pressure prior to treatment. In some embodiments, the subject has not received any previous hypertension treatment prior to treatment. In some embodiments, the subject has a very slight elevation in blood pressure prior to treatment and has not received any previous hypertension treatment prior to treatment.

The present disclosure recognizes that in some embodiments, the use of angiotensin II receptor blockers in the pharmaceutical compositions disclosed herein provides beneficial therapeutic effects including, but not limited to, a significant reduction in blood pressure in subjects with mild elevation in blood pressure, higher long-term tolerance, and reduced risk of side effects. The present disclosure recognizes that, in some embodiments, the exclusion of a lipid modulating agent, platelet function altering agent, serum homocysteine lowering agent, or a combination thereof, in a pharmaceutical composition disclosed herein provides beneficial therapeutic effects including, but not limited to, a significant reduction in blood pressure in subjects with a mild increase in blood pressure, higher long-term tolerance, and a reduced risk of side effects.

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

It is also recognized herein that, in some embodiments, the triple combination described herein comprising telmisartan, thiazide-like diuretic, and calcium channel blocker (each component being about 80% to about 150% of the minimum hypertension therapeutic dose) provides a significantly greater reduction in blood pressure (such as systolic pressure, diastolic pressure, or both) as compared to the triple combination comprising losartan as an angiotensin II receptor blocker, thiazide diuretic (such as hydrochlorothiazide), and calcium channel blocker (amlodipine besylate). In some embodiments, the triple combination described herein comprising telmisartan, a thiazide-like diuretic, and a calcium channel blocker (each component being about 80% to about 120% of the minimum hypertension treatment dose) provides a significantly greater reduction in blood pressure (such as systolic pressure, diastolic pressure, or both) as compared to triple combinations comprising losartan as an angiotensin II receptor blocker, a thiazide diuretic (such as hydrochlorothiazide), and a calcium channel blocker (amlodipine besylate).

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Composition for treating hypertension

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