WO2023047203A1

WO2023047203A1 - Combination of omzotirome and antidiabetic agent, antihypertensive agent or anti-dyslipidemic agent

Info

Publication number: WO2023047203A1
Application number: PCT/IB2022/057529
Authority: WO
Inventors: Chaitanya Dutt; Deepa Joshi; Amarinder Singh; Prashant Jamadarkhana; Sanjay Srivastava; Apurva Shah; Amol Kulkarni; Anoop Mathur; Siralee PARIKH; Deepak Rai
Original assignee: Torrent Pharmaceuticals Ltd
Priority date: 2021-09-25
Filing date: 2022-08-12
Publication date: 2023-03-30

Abstract

Present invention relates to combination comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent and use of such combination for managing cardio-metabolic based chronic diseases by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof. Present invention also relates to a pharmaceutical composition comprising omzotirome and one or more of antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent; and to a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof by administering such pharmaceutical composition.

Description

COMBINATION OF OMZOTIROME AND ANTIDIABETIC AGENT, ANTIHYPERTENSIVE AGENT OR ANTI-DYSLIPIDEMIC AGENT

Field of the Invention:

Present invention relates to combination comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent and use of such combination for managing cardio-metabolic based chronic diseases by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof. Present invention also relates to a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent; and to a method of managing cardio-metabolic based chronic diseases by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof by administering such pharmaceutical composition.

Background of the invention:

Omzotirome (TRC150094) is disclosed in WO2008149379 and process of preparation of this compound is disclosed in W02020058945.

In preclinical studies, systemic administration of TRC 150094 to high fat diet rats led to an increased activity of electron transport chain complex II and V and increased mitochondrial fatty acid import and oxidation, leading to increased energy expenditure (Cioffi et al.; The FASEB Journal; 2010; 24; 1-11: Silvestri et al.; Mol. BioSyst.; 2012; 8; 1987-2000). The effects mimic functionally, and stimulation of mitochondrial bioenergetic mechanisms are observed with di- iodothyroinine (Goglia 2005). TRC 150094 administered to obese Zucker fatty and spontaneously hypertensive (ZSF1) rats attenuated the progression of insulin resistance, dysglycemia, atherogenic dyslipidemia, and hypertension (Zambad et al., Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011; 4; 5- 16). Subsequently, to confirm the preclimcal findings in human being, TRC 150094 was administered to human subjects for a period of 4 weeks with obesity, high blood pressure and impaired hepatic & peripheral insulin sensitivity. It was observed that in contrast to the potent metabolic effects seen in experimental models in preclinical trials, TRC 150094 at a dose of 50 mg daily did not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. In particular, TRC 150094 did not improve insulin sensitivity and lipid metabolism or decrease blood pressure, hepatic steatosis in obese insulin resistant subjects with an increased cardiometabolic risk. Since data obtained in animal studies did not translate in human subjects, authors suggested that increase in the dose of the compound might work. (Valk et al; PLOS One; 2014; 9(2); 1-7). Therefore, inventors of present invention tried using 75 mg of omzotirome, particularly in combination with other agents such as ARBs, but it was observed that Omzotirome did not achieve desired results even at higher dose (as shown in figure 4) despite being used in combination with other therapeutic agents.

Inventor of the present invention surprisingly found that administration of therapeutically effective amount of omzotirome, specifically 45 mg of omzotirome, in combination with one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent significantly improved glycemic control, blood pressure control and/or lipid control in patients with high cardiometabolic risk; and this improvement was observed with the amount of omzotirome which is lower amount used in Phase II trials, as disclosed by Valk et al.

Present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Present invention also provides a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Summary of the invention:

One aspect of present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention provides a combination of omzotirome and one or more antihypertensive agent.

Another aspect of present invention provides a combination of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention provides a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention provides a pharmaceutical composition comprising omzotirome and one or more antihypertensive agent.

Another aspect of present invention provides a pharmaceutical composition comprising omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention provides a combination of 45 mg or 50 mg of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Another aspect of present invention provides a combination of 45 mg or 50 mg of omzotirome and one or more antihypertensive agent.

Another aspect of present invention provides a combination of 45 mg or 50 mg of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention provides a pharmaceutical composition comprising of 45 mg or 50 mg of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention provides a pharmaceutical composition comprising of 45 mg or 50 mg of omzotirome and one or more antihypertensive agent.

Another aspect of present invention provides a pharmaceutical composition comprising of 45 mg or 50 mg of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for use in managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof.

Another aspect of present invention provides a combination of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor for use in managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Another aspect of present invention provides a pharmaceutical composition comprising of 45 mg of omzotirome for use in managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof.

Another aspect of present invention provides a pharmaceutical composition comprising of 45 mg of omzotirome for use in managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Another aspect of present invention provides a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for use in managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof.

Another aspect of present invention provides a pharmaceutical composition comprising omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor for use in managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Another aspect of present invention is to provide use of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for preparation of medicament for managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof. Another aspect of present invention is to provide use of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor for preparation of medicament for managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antihypertensive agent.

Another aspect of the present invention is to provide a method of managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent. Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antihypertensive agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising, administering to the patient 45 mg to 50 mg of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising, administering to the patient 45 mg to 50 mg of omzotirome and one or more antihypertensive agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising, administering to the patient 45 mg to 50 mg of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising, administering to the patient 45 mg of omzotirome.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising, administering to the patient 45 mg of omzotirome.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, compnsing, administering to the patient pharmaceutical composition comprising 45 mg or 50 mg of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another aspect of present invention is to provide a method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising, administering to the patient pharmaceutical composition comprising 45 mg or 50 mg of omzotirome and one or more antihypertensive agent. Antihypertensive agent according to said aspect is selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Brief Description of Accompanying Figures:

Fig 1: Change from baseline in Non-HDL cholesterol level after administration of statin + fibrate or omzotirome+ statin + fibrate (Fig 1A); Change in LDL cholesterol level after administration of statin + fibrate or omzotirome+ statin + fibrate (Fig IB)

Fig 2: Change from baseline in fasting plasma glucose level after administration of metformin or omzotirome + metformin (Fig 2A); Change in fasting plasma glucose level after administration of metformin + sulfonylurea (SU) or omzotirome+ metformin+ sulfonylurea (SU) (Fig 2B)

Fig 3: Change from baseline in Mean Arterial Pressure after administration of Beta blocker or omzotirome + beta blocker (Fig 3A); Change in Mean Arterial Pressure after administration of ARB or omzotirome + ARB (Fig 3B)

Fig 4: Change from baseline values in blood pressure on administration of combination of 75 mg of Omzotirome with ARBs vs administration of ARBs alone in patients Detailed description of the invention:

The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and also combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The term “cardiometabolic-based chronic disease” as used herein refers to one or more conditions selected from insulin resistance, prediabetes, type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, micro- and macro-vascular complications.

The term “omzotirome” as used herein refers to 3-[4-(7-hydroxy-6-methyl-indan- 4-ylmethyl)-3,5-dimethyl-pyrazol-l-yl]-propionic acid or its pharmaceutically acceptable salt and polymorph, hydrate, solvates, complexes, prodrug or cocrystal thereof. Omzotirome may be in a form of co-crystal or pharmaceutically acceptable salt or prodrug with any of the antidiabetic agent, anti-hypertensive agent or any anti-dyslipidemic agents, as defined herein.

The term “in recognized need thereof’ as used herein refers to patients who have at least one risk factor for cardio-metabolic based chronic disease. Patient in recognized need thereof according to invention includes patients with diabetes, hypertension and/or dyslipidemia. The term “therapeutically effective amount” as used herein for omzotirome refers to the amount of omzotirome, which provides improvement in glycemic control, blood pressure control and/or lipid control. Such therapeutically effective amount may vary from 25 mg to 75 mg. preferably, therapeutically effective amount of omzotirome is 30 mg to 50 mg. More specifically, therapeutically effective amount of omzotirome is 45-50 mg or about 45 mg.

The term “antidiabetic agent” or antidiabetics as used herein is defined to mean any agent which is known to or expected to control diabetes or pre-diabetes. These agents can be alternatively mentioned as Hypoglycemic agents and include both oral as well as injectable agents. Preferably, antidiabetic agents or hypoglycemic agents include without limitation biguanides, sulfonylureas, alpha glucosidase inhibitors, PPARy agonists, PPARa agonists, PPAR6 agonists or antagonists, PPARa/y dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, SGLT2 inhibitors, Insulin, glycogen phosphorylase inhibitors, glucagon-like peptide- 1 (GLP-1), dual incretin receptor agonist and/or meglitinides, or a pharmaceutically acceptable salt, or combinations thereof.

The term “Diabetes” as used herein refers to Type-II diabetes.

The term “anti-dyslipidemic agent” as used herein is defined to mean lipid lowering agents including without limitation HMG Co A reductase inhibitors, PPAR a agonists, PPAR dual a/y agonists, PPAR 6 agonists, fibric acid derivatives, cholesterol absorption inhibitors, ileal Na+/bile acid cotransporter inhibitors, bile acid sequestrants, proprotein convertase subtilisin/Kexin 9 (PCSK 9) inhibitors and/or nicotinic acid and derivatives, or pharmaceutically acceptable salt, or combination thereof.

The term “anti-hypertensive agent” or antihypertensives as used herein is defined to mean any agent which controls the blood pressure. These agents include without limitation angiotensin converting enzyme (ACE) inhibitor, direct renin inhibitor, beta adrenergic receptor blocker, alpha adrenergic receptor blocker, calcium channel blocker, potassium channel activator, aldosterone synthase inhibitor, neutral endopeptidase (NEP) inhibitor, angiotensin II receptor blockers, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin receptor antagonist, angiotensin receptor neprilysin inhibitor (ARNI), dual angiotensin and endothelin receptor antagonist (DARA), diuretic or pharmaceutically acceptable salt, or combination thereof. Preferably, antihypertensive agents are agents acting on renin-angiotensin system. The agents acting on renin-angiotensin system includes angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blocker (ARB) and direct renin inhibitors.

The use of the terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Such combination of invention is used for managing cardio-metabolic based chronic disease in patients in recognized need thereof. More specifically, present invention provides combination of omzotirome and one or more antihypertensive agent for use in managing cardio-metabolic based chronic disease in patients in recognized need thereof.

Inventors of present invention have found that omzotirome shows synergistic effect in combination with one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent in improving glycemic control, blood pressure control and/or lipid control in patients with diabetes, hypertension and/or dyslipidemia. Preferably, combination of omzotirome improves glycemic control, blood pressure control and/or lipid control. Particularly, combination of omzotirome with antihypertensive agent provides synergistic effect in glycemic control, blood pressure control and/or lipid control.

One embodiment of present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another embodiment of present invention provides a combination of omzotirome and one or more antidiabetic agent.

The antidiabetic agents or hypoglycemic agents according to present invention include but not limited to biguanides, sulfonylureas, alpha glucosidase inhibitors, PPARy agonists, PPARa agonists, PPAR6 agonists or antagonists, PPARa/y dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dual incretin receptor agonist and/or meglitinides, or a pharmaceutically acceptable salt, or combinations thereof.

Specifically, antidiabetic agent or hypoglycemic agent can be selected from metformin, glyburide, glimepiride, glibenclamide, glipizide, gliclazide, chlorpropamide, gliquidone, glisoxepide, glyclopyramide, acarbose, camiglibose, emiglitate, miglitol, voglibose, salbostatin, rosiglitazone, pioglitazone, lobeglitazone, vildagliptin, sitagliptin, saxagliptin, linagliptin, teneligliptin , gemigliptin, anagliptin, telagliptin, omarigliptin, evogliptin, gosogliptin, dutogliptin, alogliptin, repaglinide, nateglinide, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, tofogliflozin, hanagliflozin, dorzagliatin, chiglitazar, saroglitazar, semaglutide, exenatide, liraglutide, dulaglutide, tirzepatide, Insulin, Insulin lispro, Insulin aspart, Insulin glulisine, Insulin Glargine, Insulin Detemir and pharmaceutical acceptable salt thereof and combination thereof. The antidiabetic agent according to present invention can be used in the amount ranging from 1 mg to 1000 mg, particularly antidiabetic agent can be from 250mg to 1000 mg or 30 mg to 80 mg, or 2.5 mg to 10 mg or 1 mg to 8 mg or 1.25 mg to 6 mg or 25 mg to 100 mg.

Preferably, antidiabetic agent or hypoglycemic agent is metformin, gliclazide, glipizide, glimepiride, glibenclamide, sitagliptin, teneligliptin, vildagliptin, pioglitazone, acarbose, voglibose, repaglinide or pharmaceutical acceptable salt thereof or combination thereof.

Most preferably, antidiabetic agent or hypoglycemic agent is metformin or combination of metformin and sufonylurea such as glyburide, glimepiride, glipizide, glibenclamide, gliclazide, chlorpropamide, gliquidone, glisoxepide, glyclopyramide or pharmaceutical acceptable salt thereof.

Omzotirome according to any of the embodiment of present invention can range from 25 mg to 75 mg. preferably, omzotirome ranges from 30 mg to 50 mg. More specifically, it is 45-50 mg or about 45 mg.

Combination of present invention include 45 to 50 mg of omzotirome and 1 mg to 1000 mg of antidiabetic agents. For example, combination may include 250 mg to 1000 mg of metformin or metformin HC1; 30 mg to 80 mg of gliclazide; 2.5 mg to 10 mg glipizide; 0.5mg to 8 mg of glimepiride; 1.25 mg to 6 mg of glyburide or glyburide potassium; 20 mg of teneligliptin or teneligliptin HBr; 25 mg to 100 mg of sitagliptin or sitagliptin phosphate, 50 mg to 100 mg of vildagliptin.

Such antidiabetic agents can be administered once daily, twice daily or thrice daily.

Another embodiment of present invention provides a combination of omzotirome and one or more antidiabetic agent selected from metformin, glyburide, glimepiride, glipizide, gliclazide, chlorpropamide, gliquidone, glisoxepide, glyclopyramide. acarbose, camiglibose, emiglitate, miglitol, voglibose, salbostatin, rosiglitazone, pioglitazone, lobeglitazone, vildagliptin, sitagliptin, saxagliptin, linagliptin, teneligliptin , gemigliptin, anagliptin, telagliptin, omarigliptin, evogliptin, gosogliptin, dutogliptin, alogliptin, repaglinide, nateglinide, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, Ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, tofogliflozin, hanagliflozin, dorzagliatin, chiglitazar, saroglitazar, semaglutide, exenatide, liraglutide, dulaglutide, tirzepatide, Insulin, Insulin lispro, Insulin aspart, Insulin glulisine, Insulin Glargine, Insulin Detemir and pharmaceutical acceptable salt thereof.

Another embodiment of present invention provides a combination of omzotirome and one or more of metformin, gliclazide, glipizide, glimepiride, glibenclamide, sitagliptin, teneligliptin, vildagliptin, pioglitazone, acarbose, voglibose, repaglinide, semaglutide or pharmaceutical acceptable salt thereof.

Another embodiment of present invention provides a combination of omzotirome and one or more antihypertensive agent.

The antihypertensive agents according to present invention include but not limited to angiotensin converting enzyme (ACE) inhibitor, renin inhibitor, beta adrenergic receptor blocker, alpha adrenergic receptor blocker, angiotensin receptor blockers (ARB), calcium channel blocker, potassium channel activator, aldosterone synthase inhibitor, neutral endopeptidase (NEP) inhibitor, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin receptor antagonist, angiotensin receptor neprilysin inhibitor (ARNI), dual angiotensin and endothelin receptor antagonist (DARA), diuretic or a pharmaceutically acceptable salt, or a combination thereof. Preferably, antihypertensive agents are agents acting on renin-angiotensin system. The agents acting on renin-angiotensin system include angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor. Specifically, the antihypertensive agent is selected from captopril, cilazapnl, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/ olmesartan medoxomil, candesartan/ candesartan cilexetil, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine, aliskiren and pharmaceutically acceptable salt thereof and combination thereof.

Preferably, antihypertensive agent is selected from valsartan, losartan, telmisartan, olmesartan/ olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof.

Most preferably, antihypertensive agent is angiotensin II receptor blocker (ARB) selected from valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/ olmesartan medoxomil, candesartan/ candesartan cilexetil and pharmaceutical acceptable salt thereof and combination thereof. Alternatively, preferred antihypertensive agent is ACE inhibitor selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spiraprilat, lisinopril, perindopril, pivopril, quinapril, ramipril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof. In another preferred embodiment, antihypertensive agent comprises combination of ACE inhibitor and angiotensin II receptor blocker (ARB).

In another preferred embodiment, antihypertensive agent is beta blocker selected from propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol and pharmaceutical acceptable salt thereof and combination thereof.

Another embodiment of present invention provides a combination of omzotirome and one or more antihypertensive agent selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/ olmesartan medoxomil, candesartan/ candesartan cilexetil amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine and pharmaceutically acceptable salt thereof.

Another embodiment of present invention provides combination of omzotirome and one or more antihypertensive agent selected from valsartan, losartan, telmisartan, olmesartan/olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapnl, spirapnl, lisinopril, penndopnl, pivopnl, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, aliskiren and pharmaceutical acceptable salt thereof.

In a most preferred embodiment present invention provides combination of omzotirome and one or more antihypertensive agent selected from valsartan, losartan, telmisartan, olmesartan/olmesartan medoxomil, enalapril, ramipril and pharmaceutical acceptable salt thereof.

The antihypertensive agent according to present invention can be used in the amount ranging from 0.5 mg to lOOOmg, particularly ACE inhibitors can be from 0.5 mg to 500 mg or 0.5 mg to 250 mg or 1 mg to 80 mg or 1 mg to 40 mg or 1.25 mg to 20 mg and angiotensin II receptor blocker (ARB) can be from 1 mg to 500 mg or 5 mg to 140 mg or 5 mg to 100 mg or 5 mg to 80 mg or 4 mg to 32 mg or 20 mg to 320 mg, or 25 mg to 100 mg or 40 mg to 80 mg or 75 mg to 300 mg.

Preferably, present invention provides combination of omzotirome and one or more antihypertensive agent selected from olmesartan/olmesartan medoxomil, telmisartan, enalapril, ramipril, and pharmaceutical acceptable salt thereof.

Combination of present invention include 45 to 50 mg of omzotirome and 0.5 mg to 500 mg of ACE inhibitor or angiotensin II receptor blocker (ARB). Preferably, combinations includes 1 mg to 100 mg, or 1.25 mg to 40 mg or 5mg to 40 mg or 2.5 mg to 20 mg of ACE inhibitors and/or 4 mg to 320 mg or 5 mg to 40 mg or 20 mg to 80 mg or 20 mg to 100 mg of angiotensin II receptor blocker. For example, combination may include 12.5 mg, 25 mg, 50 mg 100 mg or 150mg of captopril; 1.25mg, 2.5 mg, 5 mg, 10 mg, or 20 mg of enalapril or enalapril maleate; 1.25 mg, 2.5 mg, 5 mg or 10 mg of ramipril; 5mg, 10 mg, 20mg or 40mg quinapril HC1; 2mg, 4mg or 8 mg of perindopril erbumine or 2.5mg, 5mg, 7 mg or 10 mg of perindopril arginine; 2.5mg, 5mg, 10 mg, 20 mg, 30mg or 40mg of lisinopril; 5mg, lOmg, 20mg or 40 mg of benazepril or benazepril HC1, Img, 2mg or 4 mg of trandopril; lOmg, 20mg or 40 mg of monopril; 40 mg, 80 mg, 160 mg or 320 mg of valsartan; 25 mg, 50 mg or 100 mg of losartan or losartan potassium; 20 mg, 40 mg or 80 mg of telmisartan; 5 mg, 20 mg or 40 mg of olmesartan or olmesartan medoxomil; 75 mg, 150 mg or 300 mg of irbesartan; 40 mg or 80 mg of azilsartan or azilsartan medoximil or 4mg, 8mg, 16 mg or 32 mg of candesartan or candesartan cilexetil.

Such antihypertensive agents can be administered once daily, twice daily or thrice daily.

Another embodiment present invention provides a combination of omzotirome and one or more anti-dyslipidemic agent.

The anti-dyslipidemic agent according to present invention includes but not limited to MTP inhibitors, HMG Co A reductase inhibitors, PPAR a agonists, PPAR dual a/y agonists, PPAR 6 agonists, fibric acid derivatives, cholesterol absorption inhibitors, ileal Na+/bile acid cotransporter inhibitors, bile acid sequestrants, PCSK-9 inhibitors, and/or nicotinic acid and derivatives or pharmaceutically acceptable salt thereof or combination thereof.

Specifically, anti-dyslipidemic agent is selected from statins such as atorvastatin, rosuvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, simvastatin; fibric acid derivatives or fibrates such as fenofibrate, choline fenofibrate, cirofibrate, bezafibrate gemfibrozil; niacin, ezetimibe, volixibat, colestipol, cholestyramine, colesevelam and pharmaceutically acceptable salt thereof and combination thereof.

The anti-dyslipidemic agent according to present invention can be used in the amount ranging from 5 mg to 300 mg, particularly statins can be from 5 mg to 80 mg and fibrates can be from 30 mg to 300 mg.

Preferably, anti-dyslipidemic agent is combination of statin or pharmaceutical acceptable salt thereof and fibrates or pharmaceutical acceptable salt thereof. Most preferably, anti-dyslipidemic agent is selected from atorvastatin, rosuvastatin, fenofibrate, pharmaceutical acceptable salt thereof and combination thereof.

Therefore, another embodiment of present invention provides combination of omzotirome and one or more anti-dyslipidemic agent selected from atorvastatin, rosuvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, simvastatin fenofibrate, choline fenofibrate, cirofibrate, bezafibrate gemfibrozil, niacin, ezetimibe, volixibat, colestipol, cholestyramine, colesevelam and pharmaceutically acceptable salt thereof and combination thereof.

Combination of present invention include 45 to 50 mg of omzotirome and 5 mg to 300 mg of anti-dyslipidemic agent. Preferably, combinations includes 10 mg to 80 mg of atorvastatin or atorvastatin calcium; 5 mg to 40 mg of rosuvastatin or rosuvastatin Ca; 5 mg to 80 mg of simvastatin; 30mg to 300 mg of fenofibrate.

Such antidyslipidemic agents can be administered once daily, twice daily or thrice daily.

Another embodiment of present invention provides a combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti- dyslipidemic agent.

Such combinations include one or more antidiabetic agent selected from metformin, glyburide, glimepiride, glipizide, gliclazide, chlorpropamide, gliquidone, glisoxepide, glyclopyramide. acarbose, camiglibose, emiglitate, miglitol, voglibose, salbostatin, rosiglitazone, pioglitazone, lobeglitazone, vildagliptin, sitagliptin, saxagliptin, linagliptin, teneligliptin , gemigliptin, anagliptin, telagliptin, omarigliptin, evogliptin, gosogliptin, dutogliptin, alogliptin, repaglinide, nateglinide, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, Ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, tofogliflozin, hanagliflozin, dorzagliatin, chiglitazar, saroglitazar, semaglutide, exenatide, liraglutide, dulaglutide, tirzepatide, Insulin, Insulin lispro, Insulin aspart, Insulin glulisine, Insulin Glargine, Insulin Detemir and pharmaceutical acceptable salt thereof; one or more antihypertensive agent selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/ olmesartan medoxomil, candesartan/ candesartan cilexetil, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine, aliskiren and pharmaceutical acceptable salt thereof; and/or one or more anti-dyslipidemic agent selected from atorvastatin, rosuvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, simvastatin; fibrates such as fenofibrate, choline fenofibrate, cirofibrate, bezafibrate gemfibrozil, niacin, ezetimibe, volixibat, colestipol, cholestyramine, colesevelam and pharmaceutical acceptable salt thereof.

In a preferred embodiment, combinations include one or more antidiabetic agent selected from metformin, gliclazide, glipizide, glimepiride, glibenclamide, sitagliptin, vildagliptin, pioglitazone, acarbose, voglibose, repaglinide or pharmaceutical acceptable salt thereof; one or more antihypertensive agent selected from valsartan, losartan, telmisartan, olmesartan, atenolol, metaprolol, carvedilol, nebivolol, enalapril, ramipril, chlorthalidone, hydrochlorthiazide, amlodipine, clinidipine, levamlodipine or pharmaceutical acceptable salt thereof and/or one or more anti-dyslipidermc agent selected from atorvastatin, rosuvastatin, fenofibrate or pharmaceutical acceptable salt thereof.

Combination according to present invention are used for managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another embodiment of present invention provides a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another embodiment of the present invention provides a method of managing cardio-metabolic based chronic disease by improving glycemic control and blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent.

Another embodiment of the present invention provides a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Another embodiment of the present invention provides a method of managing cardio-metabolic based chronic disease by improving glycemic control and blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent.

Another embodiment of the present invention provides a method of improving glycemic control in a patient with uncontrolled diabetes, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent or antihypertensive agent. The patients with uncontrolled diabetes are characterized by having HbAlc >6.4 % and is taking < 2 oral hypoglycemic agents, preferably for at least 2 months prior to said administration. Preferably, the invention includes the patients who have HbAlc >7.5 % to 10 % prior to said administration.

Another embodiment of the present invention provides a method of improving blood pressure control in a patient with hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent. The patients with hypertension are characterized by having Mean Arterial Pressure (MAP) >100 mm Hg based on average of 24 hours’ ambulatory blood pressure monitoring (ABPM) or having systolic blood pressure (SBP) >130 mmHg, and diastolic blood pressure (DBP) >85 mmHg and optionally taking one or more anti-hypertensive agent particularly ACE inhibitor or angiotensin II receptor blocker. The patients are preferably on stable dose of at least one antihypertensive agent.

Another embodiment of the present invention provides a method of improving lipid control in a patient with dyslipidemia by administering therapeutically effective amount of omzotirome and one or more anti-dyslipidemic agent. The patient with dyslipidemia are characterized by having Non-HDL cholesterol of > 160mg/dL or Serum triglycerides of 150 mg/dL-400 mg/dL. Method of treating or improving or managing according to any of the embodiment of present invention include oral administration of omzotirome once daily, preferably in a dose of 45mg to 50 mg, most preferably in a dose of 45 mg.

Another embodiment of the present invention provides a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising, administering to the patient 45 mg of omzotirome.

Another embodiment of the present invention provides a method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising, administering to the patient 45 mg of omzotirome, optionally in combination with antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

The patients managed by present invention can have one or more of the conditions selected from diabetes, dyslipidemia or hypertension. Further, the patients are overweight having BMI index of 23-39 kg/m².

Patients managed by present invention also include those who are taking < 2 oral hypoglycemic agents for at least two months prior to administration of omzotirome and one or more antidiabetic agent, anti-dyslipidemic agent, or antihypertensive agent. The antidiabetic agent administered with omzotirome can be same or different from antidiabetic agents on which patients were stabilized prior to said administration.

Patients managed by any of the embodiment of present invention can have one or more of following conditions:

1. Male and female patients in the age range 30-70 years (both inclusive) 2. BMI in the range 23-39 (inclusive) kg/m²

3. HbAlc is about 6.4- 10 %, preferably about 7.5-10%

4. Stable therapy of < 2 oral hypoglycemic agents for at least two months prior to initiating omzotirome

5. Non HDL-cholesterol > 160 mg/dL.

6. Serum triglycerides 150 mg/dL-400 mg/dL

7. Fasting Glucose - > 126 mg/dL

8. Waist circumference > 90 cm (men) and >80 cm (women)

9. apolipoprotein-B (apo-B) >100 mg/dL,

10. Mean Arterial Pressure (MAP) >100 mm Hg based on average of 24 hours’ ambulatory blood pressure monitoring (ABPM) with or without anti-hypertensive treatment.

11. Diastolic BP- 85-110 mm Hg; Systolic BP 130-180 mm Hg

12. Have eGFR >30 mL/min as evaluated by Modification of Diet in Renal Disease (MDRD) method

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, Angiotensin II receptor blocker (ARB) and direct renin inhibitor.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor. Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/ olmesartan medoxomil, candesartan/ candesartan cilexetil amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine, aliskiren and pharmaceutically acceptable salt thereof.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/olmesartan medoxomil, candesartan/ candesartan cilexetil, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, mmodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine, aliskiren and pharmaceutically acceptable salt thereof.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan/olmesartan medoxomil, candesartan/ candesartan cilexetil, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, levamlodipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, propanolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, hydrochlorothiazide, chlorthalidone, sacubitril, sacubitril-valsartan, candoxatril, ecadotril, macitentan, bosentan, ambrisentan, diazoxide, nicorandil, retigabine, aliskiren and pharmaceutically acceptable salt thereof.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from valsartan, losartan, telmisartan, olmesartan/olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, aliskiren and pharmaceutical acceptable salt thereof.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient with diabetes and/or hypertension, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from valsartan, losartan, telmisartan, olmesartan/olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril, aliskiren and pharmaceutical acceptable salt thereof.

Preferably, present invention provides method of managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent selected from olmesartan/olmesartan medoxomil, telmisartan, losartan, enalapril, ramipril, lisinopril and pharmaceutical acceptable salt thereof.

Additionally, inventors of present invention surprisingly found that combination of omzotirome and one or more antihypertensive agent also improves lipid control. Clinically this is very relevant, particularly when patients have dyslipidemia; and thereby help in managing cardio-metabolic based chronic disease. Therefore, according to any of the embodiment, present invention provides omzotirome and one or more antihypertensive agent, particularly angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor, for managing cardio-metabolic based chronic disease by improving lipid control in a patient. Such lipid control can be in addition to the glycemic control and or blood pressure control.

Another embodiment of present invention provides method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient with diabetes, hypertension and/or dyslipidemia, comprising administering to the patient therapeutically effective amount of omzotirome and one or more anti-dyslipidemic agent selected from atorvastatin, rosuvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, simvastatin fenofibrate, choline fenofibrate, cirofibrate, bezafibrate gemfibrozil, niacin, ezetimibe, volixibat, colestipol, cholestyramine, colesevelam and pharmaceutically acceptable salt thereof.

Another embodiment of present invention provides a method of managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient pharmaceutical composition comprising therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

Another embodiment of present invention provides use of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for preparation of medicament for managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof. Patient in recognized need thereof according to invention includes patients with diabetes, hypertension and/or dyslipidemia. Another embodiment of present invention provides use of omzotirome and one or more antihypertensive agent for preparation of medicament for managing cardio- metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Another embodiment of present invention provides use of omzotirome and one or more antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor for preparation of medicament for managing cardio-metabolic based chronic disease by improving glycemic control and/or blood pressure control in a patient in recognized need thereof.

Present invention includes administration of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent either sequentially or simultaneously or in any order.

Omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent according to present invention can be administered together, one after the other, or separately in one combined unit dose form or in two separate unit dosage form.

Since co-administration of omzotirome with antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent show synergistic effect, it is expected that desired improvement in glycemic control, blood pressure control and/or lipid control will be achieved with lower amount of antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent than its standard amount, when combination according to present invention is administered. It is specifically useful for the population of patients in which standard amount of antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic are either in-tolerated or contraindicated because of side effects or disease condition. In another embodiment, omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent are administered in patients in the form of a pharmaceutical composition. Thus, present invention provides a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for use in managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof.

Present invention also provides a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Such compositions further comprises one or more pharmaceutically acceptable carrier.

Therefore, another embodiment of present invention provides a pharmaceutical composition comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Preferably, said pharmaceutical composition is solid oral composition and the pharmaceutical composition according to present invention, may comprise suitable carrier.

The pharmaceutical composition according to present invention comprises 45 mg or 50 mg of omzotirome and therapeutically effective amount of antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Preferably, pharmaceutical composition according to present invention comprises 45 mg of omzotirome.

The pharmaceutical composition according to present invention comprises 45 mg or 50 mg of omzotirome and therapeutically effective amount of antihypertensive agent selected from angiotensin converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB). In a preferred embodiment the pharmaceutical composition according to present invention comprises 45 mg or 50 mg of omzotirome and enalapril, ramipril, olmesartan, or telmisartan or pharmaceutically acceptable salts or mixture thereof.

Said pharmaceutical composition is solid oral composition and the pharmaceutical composition according to present invention, may comprise suitable carrier

According to present invention, ratio of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent may vary from about 1: 40 to 40 :1; or 1:40 to 50:1; preferably ratio is about 1: 20 to 20: 1.

According to present invention, ratio of amount of omzotirome and one or more antihypertensive agent may vary from about 1:40 to 40:1; or 1:20 to 50:1, preferably ratio is about 1: 20 to 20: 1 or 1:10 to 50:1.

According to present invention, ratio of amount of omzotirome and ACE inhibitor may vary from about 1:0.01 to 1: 3.4, preferably it will be about 1:0.025 to 1:0.45 or 1:0.025 to 1:0.3 or 1:0.04 to 1:0.3 or 1:0.05 to 1:0.9.

According to present invention, ratio of amount of omzotirome and ARB may vary from about 1:0.08 to 1:7.2, preferably it will be about 1:0.1 to 1:0.9 or 1:0.4 to 1:1.8 or 1:0.08 to 1:0.72 or 1:0.5 to 1:2.2 or 1:0.8 to 1:1.8

According to present invention, ratio of amount of omzotirome and olmesartan may vary from about 1:0.1 to 1:0.9 and ratio of omzotirome and telmisartan may vary from about 1:0.4 to 1:1.8 and ratio of omzotirome and enalapril may vary from about 1:0.025 to 1:0.45 while ratio of omzotirome and ramipril may vary from about 1:0.025 to 1:0.3.

In a most preferred embodiment the pharmaceutical composition according to present invention comprises omzotirome and enalapril or its pharmaceutically acceptable salts thereof in a ratio of amount between about 1:0.025 to 1:0.45 and suitable pharmaceutical carrier.

In an another most preferred embodiment the pharmaceutical composition according to present invention comprises omzotirome and olmesartan or its pharmaceutically acceptable salts thereof in a ratio of amount between about 1:0.1 to 1:0.9 and suitable pharmaceutical carrier.

In another embodiment, said pharmaceutical composition comprises omzotirome in one unit composition and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent in another unit composition and both or all the units are merged or packed to form a kit. Thus present invention also provides a kit comprising omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

In another embodiment, said pharmaceutical composition comprises omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti- dyslipidemic agent in single unit composition.

The two active agents in a single pharmaceutical composition can be either mixed together or can be separated by suitable means to overcome the problem of incompatibility. For example, omzotirome can be prepared in the form of core with suitable pharmaceutical carrier and one or more antidiabetic agent, anti- dyslipidemic agent, or antihypertensive agent are coated over such core. Said coatings may be single coating or multiple coating having one or more of antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Core and multiple coating comprising active ingredient, can be separated by using barrier coating.

Suitable pharmaceutical carrier according to present invention include diluent, binder, disintegrant, lubricant, glidant, surfactant, pH adjusting agent, buffering agent etc or mixture thereof. Suitable class of excipient used for preparation of solid composition is disclosed in Handbook of pharmaceutical Excipients, 6^th edition.

A diluent is selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof. The diluent may be present in an amount ranging from 10-98% w/w of the total composition.

A binder is selected from starches such as maize starch, corn starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, hydroxyethyl cellulose; polyvinyl pyrrolidone, gelatin, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof. The binder may be present in an amount ranging from 0.5-20% w/w of the total composition.

A lubricant or glidant is selected from talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.02-10% w/w of the total composition.

A surfactant is selected from one or more non-ionic or ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylenepolyoxypropylene block copolymers such as those sold under the brand name Poloxamer®, soy lecithin, or mixtures thereof. The surfactant may be present in an amount ranging from 0.01-20% w/w of the total composition.

A pH adjusting agent according to present invention is any agent which maintains the pH of the composition, preferably above 3. A pH adjusting agent is either organic or inorganic agent. The non limiting examples of such agent are meglumine, NaOH, KOH, NH3, ammonium hydroxide, carbonates such as sodium carbonate, magnesium carbonate or potassium carbonate and the like. pH adjusting agent also includes buffering agent. The pH adjusting agent may be present in an amount ranging from 0.01-20% w/w of the total composition.

A buffering agent is selected from phosphates such as sodium phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate; boric acid and borates such as, sodium borate and potassium borate; citric acid and citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium hydrogen carbonate and the like. The buffering agent may be present in an amount ranging from 0.01-20% w/w of the total composition.

A disintegrant is sodium starch glycolate, crospovidone, croscarmellose sodium and the like. The disintegrant may be present in an amount ranging from 0.1-15% w/w of the total composition.

Composition may be optionally film coated comprising one or more of film forming polymer. Film forming polymers is selected from polyvinyl alcohol, hydroxpropyl methylcellulose, methylcellulose, ethylcellulose, polyethylene glycol, hydroxypropyl cellulose, povidone, polydextrose, lactose, maltodextrin, acrylic polymer, or mixtures thereof. Film forming polymers may be present in an amount ranging from 0.1-10% w/w of the total composition. Alternatively, film coating can also be used as barrier coating, when composition comprising combination of present invention is prepared.

The composition according to present invention can be in the form of immediate release composition or controlled release composition. In one embodiment, pharmaceutical composition comprising combination of present invention can have one active ingredient in immediate release form and other active ingredient in either immediate release form or controlled release form. Preferably, omzotirome is in immediate release form and antidiabetic agent or antihypertensive agent or anti-dyslipidemic agent in either immediate release form or controlled release form. The pharmaceutical composition according to present invention can be uncoated or coated with a suitable coating agent.

Another embodiment of present invention provides a pharmaceutical composition comprising 45 mg of Omzotirome, 10-98% of diluent; 0.5 to 20% of binder and 0.02 to 10% of lubricant.

A further embodiment provides a pharmaceutical composition comprising 20-70% of Omzotirome, 10-98% of diluent; 0.5 to 20% of binder and 0.02 to 10% of lubricant by total weight of composition.

Preferably, composition comprises from 10-80% or 20-70% or 30-60% or 40-50% or 42-47% of diluent; 1-10% or 1-5% or 2-3% of binder; and 0.1-5% or 0.5-2% or 0.5-1% of lubricant by total weight of composition.

Such total weight of composition excludes any film coating over the tablet or capsule shell weight. Preferably, diluent according to present invention is Lactose and microcrystalline cellulose; binder is hydroxypropyl cellulose and hydroxypropyl methylcellulose and lubricant is Magnesium stearate.

“Pharmaceutically acceptable carrier suitable for controlled release” includes one or more excipients which facilitates controlled release of the active ingredient. Such excipients include polymeric or non-polymeric compounds, preferably polymeric compounds. Such polymeric compounds may further are water soluble polymers or water insoluble polymers.

“Water-soluble polymer” used in the present composition is polymer which is soluble or swellable in water. Preferably, it dissolves and/or swells in water at room temperatures. Non limiting examples include the cellulose ethers, hydrocolloid (gum), polyvinyl alcohol and polyvinyl pyrrolidone.

The cellulose ethers include carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethylmethyl cellulose, hydroxyethylethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, hydroxybutylmethyl cellulose, hydroxybutylethyl cellulose, carboxymethyl cellulose and salts thereof, hydrocolloid (gum) includes guar gum, alginic acid and its pharmaceutically acceptable salts e.g., sodium alginate and xanthan gum. Preferably, polymer is sodium carboxymethyl cellulose.

“Water insoluble polymer” used in present invention are the polymer which are substantially insoluble in water and include cellulose ethers such as ethylcellulose, butylcellulose, cellulose acetate, cellulose acetate butyrate, ethylene vinyl acetate copolymer, polyvidone acetate, polyvinyl acetate, polyvinyl butyrate, polymethacrylates, including ethylacrylate/methylmethacrylate copolymers, and ammonia methacrylate copolymers, thus including commercially available dispersions such as Kollicoat® MAE30DP, Eudragit® RL30D, Eudragit® NE30D, and Eudragit® RS30D. The pharmaceutical compositions may additionally contain excipients such as colorants selected from known F.D. & C. and D. & C. dyes, titanium dioxide and the like.

The pharmaceutical composition as described herein may be obtained in any suitable form such as tablet, capsule, powder, oral solution, suspension and the like.

Further embodiment of the present invention provides a process of preparation of pharmaceutical composition of present invention.

Composition according to present invention can be prepared by any method known in the art such as by mixing omzotirome with pharmaceutically acceptable carriers. Alternatively wet granulation or dry granulation techniques may be employed for the preparation of composition according to present invention.

In an embodiment, the pharmaceutical composition according to present invention is tablet, which is prepared by using wet granulation process, preferably using rapid mixer granulator. Process comprises granulation of Omzotirome and diluent with aqueous or non-aqueous solution of binder followed by compression to form tablet. Preferably, a part of diluent is used intragranularly and part of diluent is used extragranularly. Optionally, tablet can be film coated using aqueous or nonaqueous coating solution or suspension.

Alternatively, composition of present invention can be prepared as matrix based formulation in which omzotirome is dispersed within a matrix. Alternatively, omzotirome containing particles may be coated by suitable pharmaceutically acceptable carriers, optionally with one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent. Types of particles include granules, pellets, minitablets, microparticles or beads. The invention according to present invention may be illustrated by the following examples, which are not to be construed as limiting the scope of the invention:

Example 1

A randomized, multicentre, double-blind, placebo-controlled, parallel-group, study conducted in India.

Eligible patients were men and women having fasting plasma glucose >126 mg/dL or glycated hemoglobin (HbAlc) of >6.4% (as determined by Biorad Variant II method) or were stabilized on treatment with < 2 oral hypoglycaemic agents; high blood pressure (systolic blood pressure (SBP) >130 mmHg, and diastolic blood pressure (DBP) >85 mmHg with/without antihypertensive treatment) and dyslipidemia (Serum Triglyceride (TG) > 150 mg/dL). Patients were taking either of metformin, metformin + sulfonylurea, statin + fibrate, ARB (angiotensin II receptor blocker) or Beta blocker or combination thereof as concomitant medication.

Eligible patients were randomly assigned in 1:1.5 ratio to receive either omzotirome 50 mg or placebo once-daily taken preferably in the morning under fasting conditions with water. Study was of 32 weeks, which consisted of a 4- week placebo-run-in phase, a 24-week double -blind, placebo-controlled treatment phase, and a 4 week of follow-up phase. Participants who were found suitable as per the eligibility criteria were started on placebo for 4-weeks in the placebo run- in phase within 2- weeks of screening.

During placebo-run-in phase, compliance to treatment was checked, dose adjustment of oral hypoglycemic agents and/or concomitant medication was carried out, and counselling for lifestyle modification was done. No modification in concomitant medication was allowed till the end of the treatment or follow-up visits after randomization unless there is an emergency.

Fasting plasma glucose, blood pressure and Lipid control was checked in patients. Results:

Fasting Plasma Glucose (FPG)- Treatment with omzotirome showed a dosedependent reduction in FPG up to 50 mg dose. It was surprisingly found that combination of omzotirome with metformin or metformin + sulfonylurea improved fasting plasma glucose significantly (more than 10%) as compared to metformin alone or combination of + metformin + sulfonylurea. It shows that omzotirome work synergistically with metformin or metformin+ sulphonylurea and thus significantly improved fasting plasma glucose change. (As shown in Fig 2)

Blood Pressure- It was surprisingly found that compared to beta blockers alone, combination of beta blocker and omzotirome works synergistically and reduces the mean arterial blood pressure significantly (8mmHg) (As shown in figure 3A). Similarly, compared to administering ARB alone, the rate of increase in mean arterial blood pressure was significantly reduced (2mmHg) by administering omzotirome+ ARB (angiotensin II receptor blocker). (As shown in Fig 3B)

Lipid parameters- It was surprisingly found that compared to statin + fibrates, combination of omzotirome with statin and fibrates synergistically improved n- HDLc and LDL-c, as shown in figure 1A and IB.

Though it was expected from pre-clinical trials that omzotirome would work in improving cardio-metabolic based chronic disease, however desired outcome was not observed in Human trials, as disclosed by Valk et al. Surprisingly, when omzotirome was administered as add-on to the anti-diabetic agents, antihypertensive agent or anti-dyslipidemic agent, unexpected synergistic effect was observed in improving fasting plasma glucose, hypertension and lipid content, which would reduce cardio-metabolic based chronic disease. Further trials are being undertaken to confirm this effect in large pool of patients at risk of cardio- metabolic based chronic disease. The parameters were analyzed using one-way analysis of variance (ANOVA) to identify the statistical difference between four groups using last observation carried forward (LOCF) for missing data and after checking assumptions for normality and homogeneity of variance. The pair-wise comparison was carried out between the treatment groups and placebo using Tukey’s test. In case the variables were non-normally distributed, the Kruskal -Wallis test was performed. This was followed by post hoc analysis using the Dwass, Steel, Critchlow-Fligner (DSCF) multiple comparison procedure performed at a 5% level of significance. Statistical analyses were performed using the SAS (Statistical Analysis Software 9.4, SAS Institute Inc, Cary, North Carolina, USA)

Example 2

A randomized, double blind, parallel group, placebo controlled, multi-centre, multinational study conducted in patients receiving standard of care therapy. The study included screening, randomization, 24 weeks in main study, 26 weeks in safety extension period and post treatment follow up visit, 4 weeks post completion of treatment period. Patients completed 24 weeks of main study were rolled over to safety extension phase of 26 weeks where they were continued to receive either omzotirome 45mg, or matching placebo according to their initial randomization in the study.

Eligible patients were men and women having HbAlc >7.5 % (Estimated using HPLC/ Abbott afinion point of care device),, receiving stable therapy of < 2 oral hypoglycemic agents for at least two months prior to screening and Non HDL- cholesterol > 160 mg/dL (Non-HDL cholesterol is calculated using the formula “Non-HDL cholesterol = Total cholesterol-HDL cholesterol”. Total cholesterol and HDL-cholesterol are determined by Automated Chemistry Analyser/ Abbott afinion point of Care device) and Mean Arterial Pressure (MAP) >100 mm Hg based on average of 24 hours’ ambulatory blood pressure monitoring (ABPM) using Suntech Oscar 250 device, with or without anti-hypertensive treatment (patients taking anti-hypertensive treatment were on stable dose of antihypertensive treatment for at least two months prior to screening). Antihypertensive treatment includes enalapril maleate (5 or 10 mg/day), or olmesartan medoxomil (20 mg/day)

Results:

5 Blood pressure

It was observed that combination of Omzotirome + ACE inhibitor such as enalapril (ratio of 1:0.11 & 1:0.22) or Omzotirome + angiotensin II receptor blocker (ARB) such as olmesartan (ratio of 1: 0.44) work synergistically to reduce hypertension as given in table 1 below:

10

Table 1

SBP (Systolic Blood Pressure), DBP(Diastolic Blood Pressure) and MAP (Mean Arterial Pressure) were measured using Ambulatory Blood Pressure Monitoring Device. Data mentioned in table 1 represents change wrt baseline

15

Additionally, combination of Omzotirome + ACE inhibitor and angiotensin II receptor blocker reduces HbAlc and Non-HDL cholesterol as shown in table 2:

Table 2

Though it was expected from pre-clinical trials that omzotirome would work in improving cardio-metabolic based chronic disease, however desired outcome was not observed in Human trials, as disclosed by Valk et al. Surprisingly, when omzotirome was administered as add-on to the anti-hypertensive agent, unexpected synergistic effect was observed in improving glycemic control, lipid control & hypertension, which would reduce cardio-metabolic based chronic disease.

Example 3 Composition comprising omzotirome and metformin hydrochloride:

Manufacturing Process for Metformin Hydrochloride Blend:

1. Sift Metformin Hydrochloride, Microcrystalline cellulose, Povidone K90 and Sodium CMC through 20# sieve and collect in polybag. 2. Mix isopropyl alcohol and purified water and use it as granulation vehicle.

3. Load the materials of step no. 1.0 into Rapid Mixer Granulator and mix for 10 min. 4. Add the granulating vehicle of step no. 2.0 slowly using peristaltic pump to the dry mix of step no. 3.0 in rapid mixer granulator.

5. Dry the granules to get the desired LOD.

6. Mill granules through suitable mill screen.

7. Load milled granules into conta blender and blend for suitable time.

8. Add sifted Hydroxypropyl methyl cellulsoe into conta blender and blend for suitable time.

9. Add sifted magnesium stearate and talc to the granules of step 8.0 and lubricate for the appropriate time.

Manufacturing Process for Omzotirome Blend:

1. Sift Omzotirome and a part of Microcrystalline cellulose.

2. Add Hypromellose (3 cps) to water under stirring. Stir it to dissolve.

3. Load the materials of step no. 1.0 into Rapid Mixer Granulator and mix for 10 min.

4. Add the granulating vehicle of step no. 2.0 slowly using peristaltic pump to the dry mix of step no. 3.0 in rapid mixer granulator.

5. Dry the granules to get the desired LOD.

6. Sift dried granules through 30#.

7. Mill 30# retained granules through suitable mill screen.

8. Load milled granules and 30# passed granules in to conta blender and blend for suitable time.

9. Add sifted remaining part of microcrystalline cellulose into conta blender and blend for suitable time.

10. Add sifted magnesium stearate to the granules of step 9.0 and lubricate for the appropriate time.

Manufacturing Process for Tablets:

1. Compress metformin blend and Omzotirome blend bilayer tablets. Example 4

Composition comprising omzotirome:

Hypromellose (3 cps) was dissolved in water and Omzotirome and a part of Microcrystalline cellulose were sifted through 20# sieve and granulated using Hypromellose (3 cps)-water solution with Using Rapid Mixer Granulator. Obtained granules were dried and sifted followed by milling. Milled granules were loaded and passed through 30# and blended with remaining part of microcrystalline cellulose. Magnesium stearate was added to the blend and lubricated blend was compressed to form tablet.

Example 5

Formula composition of Omzotirome and Olmesartan Medoxomil Tablets

Manufacturing Process:

1) Sift Olmesartan Medoxomil, Omzotirome, Lactose monohydrate and Low substituted hydroxy propyl cellulose through suitable sieve and mix them in granulator.

2) Granulate step 1 mixture with Hydroxy propyl cellulose (Klucel LF) dissolved in purified water.

3) Dry the granules to achieve desire %LOD. Mill granules and mix it with microcrystalline cellulose PH 102 and Low substituted Hydroxy propyl cellulose.

4) Lubricate step 3 blend using magnesium stearate sifted through suitable sieve.

5) Compress tablets using suitable tooling and coat using Instacoat White in suitable coater.

Example 6

Formula composition of Omzotirome and Enalapril Maleate Tablets

Manufacturing Process:

1. Sift Omzotirome, Lactose monohydrate, microcrystalline cellulose PH 101, sodium starch glycollate and povidone K30 through suitable sieve and load them in fluid bed processor. 2. Dissolve Enalapril Maleate and Hydroxy propyl cellulose (Klucel LF) in purified water.

3. Granulate step 1 mixture using step 2 solution. Dry the granules to achieve desire %LOD. Mill granules and mix it with sodium starch glycollate.

4. Lubricate step 3 blend using magnesium stearate sifted through suitable sieve.

5. Compress tablets using suitable tooling and coat using Instacoat White in suitable coater.

Example 7

In-vitro study to check effect of combination of Omzotirome and ACE inhibitor or Omzotirome and ARBs on endothelin (ET-1) in human endothelial cells

Human microvascular endothelial cells (HMEC-1) were maintained in normal glucose (5mM) MCDB 131 medium containing lOng/ml epidermal growth factor, Img/ml hydrocortisone, lOmM glutamine and 10% FBS in 37°C in a humidified atmosphere containing 5% CO2.

One day before compound treatment, 1.5X10⁵ cells /well in 24 well plate were seeded. Cell seeded in high glucose (30mM) medium to generate hyper glycaemic condition. Next day of seeding, old medium was replaced with fresh phenol red free complete growth medium with 30mM glucose. Treatment of Omzotirome (50pM), Telmisartan (10pM& IpM), Ramipril (lOOnM) individually and combination of Omzotirome and ramipril or Omzotirome and telmisartan was given. Final concentration of DMSO was 0.5% in each condition.

After 48 hrs of treatment, supernatant was collected for endothelin (ET-1) quantitation. Cells were lysed and protein was estimated by BCA reagent. Secreted Endothelin were measured using Endothelin- 1 chemiluminescent Elisa (R&D systems). Protein normalized endothelin values were used for calculation and % inhibition of endothelin was calculated compared to vehicle control.

Result: Table 3 shows % reduction of endothelin (ET-1) level, which is a surrogate biomarker for endothelial dysfunction in hypertensive patients or animal models of hypertension. It was observed that combination of omzotirome and Ramipril (ACE inhibitor) (ratio of 1:0.002) as well combination of Omzotirome and telmisartan (ARB) (ratio of 1:0.02 & 1:0.2) resulted in significant synergistic reduction of ET-1 level as compared to the individual agents.

Table 3:

Example 8:

Male C57BL/6 mice were fed with a high-fat diet for 2 weeks followed by randomization to -

1. Vehicle-treated group (Polyoxyl 40 HCO, dibasic sodium phosphate,

Heptahydrate, purified water),

2. Individual drug treated groups receiving Telmisartan (0.3 mg. kg ¹, day ¹), Ramipiril (1 mg. kg ¹, day ¹) or omzotirome(15 mg. kg ¹, day ¹). 3. Combination treatment groups receiving Omzotirome 15 mg. kg ¹, day ¹ (as 7.5 mg BID) and Telmisartan 0.3 mg. kg ¹, day ¹ (OD) or omzotirome 15 mg. kg ¹, day ¹ (as 7.5 mg BID) and Ramipiril Img. kg ¹, day ¹ (OD). The total volume of administration in each treatment group was 10 ml/kg.

Animals were continued feeding on HFD during the treatment period.

Animals were treated by oral gavage for 6 weeks. Blood samples were collected from overnight-fasted animals by retro orbital venous puncture under isofluran anesthesia for analysis of serum Total Cholesterol (TC) and Tail vein blood was used for glucose quantification with a Glucometer (OneTouch Select® Plus, Life

Scan). Results are summarized in Table 4.

Table 4

Conclusion: It is evident from table 4 that combination of of omzotirome and Ramipril (ACE inhibitor) (ratio of 1:0.066) as well as combination of Omzotirome and telmisartan (ratio of 1:0.02) (ARB) resulted in synergistic effect in controlling glucose level and cholesterol level in diseased animals.

Claims

Claims:

1. A combination comprising omzotirome and one or more antihypertensive agent.

2. The combination according to claim 1, wherein antihypertensive agent is selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

3. The combination according to claim 2, wherein antihypertensive agent is selected from valsartan, losartan, telmisartan, olmesartan/ olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof.

4. The combination according to claim 3, wherein antihypertensive agent is selected from olmesartan, olmesartan medoxomil, telmisartan, enalapril, ramipril, and pharmaceutical acceptable salt thereof.

5. The combination according to claim 1, wherein combination comprises 45 mg of Omzotirome.

6. The combination according to claim 1, wherein combination comprises 1 mg to 500 mg antihypertensive agent.

7. The combination according to claim 1, wherein ratio of omzotirome and one or more antihypertensive agent is from about 1:10 to 50:1.

8. The combination according to claim 4, wherein ratio of omzotirome and olmesartan is from about 1:0.1 to 1:0.9

9. The combination according to claim 4, wherein ratio of omzotirome and enalapril is from about 1:0.025 to 1:0.45.

10. The combination according to any of the preceding claims, wherein combination further comprises one or more antidiabetic agent and/or anti- dyslipidemic agent.

11. The combination according to claim 10, wherein combination comprises 1 mg to 1000 mg of antidiabetic agent.

12. The combination according to claim 10, wherein antidiabetic agent is selected from metformin, gliclazide, glipizide, glimepiride, glibenclamide, sitagliptin, teneligliptin, vildagliptin, pioglitazone, acarbose, voglibose, repaglinide and pharmaceutical acceptable salt thereof and combination thereof.

13. The combination according to claim 10, wherein combination comprises 5 mg to 300 mg of anti-dyslipidemic agent.

14. The combination according to claim 10, wherein anti-dyslipidemic agent is selected from atorvastatin, rosuvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, simvastatin fenofibrate, choline fenofibrate, cirofibrate, bezafibrate gemfibrozil, niacin, ezetimibe, volixibat, colestipol, cholestyramine, colesevelam and pharmaceutically acceptable salt thereof and combination thereof.

15. A pharmaceutical composition comprising combination according to any of the preceding claims and one or more pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15 is solid oral composition.

17. A pharmaceutical composition comprising omzotirome, one or more antihypertensive agent and pharmaceutical acceptable carrier.

18. The pharmaceutical composition according to claim 17, wherein antihypertensive agent is selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

19. The pharmaceutical composition according to claim 18, wherein antihypertensive agent is selected from valsartan, losartan, telmisartan, olmesartan/ olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof.

20. The pharmaceutical composition according to claim 19, wherein antihypertensive agent is selected from olmesartan, olmesartan medoxomil, telmisartan, enalapril, ramipril, and pharmaceutical acceptable salt thereof.

21. The pharmaceutical composition according to claim 17, wherein composition comprises 45 mg of Omzotirome.

22. The pharmaceutical composition according to claim 17, wherein composition comprises 1 mg to 500mg of antihypertensive agent.

23. The pharmaceutical composition according to claim 17, wherein ratio of omzotirome and one or more antihypertensive agent is from about 1:10 to 50:1.

24. The pharmaceutical composition according to claim 20, wherein ratio of omzotirome and olmesartan is from about 1:0.1 to 1:0.9

25. The pharmaceutical composition according to claim 20, wherein ratio of omzotirome and enalapril is from about 1:0.025 to 1:0.45.

26. A method of managing cardio-metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof, comprising administering to the patient therapeutically effective amount of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent.

27. The method according to claim 26, wherein method comprises administering to the patient therapeutically effective amount of omzotirome and one or more antihypertensive agent.

28. The method according to claim 27, wherein antihypertensive agent is selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

29. The method according to claim 28, wherein antihypertensive agent is selected from valsartan, losartan, telmisartan, olmesartan/ olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof.

30. The method according to claim 29, wherein antihypertensive agent is selected from olmesartan, olmesartan medoxomil, telmisartan, enalapril, ramipril, and pharmaceutical acceptable salt thereof.

31. The method according to claim 26, wherein method comprises administering to the patient 45 mg of omzotirome.

32. The method according to claim 27, wherein method comprises administering to the patient Img to 500mg of antihypertensive agent.

33. The method according to claim 26, wherein patient in recognized need thereof are patients with diabetes, hypertension and/or dyslipidemia.

34. A combination of omzotirome and one or more antidiabetic agent, antihypertensive agent and/or anti-dyslipidemic agent for use in managing cardio- metabolic based chronic disease by improving glycemic control, blood pressure control and/or lipid control in a patient in recognized need thereof.

35. The combination according to claim 34, wherein combination comprises omzotirome and one or more antihypertensive agent.

36. The combination according to claim 35, wherein antihypertensive agent is selected from angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB) and direct renin inhibitor.

37. The combination according to claim 36, wherein antihypertensive agent is selected from valsartan, losartan, telmisartan, olmesartan/ olmesartan medoxomil, irbesartan, azilsartan, candesartan/ candesartan cilexetil, captopril, cilazapril, delapril, enalapril, fosinopril, libenzapril, spirapril, lisinopril, perindopril, pivopril, quinapril, ramipril, trandolapril, benazepril, imidapril, zofenopril and pharmaceutical acceptable salt thereof and combination thereof.

38. The combination according to claim 37, wherein antihypertensive agent is selected from olmesartan, olmesartan medoxomil, telmisartan, enalapril, ramipril, and pharmaceutical acceptable salt thereof.

39. The combination according to claim 34, wherein combination comprises 45 mg of Omzotirome.

40. The combination according to claims 35, wherein combination comprises 1 mg to 500mg of antihypertensive agent.

41. The combination according to claim 35, wherein ratio of omzotirome and one or more antihypertensive agent is from about 1:10 to 50:1.

42. The combination according to claim 38, wherein ratio of omzotirome and olmesartan is from about 1:0.1 to 1:0.9

43. The combination according to claim 38, wherein ratio of omzotirome and enalapril is from about 1:0.025 to 1:0.45.