WO2020213010A1

WO2020213010A1 - Synergistic lipid controlling compositions

Info

Publication number: WO2020213010A1
Application number: PCT/IN2020/050360
Authority: WO
Inventors: Rajendra Prasad T.; Dhiraj Dhamane
Original assignee: Celagenex Research (India) Pvt. Ltd.
Priority date: 2019-04-16
Filing date: 2020-04-16
Publication date: 2020-10-22
Also published as: WO2020213010A4

Abstract

The invention disclosed herein relates to synergistic lipid controlling compositions. Particularly it relates to synergistic, non-statin medicinal compositions of therapeutically active substances for lipid profile management. More particularly, the present invention provides synergistic lipid controlling composition comprising inclusion complex of bempedoic acid (BA) with 'cyclodextrin' (CD); optionally in presence of disaccharide bioenhancer called 'trehalose' along with pharmaceutically acceptable carriers. The present synergistic non-statin medicinal composition is useful for treating or controlling hyperlipidemia, hypercholesterolemia, atherosclerosis, myocardial infarction and like thereof, with improved bioavailability.

Description

SYNERGISTIC LIPID CONTROLLING COMPOSITIONS

Technical Field of the invention:

The present invention relates to synergistic medicinal compositions for controlling cardiovascular diseases. Particularly it relates to synergistic, non-statin medicinal compositions of therapeutically active substances for lipid profile management. More particularly, the present invention provides synergistic lipid controlling pharmaceutical/medicinal compositions comprising combination of‘hypolipidemic agent’ and‘oligosaccharide’ present in an effective weight ratio, wherein the hypolipidemic agent is‘bempedoic acid’ (BA) and oligosaccharide compound is ‘cyclodextrin’ (CD); optionally in presence of disaccharide bioenhancer called ‘trehalose’ along with pharmaceutically acceptable carriers. Further the present synergistic non statin medicinal composition is useful for treating or controlling cardiovascular diseases particularly hyperlipidemia, hypercholesterolemia, atherosclerosis, myocardial infarction and like thereof.

Background and Prior art:

Cardiovascular diseases are still one of the most frequent causes of mortality. According to WHO, cardiovascular diseases (CVDs) take 17.9 million lives every year, accounting for 31% of all global deaths annually.

Besides well-known risk factors such as hypertension, impaired glucose tolerance and dyslipidemia, growing evidence suggests that hormonal changes associated with various endocrine diseases also impact the cardiac morphology and function. Recent studies highlight that intracellular‘lipid’ depositions are associated with alterations in cardiac performance. Lipids are generally water insoluble bimolecules which encompass fatty acids, their derivatives (including tri-, di-, mono-glycerides and phospholipids), as well as other sterol- containing metabolites such as cholesterol.

Further, lipids have been classified into eight categories such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and polyketides.

Cholesterol, triglycerides, and high-density lipoproteins are important components of lipids found in the human body. Cholesterol and triglycerides, being nonpolar lipid substances (insoluble in water), need to be transported m the plasma associated with various lipoprotein particles. Plasma lipoproteins are separated by hydrated density; electrophoretic mobility; size; and their relative content of cholesterol, triglycerides, and protein into five major classes: chylomicrons or ultra low-density lipoproteins (ULDL), very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). HDL is good cholesterol because it carries extra cholesterol back to the liver where it can be eliminated. LDL is bad because it enables excess cholesterol to build up in the blood.

Cholesterol is an unsaturated alcohol of the steroid family of compounds; it is essential for the normal function of all animal cells and is a fundamental element of their cell membranes. It is also a precursor of various critical substances such as adrenal and gonadal steroid hormones and bile acids. Cholesterol has primary functions, like contributing to the structure of cell walls; making up digestive bile acids in the intestine; allowing the body to produce vitamin D; enabling the body to make certain hormones. Since cholesterol is an oil-based substance and minimally soluble in water, it does not mix or dissolve with the water-based blood. Therefore, it travels around the body in lipoproteins which are water-soluble.

High cholesterol can lead to fatty deposits or plaque in the blood vessels. Eventually, these deposits grow and clog arteries, making it difficult for enough blood to flow through the arteries due to its thickening. Sometimes, those deposits can break suddenly and form a clot that causes a heart attack or stroke. High cholesterol is a significant risk factor for coronary heart disease and a cause of heart attacks.

In summary, the conditions that can lead to high cholesterol levels include poor diet, consumption of saturated fat, obesity, lack of physical exercise, smoking, aging, diabetes, liver or kidney disease, polycystic ovary syndrome, pregnancy and other conditions that increase levels of female hormones, hypothyroidism treatment drugs that increase LDL cholesterol and decrease HDL cholesterol in the blood.

LDL is a microscopic blob made up of an outer rim of lipoprotein and a cholesterol center. It is bad because it becomes part of plaque which clogs arteries and increases susceptibility to heart attacks and strokes. Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia consists of elevated plasma LDL-C (hypercholesterolemia) and triglycerides (hypertriglyceridemia) and low HDL-C, thus increasing the risk of developing CVD. Hyperlipidemia is the most common form of dyslipidemia (which includes any abnormal lipid levels). A person with hyperlipidemia may have high levels of both LDL and triglycerides.

Cholesterol becomes a problem when too much bad cholesterol, or low-density lipoprotein (LDL), is produced or ingested through unhealthy foods. Hyperlipidemia means there is too much cholesterol in the blood. The excessive cholesterol in the blood accumulates over time, forming plaques on the walls of the arteries and blood vessels. This narrows the openings and reduces blood flow through the vessels. The heart has to work harder to pump the blood through the constricted areas. A build-up of cholesterol is part of the process that narrows arteries and results in a condition called atherosclerosis. In atherosclerosis, plaques form and cause restriction of blood flow.

The cholesterol plaques of atherosclerosis are the usual cause of coronary artery disease such as angina, myocardial infarction; cerebrovascular disease such as stroke, brain damage, ischemic attacks, or peripheral arterial disease such as pam on walking and poor wound healing.

The heart utilizes large amounts of lipids as energy providing substrates. Hence it is important to maintain physiologic balance of lipid uptake and prevent accumulation of excess lipids.

Over the past few decades, lipid lowering therapy by using potent synthetic drugs have been developed to lower these blood cholesterol levels. Examples of such drugs are statins/ HMG- CoA reductase inhibitors like atorvastatin (brand named Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol) rosuvastatin calcium (Crestor), simvastatin (Zocor); niacin, niacin derivatives; bile-acid resins; fibric acid derivatives, and cholesterol absorption inhibitors. Statins are structural analogues of HMG-CoA used in the pharmacological management of hyperlipidemia. Besides their effects on cholesterol levels, statins may exert direct immune modulatory effects. Atorvastatin, a commonly prescribed statin, inhibits TLR4/MyD88/NF-kB dependent NLRP3 expression in THP-1 cells in vitro, and consequently reduces IL-lb secretion [Biomed Pharmacother. 2016 Aug; 82:167-72]

Further, the use of statins has caused some debate because, like all drugs, they can have side effects which include myopathy (a muscle tissue disease), fatigue, risk of diabetes, diabetes complications and risk of cardiovascular problems.

Additionally, certain adverse cognitive reactions were observed during statin therapy such as rosuvastatin [Pharmacotherapy. 2006 Aug; 26(8): 1190-2] Statin intolerance is a real process, which might affect up to 15% of patients treated with statins. For patients with hypercholesterolemia who are intolerant to statins, new safe and effective therapy is needed to control LDL levels.

Additionally, there are patients who are unable to endure statins due to adverse effects such as muscle pain, or increased blood glucose. There is an unmet medical need for patients unable to achieve sufficient reduction in LDL cholesterol with existing treatment options and thus remain at increased risk of cardiovascular disease and the consequences thereof. Because of this, new lipid-modulating drugs are essentially required. ‘Bempedoic acid’ is a first-in-class, non-statin, drug that is designed to primarily work in the liver to inhibit cholesterol biosynthesis. It is one of the effective and safer molecules that act as lipid lowering agent. US7335799B2 discloses bempedoic acid compounds and compositions for cholesterol management and related uses.

Further, it is observed that efficacy of bempedoic acid is increased by combining the drug with statins or with other lipid lowering agents.

W 02018218147 A1 discloses bempedoic acid, its combination with ezetimibe and compositions useful in the treatment and prevention of cardiovascular disease.

Additionally, I N 02018148417 A1 reports compositions comprising bempedoic acid; ezetimibe; a statin; and one or more pharmaceutical excipients or carriers for treating hypercholesterolemia and/or dyslipidemias in a subject.

Although this combination therapy provides good therapeutic effects, there is a need to find an alternative which is cost effective and exhibits less side effects, namely a non-statin therapy to counter the growing lipid health problems.

Experimentally, it is observed that cholesterol accumulation in myeloid cells activates the

NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques.

The NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain] -containing protein 3) inflammasome, an innate immune signaling complex, is the key mediator of IL-1 family cytokine production in atherosclerosis. NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic injury, such as oxidized low-density lipoprotein and cholesterol crystals. Overloaded cholesterol crystals cause lysosomal destabilization and rupture, which induce leakage of the lysosomal enzyme, resulting in the activation of NLRP3 inflammasomes.

Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression [ Circulation Research. 2018;122:1722-1740]

The negative regulation of NLRP3 inflammasomes is a potential therapeutic target for atherosclerosis. Current drugs with potential impact on NLRP3 activation during atherogenesis include known drugs such as colchicine and statins. New drugs with capacity to regulate NLRP3 activity and disrupt cholesterol crystal formation have also been explored. However, most of these agents remain at the stage of either in vitro assays or in vivo experimentation in pre-clinical atherosclerosis models with limited data. Thus, further exploration is needed to confirm the effect of these agents on the development of atherosclerosis.

Modern therapies targeting inflammasome activation are focusing directly on one of the end products of the pathway by blocking the function of IL-1 (Interleukin- 1). However, IL-1 may be generated downstream of many inflammasomes. Global interference with inflammasome- induced innate immunity, by direct and generic targeting of IL-1, may increase susceptibility to (opportunistic) infections. Thus, a better and more specific targeting of NLRP3 is needed.

To improve therapeutic outcome, the present inventors have come up with a molecule which generally acts as a complexing agent to improve solubility of lipophilic compounds. But in the current scenario, this molecule acts in dual manner, wherein it prevents formation of atherosclerotic plaque by down regulating NLRP3 inflammasome activation in macrophages with consequent reduction of cytokine secretion as well as a coating or complexing agent to improve the solubility and bioavailability of the composition. The interaction of lipids and cholesterol with cyclodextrins has been extensively investigated in the last two decades.

The potential of cyclodextrins (CD) as active pharmaceutical ingredients for the treatment of several illnesses e.g., hypercholesterolemia, cancer, Niemann-Pick Type C disease is reported in some literatures. [Molecules 2017, 22(1), 1 ].

Siril S. Bakke, et al, 2017 discloses that BCD (beta-cyclodextrin) attenuates the CC (cholesterol crystal)-induced proinflammatory cytokine responses (e.g. inflammatory markers like IL-la, MIP-la, TNF, IL-6, and IL-8) and regulates complement-related genes in human carotid plaques. Further, Sebastian Zimmer et al. in Sci Transl Med. 2016; 8(333 ) has reported that CD treatment reduces atherosclerotic plaque size and CC load.

Additionally US4880573A describes a process for eliminating cholesterol from fatty substances of animal origin by using cyclodextrin.

Consequently, the present inventors have developed cost effective, synergistic, non-statin therapy comprising bempedoic acid composition for lowering lipid levels in humans to give improved therapeutic result. Further the efficacy of the composition is enhanced by optionally using a non reducing sugar compound. Particularly, the technology and the non-statin ingredients used in the instant invention are commercially viable that makes the composition cost effective and simple, with better results and without severe side effects, particularly cognitive side effects.

In the light of above, the present inventors have developed efficient and cost-effective medicinal compositions with non-statin groups which give synergistic effect for balancing lipid level in the body.

Object of the invention:

The primary object of the invention is to provide synergistic medicinal compositions for controlling cardiovascular diseases.

Another object of the invention is to provide synergistic, non-statin medicinal compositions that significantly regulate lipid level in a subject in need thereof.

A preferred object of the invention is to provide non-toxic, non-statin, medicinal compositions with synergistic effect for treating hyperlipidemia or dyslipidemia by concurrently eliminating formation of atherosclerosis plaque or debris.

Another object of the invention is to provide synergistic remedy for treating disorders related to cholesterol level without severe side effects.

Summary of the invention:

To meet the above objectives, the inventors of the present invention have carried out thorough experiments to establish therapeutic effects of the active and non-active ingredients present in the composition that maintain optimal lipid levels in a subject in need thereof. In an aspect, the invention relates to a synergistic medicinal composition comprising active as well as inactive moieties for lowering lipid level in a subject in need thereof. In another aspect, the invention relates to synergistic, non-statin, cost effective composition comprises combination of ‘hypolipidemic agent’ and ‘cyclic oligosaccharide’, wherein the hypolipidemic agent is ‘bempedoic acid’ (BA) and cyclic oligosaccharide compound is ‘cyclodextrin’ (CD); optionally in presence of disaccharide bioenhancer called trehalose along with pharmaceutically acceptable carriers.

In a preferred aspect, the invention relates to non-statin, medicinal composition which is composed of synergistic combination of ‘bempedoic acid’ and‘cyclodextrin’ and optionally ‘trehalose’, which are present in therapeutically effective amount. In a further aspect, the invention provides compositions for lowering lipid level and reducing plaque deposition on the blood vessel wall with improved bioavailability and efficacy of active ingredients.

Further, in the present invention one active moiety of the composition significantly lowers LDL cholesterol level; while the other moiety concomitantly prevents cholesterol plaque progression, thereby reducing plausible risk of cardiovascular diseases.

In yet another aspect, the invention relates to synergistic non-statin compositions comprising combination of bempedoic acid which is present in the range of 1-500 mg and cyclodextrin which is present in the range of 1-500 mg along with pharmaceutically acceptable excipients / carriers. Further the trehalose may be present optionally in the range of 0.1 to 50 grams per administration. In yet further aspect, the invention provides synergistic non-statin medicinal composition for treating or controlling cardiovascular diseases like hyperlipidemia, hypercholesterolemia, coronary artery diseases- such as atherosclerosis, myocardial infarction; cerebrovascular diseases such as stroke, carotid stenosis; peripheral arterial disease, high blood pressure, type 2 diabetes, chronic kidney diseases, polycystic ovary syndrome, thyroid inflammation (thyroiditis), hypothyroidism and like thereof.

Abbreviations:

ACL: Adenosine triphosphate citrate lyase

HDL: High-density lipoprotein

LDL: Low-density lipoprotein

CC: Cholesterol Crystals

BA: Bempedoic Acid

CD: Cyclodextrin

BCD: Beta Cyclodextrin

HPBCD: 2-hydroxypropyl-beta-cyclodextrin

NOD: Nucleotide-binding oligomerization domain

LRR: Leucine-rich repeat

NLRP3: NOD- LRR- and pyrin domain- containing protein 3

b.w.: body weight

CMC: Carboxymethyl cellulose Brief description of figures:

Fig.la - le illustrate the effect of test substances (G1-G5) on Lipid profile in mice Gl- Normal Control (0.5 % CMC); G2- High Fat Diet (Control-0.5 % CMC); G3- Standard (Rosuvastatin-10 mg/kg b.w); G4- (Bempedoic acid-36.99 mg/kg b.w); G5- Bempedoic acid +Beta Cyclodextrin (36.99+61.65 mg/kg b.w)

Fig.2a - 2b illustrate the effect of test substances (G1-G5) on liver function in mice Gl- Normal Control (0.5 % CMC); G2- High Fat Diet (Control-0.5 % CMC); G3- Standard (Rosuvastatin-10 mg/kg b.w); G4- (Bempedoic acid-36.99 mg/kg b.w); G5- Bempedoic acid +Beta Cyclodextrin (36.99+61.65 mg/kg b.w)

Fig.3a - 3c illustrate the effect of test substances (G1-G5) on organ weight in mice Gl- Normal Control (0.5 % CMC); G2- High Fat Diet (Control-0.5 % CMC); G3- Standard (Rosuvastatin-10 mg/kg b.w); G4- (Bempedoic acid-36.99 mg/kg b.w); G5- Bempedoic acid +Beta Cyclodextrin (36.99+61.65 mg/kg b.w)

Detailed Description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

It is further to be understood that all terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting in any manner or scope.

Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain. In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art. The singular forms“a,”“an,” and“the” include plural reference unless the context clearly dictates otherwise. Also the term‘composition’ does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

The term“pharmaceutically/ nutraceutically acceptable salt,” as use herein, represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Particularly the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.

The term“medicinal composition” refers to compositions used to cure a disease or relieve pain. Moreover, the composition comprising active ingredients pertains to curative, healing, officinal, remedial, restorative and therapeutic behavior. In a preferred embodiment, the invention provides synergistic medicinal compositions comprising specific combination of a‘non-statin hypolipidemic agent’ and an‘oligosaccharide’, wherein the‘non-statin hypolipidemic agent’ is‘bempedoic acid’ (BA) and the‘oligosaccharide’ is ‘cyclodextrin’ (CD); optionally in presence of disaccharide bioenhancer, wherein the disaccharide bioenhancer is trehalose along with pharmaceutically acceptable carriers.

In another embodiment, the invention provides synergistic lipid controlling non-statin compositions comprising specific combination of bempedoic acid and cyclodextrin; wherein the bempedoic acid increases clearance of LDL-cholesterol from the bloodstream by suppressing cholesterol biosynthesis via ATP-citrate lyase (ACL) inhibition and cyclodextrin simultaneously reduces cholesterol crystal or plaque formation by down regulating NLRP3 inflammasome activation in macrophages with consequent reduction of cytokine secretion.

Additionally, trehalose is added as bioenhancer to reduce atherosclerotic plaque through autophagy-lysosome pathway (ALP).

In another embodiment, the invention provides cyclodextrin based amphiphilic macromolecules which are complexed with bempedoic acid to establish lipid lowering therapy with synergy. This dual efficacy formulation effectively inhibits cholesterol abundance and regulates cholesterol homeostasis.

The chemical formula (I) of ‘Bempedoic acid’, also referred to as ‘8-hydroxy-2,2,14,14- tetramethylpentadecanedioic acid’ is as below:

Bempedoic acid

(I)

It is a non-statin, low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase.

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Acetyl-CoA serves important biosynthetic pathways, including lipogenesis and cholesterogenesis in animals. In another embodiment, bempedoic acid increases clearance of low-density lipoprotein cholesterol LDL-C from the bloodstream by suppressing cholesterol biosynthesis via ATP-citrate lyase (ACL) inhibition. The bempedoic acid monotherapy exhibits 30-40 % lowering in LDL cholesterol.

Bempedoic acid promotes low density lipoprotein (LDL) receptor mediated clearance of LDL- cholesterol (LDL-C) by inhibition of adenosine triphosphate citrate lyase (ACL) enzyme which is an important enzyme on the cholesterol biosynthesis pathway. By inhibiting ACL, bempedoic acid reduces cholesterol synthesis in liver cells and triggers compensatory LDL receptor upregulation. In this context, ATP citrate lyase (ACL) inhibition, mediated by bempedoic acid leads to decrease in cholesterol biosynthesis, up regulation of LDL receptors, and reduction in LDL-C levels. Therefore, the further formation of cholesterol crystals or plaques due to excessive cholesterol is eliminated. In another embodiment, the invention provides a synergistic, non-statin medicinal composition comprising a therapeutically effective amount of bempedoic acid along with pharmaceutically acceptable salts thereof, wherein bempedoic acid is present in the range of 1-500 mg of the total composition.

In a preferred embodiment, the bempedoic acid is present in the range of 1-300 mg of the total composition.

In another preferred embodiment, the invention provides synergistic compositions of bempedoic acid with cyclodextrin (CD). Cyclodextrins are‘bucketlike’ or‘conelike’ toroid molecules, with a rigid structure and a central cavity, the size of which varies according to the cyclodextrin type. The internal surface of the cavity is hydrophobic and the external surface of the torus is hydrophilic. This arrangement permits the cyclodextrin to accommodate a guest molecule within the cavity, forming an inclusion complex.

‘Cyclodextrins’ are crystalline non-reducing cyclic glucose oligosaccharides. They form soluble inclusion compounds with less-hydrophilic molecules that fit into their cavities. There are three common cyclodextrins with 6, 7 or 8 D-glucopyranosyl residues (a-, b-, and g-cyclodextrin respectively) linked in a ring by a-1 , 4 glycosidic bonds. All three cyclodextrins have similar structures apart from the different number of glucose residues. The chemical structures (Ila, lib and lie) of the three cyclodextrins are provided below:

(Ha) (lib) (lie)

cyclodextrins

In another embodiment, the invention provides cyclodextrin based amphiphilic macromolecules which are complexed with bempedoic acid, wherein CD performs dual function, firstly it acts as a complexing agent to form inclusion or cyclodextrin-cholesterol complex by promoting formation of water soluble complexes with lipophilic water insoluble molecules i.e. cholesterol. The complexed cholesterol cannot be absorbed into the blood and thus it is eliminated through excretion. Secondly, CD performs the role of an active moiety, wherein it reduces cholesterol crystal or plaque formation by down regulating NLRP3 inflammasome activation in macrophages with consequent reduction of cytokine secretion. CD treatment results in a regression of atherosclerotic plaques by approximately 45%. [J Immunol March 15, 2014, 192 (6) 2837-2845]

Further it is observed that cholesterol crystalline substances can induce inflammation by stimulating the caspase-1 -activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-l family cytokines.

Accordingly, cyclodextrin moiety reduces cholesterol in the endoplasmic reticulum membranes that abolishes casp-1 activation and IL-Ib secretion and ablates NLRP3 inflammasome assembly. Moreover, cyclodextrin regulates athero-protective pathways wherein it reduces formation of cholesterol plaque and enhances cholesterol efflux by inhibiting NLRP3 inflammasome in macrophages via suppression of oxidized-LDL uptake.

In another embodiment, the cyclodextrin is selected from the group consisting of a (alpha)- cyclodextrin, b (beta)-cyclodextrin, g (gamma)-cyclodextrin, alkyl, hydroxyl derivatives of cyclodextrin, 2-(hydroxypropyl) beta-cyclodextrin (2-HPCD), 0,0-dimethyl-beta-cyclodextrin (DMCD)either alone or combination thereof.

In a preferred embodiment, the cyclodextrin moiety is beta cyclodextrin. In yet another embodiment, the invention provides a complex of bempedoic acid with cyclodextrin, wherein the cyclodextrin complex improves solubility, bioavailability and stability of the composition. In a preferred embodiment, the invention provides an inclusion complex of bempedoic acid with cyclodextrin or encapsulations of cyclodextrin-drug inclusion complexes wherein drug or host molecule is bempedoic acid.

After administration of composition, cyclodextrin releases bempedoic acid in the blood vessels and forms complex with cholesterol crystals which are easily extracted from blood stream. Cyclodextrin also reduces further formation of cholesterol crystals or plaque by down regulating NLRP3 inflammasome activation.

In further embodiment, the invention provides a synergistic medicinal, non-statin composition comprising a therapeutically effective amount of cyclodextrin along with pharmaceutically acceptable salts thereof, wherein the cyclodextrin is present in the range of 1-500 mg of the total composition.

In a preferred embodiment, the cyclodextrin is present in the range of 1-400 mg of the total composition.

In an additional embodiment, the present non-statin composition therapeutic efficacy is enhanced by adding disaccharide compound, where in the disaccharide compound is trehalose.

Trehalose (a-D-glucopyranosyl- (-D-glucopyranoside) is a naturally occurring, non-reducing disaccharide which is available commercially in the dihydrate form. Trehalose is a disaccharide composed of glucose. Trehalose is mostly found as a component of mushrooms in the diet, with limited exposure in the human diet otherwise.

In an embodiment, trehalose incorporation induces macrophage autophagy-lysosomal biogenesis thus reducing atherosclerotic plaque burden in high-cholesterol subject. Therefore the efficacy of the composition is improved.

Particularly, trehalose activates a molecule called (TFEB)-transcription factor EB. TFEB is a master regulator of lysosomal biogenesis. Once activated by trehalose, TFEB then goes into the nuclei of macrophages and binds to the DNA. When the molecule binds to the DNA, this causes various genes to be expressed, instructing the cell to create additional lysosomes. These additional lysosomes gobble up toxic waste like atherosclerotic plaques.

In a further embodiment, the invention provides a synergistic medicinal, non-statin composition comprising a therapeutically effective amount of trehalose along with pharmaceutically acceptable salts thereof, wherein trehalose is present in the range of 0.1 to 50 g per administration.

In a preferred embodiment, the trehalose is present in the range of 5 to 500 mg per administration. Further trehalose is used in the form of trehalose dehydrate powder, amorphous trehalose, anhydrous amorphous trehalose, anhydrous crystalline trehalose or mixtures thereof.

In another preferred embodiment, the invention provides non-statin, cost effective, pharmaceutical or medicinal synergistic composition with less adverse effects, wherein bempedoic acid reduces cholesterol synthesis in liver cells by inhibiting ATP citrate lyase enzyme which is responsible for cholesterogenesis and cyclodextrin simultaneously or subsequently enhances cholesterol efflux by inhibiting NLRP3 inflammasome in macrophages via suppression of ox-LDL uptake. Optionally, trehalose is added to reduce the atherosclerotic plaque through autophagy-lysosomal pathway (ALP).

In one preferred embodiment, the invention provides a synergistic, non-statin medicinal composition for treating cardiovascular diseases, comprising an inclusion complex of a ‘hypolipidemic agent’ with an ‘oligosaccharide’, wherein the hypolipidemic agent and the oligosaccharide are present in the weight ratio of 1 :0.1 to 1 :5 along with pharmaceutically acceptable excipients.

In another preferred embodiment, the invention provides a synergistic, non-statin medicinal composition, wherein the hypolipidemic agent is“bempedoic acid” and the oligosaccharide is “cyclodextrin”.

In another preferred embodiment, the invention discloses synergistic, non-statin, medicinal composition comprising combination of bempedoic acid and cyclodextrin which are present in the weight ratio of 1 : 0.1 to 1 : 5.

In yet another preferred embodiment, the invention discloses non-statin, synergistic medicinal composition comprising inclusion complexes of bempedoic acid with beta-cyclodextrin, wherein bempedoic acid to betacyclodextrin weight ratio is in the range of 1 : 0.5 to 1 : 5.

In a further embodiment, the invention provides non-statin, synergistic medicinal composition comprising bempedoic acid in the range of 20% to 50% by weight of the total composition.

In a preferred embodiment, the bempedoic acid is in crystalline form. In another embodiment, the invention provides non-statin, synergistic medicinal composition comprising betacyclodextrin in the range of 40% to 80 % by weight of the total composition.

In a preferred embodiment, the betacyclodextrin is either in crystalline solid or fine powder form. In another preferred embodiment, the invention provides a lipid lowering composition comprising an inclusion complex of a non-statin hypolipidemic agent with a cyclodextrin, wherein the hypolipidemic agent to the cyclodextrin weight ratio is in the range of 1 : 0.5 to 1 :5.

In another embodiment, the invention provides inclusion complex of bempedoic acid with betacyclodextrin with improved lipid lowering efficacy. More particularly betacyclodextrin increases the solubility, bioavailability and stability of bempedoic acid.

In the present invention, one active moiety of the composition significantly lowers LDL cholesterol level; while the other moiety simultaneously prevents cholesterol plaque progression, thereby reducing plausible risk of cardiovascular diseases like hyperlipidemia.

In another embodiment, the invention provides a synergistic medicinal composition for treating cardiovascular diseases. In a preferred embodiment, the present invention provides a composition for treating dyslipidemia. Moreover, the composition is useful for treating or controlling hyperlipidemia, hypercholesterolemia, coronary artery diseases such as atherosclerosis, myocardial infarction, cerebrovascular diseases- such as stroke, carotid stenosis, peripheral arterial disease, high blood pressure, type 2 diabetes, chronic kidney diseases, polycystic ovary syndrome, thyroid inflammation (thyroiditis), hypothyroidism and like thereof. As used herein, the term“therapeutically effective amount” is an amount of the compound of the present invention that is effective in reducing or eliminating dyslipidemia by treatment and/or prophylaxis. In the context of the present invention, the terms“treatment” and the like refer to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, down regulate, up regulate, improve, moderate, prevent, inhibit, stabilize, ameliorate or cure, heal conditions related to higher blood lipid levels. The treatment further includes delaying or reversing or preventing or reducing or dampening or breaking the development or progression or formation or occurrence of conditions or indications related to high blood levels of low-density lipoprotein (LDL) cholesterol, and fats called triglycerides, or both.

The‘subject in need thereof pertains to a subject preferably mammal, more preferably a human with pre-existing symptoms of hyperlipidemia or in a subject to whom the composition is administered to prevent occurrence of hyperlipidemia or to a subject with statin intolerance.

The therapeutically effective amount of such actives will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

Thus, a "therapeutically effective" amount is an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides some alleviation, mitigation, and/or reduction of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or decrease in at least one clinical symptom of a disease or disorder (e.g., hyperlipidemia).

An effective dose is a dose that produces a desirable clinical outcome by, for example, improving a sign or symptom of hyperlipidemia and its progression.

In an embodiment, the effective unit dose of the composition for oral administration is in the range of 100 to 1000 mg and administered once or twice or three to four times in a day based on the intensity of the lipid level in a subject in need thereof.

In a preferred embodiment, the effective unit dose for oral administration is in the range of 150 to 600 mg.

Notably the oral administration of an effective dose of the present composition controls lipid level significantly.

In another embodiment, the invention relates to a synergistic composition prepared in a manner well known in the pharmaceutical art, and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. The preferable route of administration includes but is not limited to topical, parenteral, or oral.

Therapeutic (prescription) supplements are generally administered by the oral or parenteral routes for the treatment of indications including hyperlipidemia. The therapeutic administration of compositions of the present invention may be in conjunction with other therapies.

In one embodiment, the present synergistic medicinal composition is administered to a subject in a form suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, or syrup. In another embodiment, the composition is formulated for parenteral use including intravenous, subcutaneous, intramuscular, and intravascular or infusion routes of administration.

In some embodiment, the oral administration of effective dose of the present medicinal composition comprising inclusion complex of bempedoic acid with betacyclodextrin not only significantly lowers blood lipid level but also improves liver and adipose tissue functioning.

As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is intended to mean, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agents such as liposomes and cyclodextrins, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anti caking agent, additives, or waters of hydration. In some embodiment of the invention, the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, b-cyclodextrin, dextrates, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

In some embodiment of the invention, the amount of diluent in the composition/formulation is present in the range of 1 % to 30% by weight of the total composition/formulation.

In some embodiment, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxyl ethylmethyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colourants and wax.

In some embodiment of the invention, the amount of binder in the composition/formulation is present in the range of 0.1 to 40% by weight of the composition/formulation.

In a further embodiment, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium benzoate or the like.

In some embodiment of the invention, the amount of lubricant in the composition/formulation is present in the range of 0.1% to 5.0% by weight of the total composition/formulation.

In another embodiment of the invention, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrobdone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprybn, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

In an embodiment of the invention, the amount of solubilizing agent or surfactant in the composition/formulation is present in the range of 0.1% to 10%, by weight of the composition/formulation. In a preferred embodiment of the invention, the amount of solubilizing agent or surfactant is present in the range of 0.1% to 5.0% by weight of the composition/formulation. In some embodiment of the invention, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like. In some embodiment of the invention, the amount of glidant is present in the range of 0.1% to 5.0% by weight of the total composition/ formulation.

In some embodiment of the inventions, the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise. In some embodiment of the invention, the amount of stabilizers in the composition/formulation ranges from 0.1% to 10.0% by weight of the total composition/ formulation.

In some embodiment, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

In some embodiment of the invention, the amount of solvent in the composition/formulation is present in a quantity sufficient to 100% by weight of the composition/formulation.

The additional additives include polymer, a plasticizer, a sweetener, and a powdered flavor, preservative, colorant, surfactant and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used. The additives are used in the range of 1 to 30 % w/w of unit dose.

In another embodiment, the present invention provides synergistic, non-statin medicinal composition, wherein the diluent is present in the range of 1 to 30%; the binder is present in the range of 0.1 to 30%; the lubricant is present in the range of 0.1 to 5.0 %; the glidant is present in the range of 0.1 to 5.0%; the additive is present in the range of 1 to 20%; the surfactant is present in the range of 0.1 to 5.0%; the stabilizer is present in the range of 0.1 to 10.0% by weight of total composition.

Surprisingly, the synergistic non-statin composition of the present invention is non-hazardous, non-toxic and safe for human consumption without any severe side effects and can also be used under preventive therapy in healthy subjects.

In one embodiment, the composition is administered to a subject in a form suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release), hard gelatin capsules, soft gelatin capsules in an oily vehicle, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, or syrup. In another embodiment, the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular or infusion routes of administration.

In a preferred embodiment, the present medicinal composition/formulation is formulated for oral administration. Specifically, the solid medicinal compositions, for example, can be in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions or modified release formulations.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

All references cited herein are incorporated by reference in their entireties. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

This invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

EXAMPLES:

Example-1

i. Composition 1: Synergistic - Inclusion complex

ii. Composition 2: Tablet / Capsule

iii. Composition 3: Tablet / Capsule

iv. Composition 4: Tablet / Capsule

v. Composition 5: Tablet / Capsule

vi. Composition 6: Tablet / Capsule

vii. Composition 7: Tablet / Capsule

viii. Composition 8: Tablet / Capsule

Example-2: Animal Study

Evaluation of lipid lowering activity of test substances on high fat diet induced hyperlipidemia in experimental mice.

Animal House conditions-

Lighting: 12 / 12 hour light-dark cycle

Temperature: 22 ± 3 °C

Relative Humidity: 30 to 70%

Animals had continuous access to fresh, potable, uncontaminated drinking water.

Feed: High Fat diet (Reference: HFD (60%) Feeds, PMI Nutrition International) was provided to all the animals throughout the experiment.

Each animal was marked by picric acid and numbering was given individually to each animal. Each cage was numbered separately to identify the group. In each cage, a single animal was housed in standard stainless-steel cage having facilities for pelleted food and drinking water in bottle. The study was approved by Institutional Animal Ethical Committee (IAEC) of Radiant Research Services Pvt. Ltd.

Test System and Animal Husbandry

Species: Mice

Strain: C57, Black

Sex: Male

No. of animals: 30 Animals (n=6 per group)

Body weight: 25-30gm

CPC SEA Registration Number- 1803/PO/RcBi/S/2015/CPCSEA

Group, Designation and Dose Levels

Table 1: Animal grouping and treatment details

Experimental Procedure:

Total 30 male mice were divided into five groups and each group consists of six animals. Treatment was given orally for 28 days along with HFD induction. Group 1 was served as normal control treated with 0.5% CMC and Group 2 served as High Fat Diet Control and received 0.5% CMC along with High Fat Diet. Further Group 3 (Standard) received Rosuvastatin (lOmg/kg b.w). Group 4 received test substance (36.99 mg/kg b.w) and Group 5 received test substance (36.99 mg/kg +61.65 mg/kg b.w) daily along with HFD for 28 days. All the groups except Normal control group received High Fat Diet for 28 days along with treatment. At the end of the experimental period on 29th day, overnight fasted animals (for 12 hr) were given mild isoflurane anesthesia and blood was collected by retro orbital puncture in EDTA coated vials. Plasma was separated by using cold centrifugation (4°C) of the vials for 10 min at 3000 rpm for Bio chemical analysis like Lipid Profile Test and Liver Function Test. Later animals were sacrificed by decapitation and liver and adipose fat tissue weight was measured.

The significance of in vivo data was analyzed by one way anova followed by Dunnet test.

P < 0.05 was considered as significant.

Results:

Table 1: Effect of test substance on Lipid profile

Values were expressed as mean ± SEM (n = 6) (* P Value < 0.05; ** P Value < 0.001; *** P Value < 0.0001). Table 2: Effect of test substance on Liver Function Test

Values were expressed as mean ± SEM (n = 6), (* P Value < 0.05; ** P Value < 0.001; *** P Value < 0.0001).

Table 3: Effect of test substance on organ weight

Discussion

The lipid profile test showed significant decrease in biochemical parameters like Cholesterol, Triglycerides, LDL, and VLDL levels in the groups (G3-G5) when compared with High Fat Diet Control group (G2). There was a significant increase in the HDL level in the entire group compared to the High Fat Diet Control group (Table 1 & Figure la - le).

Table 2 & Figure 2a - 2b indicate that SGOT and SGPT levels significantly decreased in groups (G3-G5) compared to the High Fat Diet Control group (G2). Organ weight of the mice such as liver, epididymal adipose tissue and subcutaneous adipose tissues were showing significant decrease in the groups (G3-G5) compared to the High Fat Diet Control group (G2) (Table 3 & Figure 3a - 3c).

Conclusion:

It is clear that treatment with test substances (G3-G5) significantly lowers lipid levels (LDL) and elevates HDL levels; thus concluding that test substances G4 and G5 possess lipid lowering activity in experimental mice. Moreover, a synergistic combination of bempedoic acid and cyclodextrin in group G5 showed approximately similar results in controlling lipid level in HFD subject when otherwise treated with statin group G2. In view of above, the present combination is the best alternative medicine over the conventional statin drug therapy without any severe side effects.

Claims

We Claim:

1. A synergistic, non-statin medicinal composition for treating cardiovascular diseases comprising an inclusion complex of a‘hypolipidemic agent’ with an‘oligosaccharide’, wherein the hypolipidemic agent and the oligosaccharide are present in the weight ratio of 1 :0.1 to 1 :5 along with pharmaceutically acceptable excipients.

2. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the hypolipidemic agent is“bempedoic acid” and the oligosaccharide is“cyclodextrin”.

3. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the cyclodextrin is selected from the group consisting of (alpha)-cyclodextrin, (beta)-cyclodextrin, (gamma)-cyclodextrin, alkyl, hydroxyl derivatives of cyclodextrin, 2-(hydroxypropyl) beta- cyclodextrin (2-HPCD), 0,0-dimethyl-beta-cyclodextrin (DMCD) either alone or combination thereof.

4. The synergistic, non-statin medicinal compositions as claimed in claim 3, wherein the cyclodextrin is beta-cyclodextrin.

5. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the bempedoic acid is present in the range of 20% to 50 % by the weight of total composition.

6. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the beta-cyclodextrin is present in the range of 40% to 80 % by the weight of total composition.

7. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from a diluent, a binder, a surfactant, a lubricant, a glidant, an additive, a stabilizer, solvent or mixtures thereof.

8. The synergistic, non-statin medicinal composition as claimed in claim 7, wherein the amount of diluent is present in the range of 1 to 30%; the amount of binder is present in the range of 0.1 to 30%; the amount of lubricant is present in the range of 0.1 to 5.0 %; the amount of glidant is present in the range of 0.1 to 5.0%; the amount of additive is present in the range of 1 to 20%; the amount of surfactant is present in the range of 0.1 to 5.0%; the amount of stabilizer is present in the range of 0.1 to 10.0%, by weight of total composition.

9. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the oral administration of an effective dose of the composition improves liver and adipose tissue functioning.

10. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the oral administration of the effective dose of the composition lowers blood lipid level.

11. The synergistic, non-statin medicinal composition as claimed in claim 1, wherein the effective unit dose for oral administration is in the range of 150 to 600 mg.

12. A lipid lowering composition comprising an inclusion complex of a non-statin hypolipidemic agent with a cyclodextrin, wherein the weight ratio of the hypolipidemic agent to the cyclodextrin is in the range of 1 :0.5 to 1 :5.

13. The lipid lowering composition as claimed in claim 12, wherein the hypolipidemic agent is bempedoic acid and the cyclodextrin is beta-cyclodextrin.

14. The lipid lowering composition as claimed in claim 12, wherein the amount of bempedoic acid is present in the range of 20 to 50% by the weight of total composition.

15. The lipid lowering composition as claimed in claim 12, wherein the amount of beta- cyclodextrin is present in the range of 40 to 80% by the weight of total composition.