Palatable icosapent ethyl formulation with statin and method thereof

Abstract

The disclosed embodiment relates to a palatable icosapent ethyl formulation with statin. More particularly, the formulation comprises of icosapent ethyl, antioxidant, statin, alkalizer, wetting agent, suspending agent, diluent, flavouring agent, and sweetening agent. Furthermore, the statin is rosuvastatin calcium; the antioxidant is tocopherol; the alkalizer is magnesium oxide; the wetting agent is docusate sodium; the suspending agent is colloidal silicon dioxide; the diluent is miglyol 812; the flavouring agent is peppermint oil; and the sweetening agent is sucralose. The said formulation is an oral suspension for reduction of triglyceride (TG) levels and stabilization of atherosclerotic plaque.

Description

PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN AND METHOD THEREOFPRIORITY CLAIMThe instant patent application is related to and claims priority from the India provisional patent application entitled, “PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN”, Patent Application no: 202441022760, Filed on: 23rdMarch 2024, which is incorporated in its entirety herewith.TECHNICAL FIELD OF THE DISCLOSED EMBODIMENT

[0001] The present disclosure is in the technical field of palatable icosapent ethyl formulation with statin. More particularly, the formulation comprises of icosapent ethyl, antioxidant, statin, alkalizer, wetting agent, suspending agent, diluent, flavouring agent, and sweetening agent.BACKGROUND OF THE DISCLOSED EMBODIMENT

[0002] Cardiovascular disease (CVD) refers to a class of disorders affecting the heart and blood vessels, and it stands as a major global health concern. These diseases can manifest in various forms, including coronary artery disease, heart failure, valvular heart diseases, and disorders of the vascular system, among others. CVD is a leading cause of morbidity and mortality worldwide, contributing to a significant burden on healthcare systems.

[0003] At present, tablets containing statins such as rosuvastatin and lOOOmg capsules of icosapent ethyl are commercially available. The recommended oral intake for icosapent ethyl involves consuming four capsules daily. Given the size of these capsules and the frequency with which they need to be taken, it's worth noting that a significant number of subjects encounter challenges in swallowing solid dosage forms.

[0004] Statins constitute a category of medications designed to address elevated levels of cholesterol and lipids in the bloodstream, conditions commonly referred to as hypercholesterolemia and hyperlipidemia. These conditions are recognized as significant risk factors for the development of atherosclerosis and coronary heart disease.

[0005] A method for manufacturing the product which is of such a nature that, during production and daily use (with shaking before use and daily reduction of the contents of the package) the palatability of the formulation will remain unaltered. Generally, there is chance of rancidity of oily formulations in the presence of water which leads to bad odour.

[0006] Therefore, there is an urgent need to develop a palatable and drinkable pharmaceutical oral liquid formulation comprising icosapent ethyl and statin which can be administered as unit dose in liquid form as an oral suspension to the subjects of all the age groups.SUMMARY OF THE DISCLOSED EMBODIMENT

[0007] In an embodiment, palatable liquid oral formulation; wherein the formulation comprises of: a) icosapent ethyl; b) statin; c) antioxidant d) alkalizer; e) wetting agent; and f) suspending agent.

[0008] In another embodiment, the formulation further comprises of a diluent, a flavouring agent and a sweetening agent.

[0009] In one more embodiment, wherein the statin is rosuvastatin calcium; wherein the antioxidant is tocopherol; wherein the alkalizer is magnesium oxide; wherein the wetting agent is docusate sodium; wherein the suspending agent is colloidal silicon dioxide; wherein the diluent is miglyol 812; wherein the flavouring agent is peppermint oil; and wherein the sweetening agent is sucralose.

[0010] In further embodiment, wherein icosapent ethyl from 60- 76.57% (w / w); wherein the antioxidant is about 0.2% (w / w); wherein the stain ranges from 0.20-0.80% (w / w) ; wherein the alkalizer ranges from 0.80- 1.07% (w / w); wherein the wetting agent ranges from 0.50- 0.77% (w / w); wherein the suspending agent ranges from 0.80- 1.07% (w / w); wherein the diluent is about 6.00- 7.66% (w / w); wherein the flavouring agent ranges from 6.00- 7.66 % (w / w); and wherein the sweetening agent ranges from 2.00- 3.82% (w / w).[Oi l] In an embodiment, wherein the statin is selected from rosuvastatin calcium, atorvastatin calcium, simvastatin, pravastatin.

[0012] In one embodiment, wherein the alkalizer is selected from magnesium oxide, meglumine, sodium carbonate and sodium bicarbonate.

[0013] In an embodiment, wherein the wetting agent is selected from docusate sodium, span 80, sodium lauryl sulfate, poloxamer 188 and lecithin.

[0014] In an embodiment, wherein the flavouring agent is selected from peppermint oil, strawberry, mixed fruit and vanilla; wherein the flavouring agent is peppermint oil.

[0015] In an embodiment, wherein the suspending agent is selected from colloidal silicon dioxide, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and carbopol.

[0016] In an embodiment, wherein the diluent is selected from miglyol 812 and canola oil.

[0017] In one more embodiment, wherein the flavouring agent is selected from peppermint oil, strawberry, mixed fruit and vanilla.

[0018] In further embodiment, wherein the sweetening agent is selected from sucralose and aspartame.

[0019] In an embodiment, wherein the formulation is a colloidal suspension comprising statin of particle size ranging from 10-100 microns; wherein the suspension comprises a continuous phase and a dispersed phase; wherein the continuous phase comprises of icosapent ethyl, miglyol 812, docusate sodium and peppermint oil; wherein the dispersed phase comprises of rosuvastatin calcium, colloidal silicon dioxide, magnesium oxide and sucralose.

[0020] In an embodiment, wherein the formulation is an oral suspension.

[0021] In one more embodiment, wherein the formulation exhibits an in vitro percentage release of statin is 95% after 10 minutes; 97% after 15 minutes; 97% after 20 minutes; 97% after 30 minutes; and 97% after 45 minutes.

[0022] In an embodiment, wherein the in vitro percentage release of icosapent ethyl is 30% after 10 minutes, 61% after 20 minutes, 81% after 30 minutes, 93% after 45 minutes, 95% after 60 minutes, 96% after 120 minutes, and 97% after 180 minutes.

[0023] In another embodiment, wherein the wetting agent docusate sodium facilitates the dissolution of statin; wherein the percentage release of statin without docusate sodium is 4% after 10 minutes; 8% after 15 minutes; 10% after 20 minutes; 13% after 30 minutes; 17% after 45 minutes; wherein the percentage release of statin with docusate sodium is 95% after 10 minutes; 97% after 15 minutes; 97% after 20 minutes; 97% after 30 minutes; and 97% after 45 minutes.

[0024] In further embodiment, wherein the alkalizer magnesium oxide stabilizes the statin by removal of lactone impurities; wherein the total impurity profile of rosuvastatin without magnesium oxide is 0.066% initially; 2.063% after subjected to 40°C / 75% RH for 1 month; 2.389% after subjected to 40°C / 75% RH for 2 months; wherein the total impurity profile of rosuvastatin with magnesium oxide is 0.033% initially; 0.163% after subjected to 40°C / 75%RH for 3 months; 0.212% after subjected to 40°C / 75% RH for 6 months; 0.141% after subjected to 25°C / 60% RH for 6 months.

[0025] In one more embodiment, wherein the viscosity of the formulation ranges from 40-60 cps; wherein shelf-life period of the formulation is for about 24 months.

[0026] In one embodiment, a method for preparation of palatable liquid oral formulation; wherein the method comprises of: a) mixing of icosapent ethyl and tocopherol under stirring; b) combining miglyol 812 to mixture [from step (a)] under stirring to form a uniform continuous phase; c) adding docusate sodium to the continuous phase [from step (b)]; homogenizing for 10-30 minutes at 2000 to 5000 RPM to obtain a clear solution; d) adding rosuvastatin calcium, colloidal silicon dioxide, and magnesium oxide to the suspension [from step (c)] under stirring; homogenizing for another 10-30 minutes at 2000 to 5000 RPM to obtain a suspension; e) incorporating of sucralose into the suspension [from step (d)]; homogenizing for 5 minutes at 2000-5000 RPM; f) mixing peppermint oil into the suspension [from step (e)] under stirring for 5-10 minutes; g) obtaining a palatable liquid oral suspension; and packing the formulated suspension into containers.

[0027] In one embodiment, a method for assessing organoleptic properties of liquid oral formulation; wherein the method comprises of: a) selecting a panel of subjects to evaluate organoleptic properties including, but not limited to taste, mouth feel, and flavour; b) preparing an oral formulation; administering the oral formulation to the subjects; c) preparing a feedback form for the subjects; d) requesting subjects to assign scores to the organoleptic properties based on a predefined scoring system, wherein the scoring system utilizes qualitative and quantitative scales; e) collecting, recording, and storing the scores provided by the subjects; and f) analysing the collected scores to determine the acceptability, preference, and quality of the formulation.

[0028] In an embodiment, wherein the oral formulation comprises of 60- 76.57% of icosapent ethyl, 0.2 % of tocopherol, 0.20-0.80% of rosuvastatin calcium, 1.00- 1.65% of colloidal silicon dioxide, 0.80- 1.07% of magnesium oxide, 0.50- 0.77% of docusate sodium, 6.00- 7.66% of miglyol 812, 6.00- 7.66% of peppermint oil and 2.00- 3.82% of sucralose.

[0029] In an embodiment, wherein the scoring system involves a five-point scale for each property.

[0030] In an embodiment, wherein the acceptance of palatability is about 96%; wherein the acceptance of mouth feel property is about 84%; wherein the acceptance of flavour property is about 80%.

[0031] Several aspects of the invention are described below with reference to examples for illustration. However, one skilled in the relevant art will recognize that the invention can be practiced without one or more of the specific details or with other methods, components, materials and so forth. In other instances, well-known structures, materials, or operations are not shown in detail to avoid obscuring the features of the invention. Furthermore, the features / aspects described can be practiced in various combinations, though only some of the combinations are described herein for conciseness.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The disclosed embodiment will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0033] FIG. 1 illustrates a flowchart of method for preparation of icosapent ethyl-statin formulation (Formulation No 6), according to the aspects of the disclosed embodiment.

[0034] FIG. 2 illustrates a flowchart of method for assessing organoleptic properties of icosapent ethyl-statin formulation (Formulation No 6), according to the aspects of the disclosed embodiment.

[0035] FIG. 3 illustrates the percentage release of rosuvastatin from the icosapent ethyl-statin formulation (Formulation No 6) in comparison to the reference product (commercially available rosuvastatin), according to the aspects of the disclosed embodiment.

[0036] FIG. 4 illustrates the percentage release of icosapent ethyl from the icosapent ethyl- statin formulation (Formulation No 6) in comparison to the reference product (commercially available icosapent ethyl capsules), according to the aspects of the disclosed embodiment.

[0037] In the drawings, like reference numbers generally indicate identical, functionally similar, and / or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENT

[0038] It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0039] The use of “including”, “comprising” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. Further, the use of terms “first”, “second”, and “third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.

[0040] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise. By way of example, “a dosage” refers to one or more than one dosage.

[0041] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps.

[0042] All documents cited in the present specification are hereby incorporated by reference in their totality. In particular, the teachings of all documents herein specifically referred to are incorporated by reference.

[0043] Example embodiments of the present invention are described with reference to the accompanying figures.

[0044] In the drawings, like reference numbers generally indicate identical, functionally similar, and / or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.

[0045] DEFINITIONS

[0046] The term “icosapent ethyl” refers to an ethyl ester of eicosapentaenoic acid (EPA) that reduces synthesis and enhances clearance of triglycerides that is used to treat patients with severe hypertriglyceridemia.

[0047] The term “statins” refers to a class of drugs used to lower cholesterol. The drugs work by reducing the amount of cholesterol the liver makes and helping the liver remove cholesterol from the blood.

[0048] The term “rosuvastatin” refers to a statin medication that belongs to the class of HMG- CoA reductase inhibitors. It is a lipid lowering agent to lower elevated levels of cholesterol and triglycerides in the blood.

[0049] The term “omega-3” refers to polyunsaturated fatty acids (PUFAs)” with more than one carbon-carbon double bond in their backbone.

[0050] The term “hyperlipidaemia” refers to elevated level of lipids like cholesterol and triglycerides in blood.

[0051] The term “hypercholesterolemia” refers to a clinical condition indicating high levels of cholesterol in the blood.

[0052] The term “tocopherol” refers to a fat-soluble compound with vitamin E activity. It is a type of antioxidant that inhibits autooxidation of lipids by free radical scavenging activity.

[0053] The term “miglyol 812” refers to a medium-chain triglyceride used in toxicology studies as an excipient to improve test compound solubility / absorption.

[0054] The term “lactone impurities” refers to chemical byproducts or degradation products that contain a lactone functional group, which is a cyclic ester. These impurities can form during the synthesis, storage, or degradation of pharmaceutical compounds, particularly in drugs with ester or lactone structures.

[0055] The term “diluent” refers to an inactive ingredient that serves as a medium or vehicle for dispersing the active pharmaceutical ingredient (API).

[0056] The term “bioavailability” refers to the extent drug becomes completely available to its intended biological destination.

[0057] The term “continuous phase” refers to an oily medium in which the other solid or insoluble components are dispersed.

[0058] The term “dispersed phase” refers to solid or insoluble components spread in the oily medium.

[0059] The term “dissolution” refers to the process by which the dispersed solid particles within the suspension dissolve into the oily medium.

[0060] The term “interfacial tension” refers to the force per unit length that acts at the interface between two immiscible phases, such as a liquid and another liquid, gas, or solid. It arises due to the differences in molecular interactions between the two phases.(1) EMBODIMENTS OF THE DISCLOSURE

[0061] The present disclosure relates to palatable icosapent ethyl formulation with statin. More particularly, the formulation comprises of icosapent ethyl, antioxidant, statin, alkalizer, wetting agent, suspending agent, diluent, flavouring agent, and sweetening agent.

[0062] In one embodiment, the formulation is a palatable and drinkable pharmaceutical oral suspension that can easily be administered as unit dose in liquid form as oral suspension to the subjects of all age groups.

[0063] (A) PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN

[0064] A palatable liquid oral formulation (Formulation No 6); wherein the formulation comprises of an: a) icosapent ethyl; b) statin; c) antioxidant; d) alkalizer; e) wetting agent; f) suspending agent; g) diluent; h) flavouring agent; and i) sweetening agent.

[0065] The above ingredients a-i of the formulation is explained in the further embodiment.

[0066] (a) ICOSAPENT ETHYL

[0067] Icosapent ethyl (IPE) is an ethyl ester of eicosapentaenoic acid (EP A), which is a purified and concentrated form of EPA derived from fish oil. As the primary active pharmaceutical ingredient, icosapent ethyl constitutes about 60- 76.57% (w / w) of the formulation.

[0068] Icosapent ethyl (IPE) serves as an adjunct therapy for severe hypertriglyceridemia (triglyceride levels exceeding 500 mg / dL) and for reducing the risk of cardiovascular events in patients with elevated triglycerides. The compound functions by reducing the synthesis and / or secretion of very low-density lipoprotein triglycerides (VLDL-TG) in the liver and enhancing the clearance of triglycerides from circulating VLDL particles. The potential mechanisms of action include, but are not limited to, promoting [3-oxidation, inhibiting acyl-CoA: l,2- diacylglycerol acyltransferase (DGAT) activity, decreasing hepatic lipogenesis, and increasing the activity of plasma lipoprotein lipase.

[0069] (b) STATIN

[0070] Statins are lipid-lowering agents that work by inhibiting the enzyme HMG-CoA reductase to facilitate reduction of blood cholesterol levels, in particular low density lipoprotein cholesterol (LDL-C). In one embodiment, the statin is selected from rosuvastatin calcium, atorvastatin calcium, simvastatin, pravastatin; wherein the statin is from rosuvastatin calcium. Rosuvastatin calcium, comprising about 0.20-0.80% (w / w) of the formulation, has a high potency and long half-life, making it suitable for combination therapy. Rosuvastatin not only reduces low-density lipoprotein (LDL) cholesterol but also raises high-density lipoprotein (HDL) cholesterol levels, providing a dual benefit in managing dyslipidaemia. Its inclusion complements the triglyceride-lowering action of icosapent ethyl, addressing a broader range of lipid abnormalities.

[0071] (c) ANTIOXIDANT

[0072] Antioxidants are crucial for stabilizing polyunsaturated fatty acids, which are prone to oxidation. Oxidation can lead to rancidity, compromising the effectiveness of the formulation and causing undesirable sensory changes. In one embodiment, the antioxidant is tocopherol. Tocopherol, commonly known as Vitamin E, is included in the formulation at a concentration of about 0.2% (w / w). Tocopherol prevents oxidative degradation of Icosapent ethyl by neutralizing free radicals. It donates a hydrogen atom to free radicals, stabilizing them and preventing them from reacting with other molecules, such as lipids in fats and oils.

[0073] In fats and oils, tocopherol interrupts the chain reaction of lipid peroxidation, where free radicals attack unsaturated fatty acids, leading to rancidity. By halting this process, tocopherol preserves the quality and shelf life of the suspension. This ensures the formulation remains effective and stable over its shelf life.

[0074] (d) ALKALIZER

[0075] The inclusion of an alkalizer is critical in maintaining the pH of the formulation to ensure the stability of statins, which are susceptible to degradation and formation of lactone impurities in acidic environments. Lactone impurities in drug formulations can alter polymer properties, form insoluble complexes with APIs or excipients, and change the pH of the formulation's microenvironment. These effects can reduce solubility, slow down drug release, and even degrade active ingredients, compromising drug efficacy.

[0076] In one embodiment, the alkalizer is selected from magnesium oxide, meglumine, sodium carbonate and sodium bicarbonate; wherein the alkalizer is magnesium oxide, constituting about 0.80- 1.07% (w / w) of the formulation. Magnesium oxide creates an alkaline environment that prevents the conversion of rosuvastatin into its lactone form, thereby maintaining its therapeutic efficacy at the target site.

[0077] (e) WETTING AGENT

[0078] Wetting agents are added to facilitate dissolution of statin. In one embodiment, the wetting agent is selected from docusate sodium, span 80, sodium lauryl sulfate, poloxamer 188 and lecithin; wherein the wetting agent is docusate sodium. Docusate sodium, added at about 0.50- 0.77% (w / w), reduces the interfacial tension between the hydrophilic and lipophilic phases.

[0079] Docusate sodium is an anionic surfactant employed as a wetting agent in oily suspensions due to its amphiphilic structure, which includes hydrophobic alkyl chains (hydrophobic) and a hydrophilic sulfonate group. Docusate sodium functions as a wetting agent in oily suspensions by adsorbing at the surface of suspended solid particles, where its hydrophilic and hydrophobic ends align at the interfaces. This alignment reduces surface tension, improving particle wetting and enhancing the spread of the liquid medium, which prevents clumping and ensures even dispersion. Additionally, its negatively charged sulfonate groups create an electrostatic barrier between particles, maintaining stability and preventing re-agglomeration. The hydrophobic chains of docusate sodium also interact effectively with oils, making it particularly suitable for emulsifying or wetting particles in nonpolar environments.

[0080] Mechanism of action:

[0081] The statin rosuvastatin calcium is added in the form of a powder (dispersed phase) to the oily medium (continuous phase), resulting in development of hydrophobicity wherein oil globules get coated on the statin and prevent drug release. Docusate sodium was added for dissolution of statin, thereby enhancing bioavailability and therapeutic efficacy of the oral suspension.

[0082] (f) SUSPENDING AGENT

[0083] Suspending agent is included to maintain the uniform dispersion of insoluble particles in the suspension, preventing sedimentation during storage. It enhances the consistency and viscosity of the liquid, this ensures that the suspended particles remain evenly distributed, reducing sedimentation over time, enhances stability of the suspension and ensures that the correct dosage of active ingredients is administered with each use.

[0084] In one embodiment, the suspending agent is selected from colloidal silicon dioxide, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and carbopol; wherein the suspending agent is colloidal silicon dioxide, added at a concentration of about 1.00- 1.65 % (w / w). Colloidal silicon dioxide enhances the viscosity of the suspension, ensuring that theactive ingredients remain evenly distributed. This not only improves the physical stability of the formulation but also ensures accurate dosing and consistent therapeutic outcomes.

[0085] (g) DILUENT

[0086] Diluent is an inactive ingredient that serves as a medium or vehicle for dispersing the active pharmaceutical ingredient. In one embodiment, the diluent is selected from miglyol 812 and canola oil; wherein the diluent is miglyol 812, included at about 6.00 - 7.66% (w / w). Miglyol 812 is a medium-chain triglyceride that functions as a diluent or an oily vehicle for enhancing solubility and bioavailability of orally administered suspension.

[0087] (h) FLAVOURING AGENT

[0088] Flavouring agents are essential for improving the taste profile of liquid formulations, particularly those containing omega-3 fatty acids and statins, which can have a bitter or oily taste. In one embodiment, the flavouring agent is selected from peppermint oil, strawberry, mixed fruit and vanilla; wherein the flavouring agent is peppermint oil, included at about 6.00- 7.66% (w / w).

[0089] Peppermint oil imparts a pleasant taste and fragrance to the formulation to mask the unpleasant odour from icosapent ethyl (sourced from fish oil), thereby effectively masking bitterness and enhancing the overall sensory experience. Its inclusion ensures better compliance, especially in patients who might otherwise find the formulation unpalatable.

[0090] (i) SWEETENING AGENT

[0091] Sweetening agents are critical for masking bitterness and improving the overall taste of the suspension. In one embodiment, the sweetening agent is selected from sucralose and aspartame; wherein the sweetening agent is sucralose, included at a concentration of about 2.00- 3.82 % (w / w). Sucralose is a non-caloric sweetener, making it suitable for subjects with dietary restrictions, such as those with diabetes. Its inclusion significantly enhances the palatability of the formulation, thereby meeting the needs of user-acceptance.

[0092] TABLE 1: PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN

[0093] MODE OF THE FORMULATION

[0094] The formulation is an oral suspension; wherein the suspension comprises of two phases namely continuous and disperse phases. The continuous phase includes IPE, miglyol 812, docusate sodium and peppermint oil whereas the dispersed phase comprises of rosuvastatin calcium, colloidal silicon dioxide, magnesium oxide and sucralose.

[0095] SYNERGISTIC EFFECT OF THE FORMULATION

[0096] Icosapent ethyl and rosuvastatin calcium are active pharmaceutical ingredients for lowering triglyceride levels in cardiovascular conditions. Tocopherol being a form of Vitamin E is an antioxidant to prevent rancidity and oxidative degradation of icosapent ethyl in the oral suspension. Colloidal silicon dioxide is a suspending agent for uniform distribution of the solid active pharmaceutical ingredients (API) , magnesium oxide functions as an alkalizer or pH regulator for preventing the formation of lactone impurities thus leading to enhanced bioavailability and therapeutic efficacy of the suspension, miglyol 812 is a carrier oil functioning as a continuous phase for the dispersed solid API , docusate sodium is a wetting agent for reduction of interfacial tension between the solid active pharmaceutical ingredients and the oily medium by facilitating particle-oil interaction to prevent clumping or floating of the particles, thus maintains the homogeneity of the oral suspension.

[0097] Peppermint oil is a flavouring and odour masking agent, and sucralose is a sweetening agent found to be compatible with rest of the ingredients in formulation.

[0098] The combination of icosapent ethyl, tocopherol, rosuvastatin calcium, colloidal silicon dioxide, magnesium oxide, miglyol 812, docusate sodium, peppermint oil, and sucralose, is essential to formulate an oral liquid suspension for enhanced bioavailability, therapeutic efficacy odour, palatability for subject compliance.

[0099] (B) METHOD FOR PREPARATION OF PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN

[0100] A method for preparation of palatable liquid oral formulation (Formulation No 6); wherein the method comprises steps of:a) The active pharmaceutical ingredient (API) icosapent ethyl of 60- 76.57 % was combined with 0.2% tocopherol in a vessel under stirring conditions. Tocopherol was selected for its antioxidant properties, which prevents the oxidation and rancidity of the formulation (102). b) 6.00- 7.66% of miglyol oil was gradually added to the mixture obtained in step (a) under controlled stirring conditions. The addition of miglyol 812 was carried out until a homogenous continuous phase was obtained, ensuring uniform dispersion of the API in the oily medium (104). c) Docusate sodium was then gradually incorporated as a wetting agent at a weight of 0.50- 0.77 % into the continuous phase [from step (b)] to facilitate the wettability and dissolution of the active pharmaceutical ingredients (106). The mixture was then subjected to homogenization using a high-shear homogenizer operated at a speed range of 2000 to 5000 RPM for 10-30 minutes to obtain a clear solution. d) The statin (rosuvastatin calcium) of about 0.20-0.80% (w / w), suspending agent (colloidal silicon dioxide) of about 1.00- 1.65%, and alkalizer of about 0.80- 1.07 % (w / w) (magnesium oxide) were introduced sequentially into the solution [from step (c)] under continuous stirring to form a suspension. The addition of an alkalizer was necessary to maintain a pH environment conducive to the stability of the statin and to minimize the formation of lactone impurities. The suspension was homogenized again for a duration of 10-30 minutes at a speed of 2000 to 5000 RPM (108). This step ensured uniform distribution of all ingredients and enhanced stability required suspension. f) Sucralose was employed as a sweetening agent at a weight of about 2.00- 3.82% to the suspension to enhance the palatability of the formulation. The mixture underwent an additional homogenization step for 5 minutes at the same speed to ensure even dispersion of sucralose throughout the suspension (110). g) Further, peppermint oil was subsequently introduced as a flavouring agent at a weight of about 6.00- 7.66% (w / w) into the formulation to further improve its sensory characteristics. The mixture was stirred for an additional 5-10 minutes to ensure thorough incorporation of the flavouring agent into the suspension (112). h) The final suspension was filled into appropriate containers under controlled environmental conditions to maintain the integrity and quality of the product (114). The containers were sealed and packaged in suitable materials to ensure the stability and protection of the formulation during storage and transportation.

[0101] The oral formulation was prepared in a high shear homogenizer while maintaining room temperature throughout the procedure.

[0102] (C) METHOD FOR ASSESSING ORGANOLEPTIC PROPERTIES OF PALATABLE ICOSAPENT ETHYL FORMULATION WITH STATIN

[0103] A method for assessing palatability of the liquid oral formulation; wherein the method comprises of: a) A panel of human subjects were selected to evaluate organoleptic properties including, but not limited to taste, mouth feel, and flavour (202). An oral formulation comprising 60- 76.57% of icosapent ethyl, 0.2 % of tocopherol, 0.20-0.80% of rosuvastatin calcium, 1.00- 1.65% of colloidal silicon dioxide, 0.80- 1.07% of magnesium oxide, 0.50- 0.77% of docusate sodium, 6.00- 7.66% of miglyol 812, 6.00- 7.66% of peppermint oil and 2.00- 3.82% of sucralose (204). b) A feedback form was prepared to check if the formulation is meeting the criteria of subject compliance (206). The subjects were requested to assign scores to the organoleptic properties based on a predefined scoring system, wherein the scoring system utilizes qualitative and quantitative scales (208). c) The scores provided by the subjects were collected, recorded, and stored (210). d) The collected scores were analyzed to determine the acceptability, preference, and quality of the formulation (212) as illustrated in (FIG.2).

[0104] The palatability of Formulation No 6 was evaluated in a study with five human volunteers. Each participant provided feedback on various sensory parameters, including taste, mouth feel, flavour, and user acceptance. The findings, as detailed in Table 2, provide a comprehensive overview of the sensory evaluation results, showcasing a gradient of feedback ranging from extremely negative to highly positive.

[0105] TABLE 2: SENSORY EVALUATION CRITERIA FOR ICOSAPENT ETHYL-STATIN FORMULATION NO 6

[0106] TABLE 3: PARTICIPANT-WISE SENSORY EVALUATION SCORES FORICOSAPENT ETHYL- STATIN FORMULATION NO 6

[0107] The overall acceptability of the formulation, as summarized in Table 3, was found to be satisfactory, reflecting the effectiveness of the formulation in addressing factors influencing palatability. This study underscores the importance of sensory optimization in pharmaceutical formulations to enhance subject compliance and ensure effective delivery of active ingredients icosapent ethyl and rosuvastatin.

[0108] Results of the study:

[0109] The scoring system involves a five-point scale for each properties taste, mouth feel and flavour.

[0110] In one embodiment, the acceptance of palatability is about 96%; wherein the acceptance of mouth feel property is about 84%; wherein the acceptance of flavour property is about 80%. The overall user-acceptance score provided by the subjects was found to be around 80%.

[0111] (2) EXAMPLE EMBODIMENTS

[0112] The disclosed embodiment will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosed embodiment in any manner.

[0113] EXAMPLE 1: ICOSAPENT ETHYL- STATIN FORMULATION NO 1

[0114] TABLE 4: ICOSAPENT ETHYL- STATIN FORMULATION NO 1

[0115] Procedure: The manufacturing procedure includes blending icosapent ethyl and miglyol 812, followed by the combination of rosuvastatin calcium, magnesium oxide, and colloidal silicon dioxide. Subsequently, the mixture undergoes homogenization to create a suspension.

[0116] Inference: The odour and taste were found to be inadequate and the dissolution of rosuvastatin calcium was not meeting the required specification.

[0117] EXAMPLE 2: ICOSAPENT ETHYL- STATIN FORMULATION NO 2

[0118] TABLE 5: ICOSAPENT ETHYL- STATIN FORMULATION NO 2

[0119] Procedure: The manufacturing process involves homogenization of icosapent ethyl, miglyol 812, docusate sodium together followed by combining rosuvastatin calcium, magnesium oxide, colloidal silicon dioxide and homogenizing to form a suspension.

[0120] Inference: Rosuvastatin dissolution is meeting the required specification. The odour and taste are not convincing.

[0121] EXAMPLE 3: ICOSAPENT ETHYL- STATIN FORMULATION NO 3

[0122] TABLE 6: ICOSAPENT ETHYL- STATIN FORMULATION NO 3

[0123] Procedure: The manufacturing process involves homogenization of icosapent ethyl, miglyol 812, docusate sodium together followed by mixing rosuvastatin calcium, magnesium oxide, colloidal silicon dioxide and homogenized to form a suspension. Peppermint oil was mixed with above suspension to mask odour and enhance the flavour.

[0124] Inference: The odour and taste are not convincing.

[0125] EXAMPLE 4: ICOSAPENT ETHYL- STATIN FORMULATION NO 4

[0126] TABLE 7: ICOSAPENT ETHYL- STATIN FORMULATION NO 4

[0127] Procedure: The manufacturing process involves homogenization of icosapent ethyl, miglyol 812, docusate sodium together followed by combining rosuvastatin calcium, magnesium oxide, colloidal silicon dioxide and homogenizing to form a suspension. Vanilla was mixed with the suspension as a flavouring agent to mask odour and impart a pleasant flavour.

[0128] Inference: Fishy odour was present and colour change was observed on storage.

[0129] EXAMPLE 5: ICOSAPENT ETHYL- STATIN FORMULATION NO 5

[0130] TABLE 8: ICOSAPENT ETHYL- STATIN FORMULATION NO 5

[0131] Procedure: The manufacturing process involves homogenization of icosapent ethyl, miglyol 812, docusate sodium together followed by combining rosuvastatin calcium, magnesium oxide, colloidal silicon dioxide and homogenizing to form a suspension. Peppermint oil mixed with above suspension as a flavouring agent to mask odour and impart a pleasant flavour.

[0132] Inference: The odour was acceptable however; taste of the formulation was not convincing.

[0133] EXAMPLE 6: ICOSAPENT ETHYL- STATIN FORMULATION NO 6

[0134] TABLE 9: ICOSAPENT ETHYL- STATIN FORMULATION NO 6

[0135] Procedure: The manufacturing process involves homogenization of icosapent ethyl, miglyol 812, and docusate sodium together for NMT 60 min followed by combining rosuvastatin calcium, magnesium oxide, colloidal silicon dioxide, sucralose and homogenizing for NMT 30 min to form a suspension. Peppermint oil was mixed with above suspension for NMT 15 minutes to mask odour and impart a pleasant flavour; while sucralose was added as sweetener for subject compliance.

[0136] Inference: The odour and the taste of the formulation were found to be highly adequate meeting the requirements of subject compliance.

[0137] EXAMPLE 7: IN VITRO DISSOLUTION STUDY PERFORMED FOR ICOSAPENT ETHYL- STATIN FORMULATION NO 6 IN COMPARISON WITH REFERENCE DRUG PRODUCT

[0138] (A) IN VITRO DISSOLUTION STUDY TO DETERMINE % RELEASE OF ROSUVASTATIN

[0139] Materials and Conditions:

[0140] Medium: pH 6.6 citrate buffer

[0141] Apparatus: USP II (Paddle)

[0142] Volume: 900 mL

[0143] Rotation Speed: 50 rpm

[0144] Temperature: 37 ± 0.5°C

[0145] Steps followed in the dissolution study:

[0146] The USP II paddle apparatus was cleaned, calibrated, and set up following standard procedures. Each dissolution vessel was filled with 900 mL of pH 6.6 citrate buffer to act as the dissolution medium.

[0147] The dissolution medium was preheated to 37 ± 0.5°C and maintained at this temperature throughout the experiment using a temperature-controlled system.

[0148] The dosage form was accurately weighed and placed at the bottom of the dissolution vessel, directly beneath the paddle.

[0149] The paddle rotation speed was set to 50 rpm, and the apparatus was activated. The movement of the paddles was monitored to ensure steady rotation without any deviation from the set parameters.

[0150] Samples of the dissolution medium were collected at predefined intervals (e.g., 5, 10, 15, 30, 45, 60 minutes) using a syringe. Care was taken to avoid disturbing the medium or the dosage form during the sampling process.

[0151] Each sample was immediately filtered using a 0.45 pm filter to remove undissolved particles that could interfere with the analysis.

[0152] An equal volume of freshly prepared pH 6.6 citrate buffer, maintained at the same temperature, was used to replace the withdrawn samples to ensure consistent experimental conditions.

[0153] The filtered samples were analysed using UV-visible spectrophotometry or HPLC to determine the concentration of the dissolved drug in the medium.

[0154] A dissolution profile was constructed by plotting the percentage of drug release against time. The results were compared with reference product data for compliance evaluation.

[0155] TABLE 10: PERCENTAGE RELEASE OF ROSUVASTATIN

[0156] B) IN VITRO DISSOLUTION STUDY TO DETERMINE % RELEASE OFICOSAPENT ETHYL

[0157] Materials and Conditions:

[0158] Medium: Water containing 5% Triton

[0159] Apparatus: USP II (Paddle)

[0160] Volume: 900 mL

[0161] Rotation Speed: 50 rpm

[0162] Temperature: 37 ± 0.5°C

[0163] Steps followed in the dissolution study:

[0164] The USP II paddle apparatus was cleaned and calibrated according to standard procedures. Each dissolution vessel was filled with 900 mL of water containing 5% Triton as the dissolution medium.

[0165] The medium was preheated to 37 ± 0.5°C and maintained throughout the study using a controlled temperature system.

[0166] The dosage form was accurately weighed and placed at the bottom of each dissolution vessel, directly beneath the paddle.

[0167] The paddle rotation speed was set to 50 rpm, and the apparatus was started. Continuous monitoring ensured that the paddle's movement was steady, with no deviation from the set parameters.

[0168] Samples of the medium (approximately 5 mL) were withdrawn at predefined intervals (e.g., 5, 10, 15, 30, 45, 60, 120, 180 minutes) using a syringe. Care was taken not to disturb the medium or the dosage form during sample collection.

[0169] The withdrawn samples were immediately filtered using a 0.45 pm filter to eliminate undissolved particles that could interfere with the analysis.

[0170] The volume of the medium withdrawn during sampling was replaced with freshly prepared medium at the same temperature to ensure consistent test conditions.

[0171] The filtered samples were analyzed using UV- visible spectrophotometry or HPLC to quantify the concentration of the dissolved drug in the medium.

[0172] A dissolution profile was constructed by plotting the percentage of drug released against time. Results were compared to reference product data to evaluate compliance.

[0173] TABLE 11: PERCENTAGE RELEASE OF ICOSAPENT ETHYL

[0174] EXAMPLE 8: STABILITY STUDY OF ICOSAPENT ETHYL- STATIN FORMULATION NO 6 WITHOUT MAGNESIUM OXIDE

[0175] Rosuvastatin is unstable in the absence of alkalizer as rosuvastatin lactone impurity forms significantly. Lactone impurities in drug formulations can alter polymer properties, form insoluble complexes with APIs or excipients, and change the pH of the formulation's microenvironment. These effects can reduce solubility, slow drug release, and even degrade active ingredients, compromising drug efficacy. To avoid this, alkalizer like magnesium oxide was used in the formulation. The stability study of rosuvastatin in the formulation without magnesium oxide demonstrated the formation of significantly higher levels of lactone impurities from 0.035% to 1.823% in just 1 month under accelerated stability condition. This impurity exceeded the specification limit of 0.5%, posing a critical challenge to the formulation's stability and compliance. As magnesium oxide plays an important role as an alkalizer, its absence likely led to an unfavourable environment that accelerated impurity formation. The stability data, as described in the Table 11, highlights the progressive development of lactone impurity over time, underscoring the necessity of magnesium oxide in the formulation.

[0176] TABLE 12: STABILITY STUDY OF ICOSAPENT ETHYL-STATIN FORMULATION NO 6 WITHOUT MAGNESIUM OXIDE

[0177] ND: Not detected

[0178] EXAMPLE 9: STABILITY STUDY OF ICOSAPENT ETHYL- STATIN FORMULATION NO 6 WITH MAGNESIUM OXIDE

[0179] Icosapent ethyl-statin formulation No 6 was subjected to accelerated (40°C / 75% RH for 6 months) and long-term (25°C / 60% RH for 6 months) stability analysis and the observed results were presented below. The total impurity profiles of both rosuvastatin and icosapent ethyl in the suspension formulation were well maintained without any significant change in impurity level. From the results, it was obvious that icosapent ethyl-statin formulation No 6 is stable at the above-mentioned conditions.

[0180] TABLE 13: STABILITY STUDY RESULTS ICOSAPENT ETHYL-STATIN FORMULATION NO 6 WITH MAGNESIUM OXIDE0181] ND: Not detected

[0182] EXAMPLE 10: DISSOLUTION ENHANCEMENT OF ICOSAPENT ETHYL- STATIN FORMULATION NO 6 THROUGH DOCUSATE SODIUM AS A WETTING AGENT

[0183] Docusate sodium plays a critical role as a wetting agent in the formulation, significantly enhancing the solubility and dissolution of the statin (rosuvastatin). By reducing interfacial tension and improving the wettability of the drug particles, docusate sodium facilitates better drug release and absorption. To evaluate its effectiveness, the dissolution profile of rosuvastatin was analysed in formulations prepared both with and without docusate sodium. The comparative dissolution data, as described in the Table 14, highlight the substantial improvement in drug release due to the inclusion of the wetting agent.

[0184] Table 14: IN VITRO DISSOLUTION STUDY OF ICOSAPENT ETHYL- STATIN FORMULATION NO 6 WITH AND WITHOUT DOCUSATE SODIUM

[0185] The results represented in Table 14 underscores the importance of docusate sodium in optimizing the formulation for enhanced bioavailability. The in vitro percentage release of statin without docusate sodium is 4% after 10 minutes; 8% after 15 minutes; 10% after 20 minutes; 13% after 30 minutes; 17% after 45 minutes; wherein the percentage release of statin with docusate sodium is 95% after 10 minutes; 97% after 15 minutes; 97% after 20 minutes; 97% after 30 minutes; and 97% after 45 minutes.

[0186] (3) ADVANTAGES OF THE DISCLOSED EMBODIMENT

[0187] The said palatable icosapent ethyl-statin formulation is an oral suspension for facilitating the process of swallowing in aged population.

[0188] The oral suspension is made with suitable odouring, flavouring and sweetening agents for subject compliance.

[0189] The said formulation comprises of an alkalizer to maintain the pH, prevent formation of lactone impurities which results in enhanced therapeutic efficacy.

[0190] The wetting agent docusate sodium facilitates proper dissolution of statin, while added flavouring agent peppermint oil and sweetening agent sucralose enhances palatability.

[0191] Formulations comprising a combination of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), are more likely to increase low-density lipoprotein cholesterol (LDL- C) levels compared with pure EPA-only products. Therefore, the disclosed embodiment is focused on employing an ethyl ester derivative of EPA, icosapent ethyl. Therefore, by combining statins with icosapent ethyl will have synergistic effect in reducing LDL cholesterol and triglycerides in subjects of all age groups.

[0192] (4) USES, APPLICATIONS AND BENEFITS OF THE DISCLOSED EMBODIMENT

[0193] Potential mechanisms for the cardio protective effects of icosapent ethyl include reducing triglyceride (TG) levels and stabilizes atherosclerotic plaque.

[0194] The disclosed formulation is an oral suspension making it simple for palatability in all specially for the aged population.

[0195] (5) BEST MODE TO USE THE DISCLOSED EMBODIMENT

[0196] Best mode to practice the disclosed embodiment is by manufacturing and commercialization of the said oral suspension.

[0197] The said formulation will be packed in suitable container as once a day unit dosage form.

[0198] The said oral suspension is made palatable for facilitating the process of swallowing in aged population.

[0199] Merely for illustration, only representative number / type of graph, chart, block, and subblock diagrams were shown. Many environments often contain many more block and subblock diagrams or systems and sub-systems, both in number and type, depending on the purpose for which the environment is designed.

[0200] While specific embodiments of the invention have been shown and described in detail to illustrate the inventive principles, it will be understood that the invention may be embodied otherwise without departing from such principles.

[0201] Reference throughout this specification to “one embodiment”, “an embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosed embodiment. Thus, appearances of the phrases “in one embodiment”, “in an embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0202] It should be understood that the figures and / or screen shots illustrated in the attachments highlighting the functionality and advantages of the disclosed embodiment are presented for example purposes only. The disclosed embodiment is sufficiently flexible and configurable, such that it may be utilized in ways other than that shown in the accompanying figures.

[0203] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0000] REFERENCES1. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189: 19-30.2. Skulas-Ray AC, West SG, Davidson MH, Kris-Etherton PM. Omega-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia. Expert OpinPharmacother. 2008; 9: 1237-48.3. Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. CurrAtheroscler Rep. 2011; 13:474-83.4. Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J ClinLipidol. 2012; 6:5-18.5. Tatsuno I, Saito Y, Kudou K, Ootake J. Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the Omega-3 fatty acids Randomized Double-blind (ORD) study. J ClinLipidol. 2013; 7:199-207.

Claims

I / We claim:1) A palatable liquid oral formulation; wherein the formulation comprises of: a) icosapent ethyl; b) statin; c) antioxidant; d) alkalizer; e) wetting agent; and f) suspending agent.2) The formulation as claimed in claim 1 , further comprises of diluent, flavouring agent and sweetening agent.3) The formulation as claimed in claim 1 and 2, wherein the statin is rosuvastatin calcium; wherein the antioxidant is tocopherol; wherein the alkalizer is magnesium oxide; wherein the wetting agent is docusate sodium; wherein the suspending agent is colloidal silicon dioxide; wherein the diluent is miglyol 812; wherein the flavouring agent is peppermint oil; and wherein the sweetening agent is sucralose.4) The formulation as claimed in claim 3, wherein icosapent ethyl ranges from 60- 76.57% (w / w); wherein the antioxidant is about 0.2% (w / w); wherein the stain ranges from 0.20- 0.80% (w / w) ; wherein the alkalizer ranges from 0.80- 1.07% (w / w); wherein the wetting agent ranges from 0.50- 0.77% (w / w); wherein the suspending agent ranges from 0.80- 1.07% (w / w); wherein the diluent ranges from 6.00- 7.66% (w / w); wherein the flavouring agent ranges from 6.00- 7.66 % (w / w); and wherein the sweetening agent ranges from 2.00- 3.82% (w / w).5) The formulation as claimed in claim 1 , wherein the statin is selected from rosuvastatin calcium, atorvastatin calcium, simvastatin, pravastatin.6) The formulation as claimed in claim 1 , wherein the alkalizer is selected from magnesium oxide, meglumine, sodium carbonate and sodium bicarbonate.7) The formulation as claimed in claim 1, wherein the wetting agent is selected from docusate sodium, span 80, sodium lauryl sulfate, poloxamer 188 and lecithin.8) The formulation as claimed in claim 1, wherein the suspending agent is selected from colloidal silicon dioxide, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and carbopol.9) The formulation as claimed in claim 2, wherein the diluent is selected from miglyol 812 and canola oil.10) The formulation as claimed in claim 2, wherein the flavouring agent is selected from peppermint oil, strawberry, mixed fruit and vanilla.11) The formulation as claimed in claim 2, wherein the sweetening agent is selected from sucralose and aspartame.12) The formulation as claimed in claim 1, wherein the formulation is a colloidal suspension comprising statin of particle size ranging from 10-100 microns; wherein the suspension comprises a continuous phase and a dispersed phase; wherein the continuous phase comprises of icosapent ethyl, miglyol 812, docusate sodium and peppermint oil; wherein the dispersed phase comprises of rosuvastatin calcium, colloidal silicon dioxide, magnesium oxide and sucralose.13) The formulation as claimed in claim 1, wherein the formulation is an oral suspension.14) The formulation as claimed in claim 1, wherein the in vitro percentage release of statin is 95% after 10 minutes; 97% after 15 minutes; 97% after 20 minutes; 97% after 30 minutes; and 97% after 45 minutes.15) The formulation as claimed in claim 1, wherein the in vitro percentage release of icosapent ethyl is 30% after 10 minutes, 61% after 20 minutes, 81% after 30 minutes, 93% after 45 minutes, 95% after 60 minutes, 96% after 120 minutes, and 97% after 180 minutes.16) The formulation as claimed in claim 1, wherein the in vitro percentage release of statin without docusate sodium is 4% after 10 minutes; 8% after 15 minutes; 10% after 20 minutes; 13% after 30 minutes; 17% after 45 minutes; wherein the percentage release of statin with docusate sodium is 95% after 10 minutes; 97% after 15 minutes; 97% after 20 minutes; 97% after 30 minutes; and 97% after 45 minutes.17) The formulation as claimed in claim 1, wherein the total impurity profile of statin without magnesium oxide is 0.066% at day 0; 2.063% after subjected to 40°C / 75% RH for 1 month; 2.389% after subjected to 40°C / 75% RH for 2 months; wherein the total impurity profile of statin with magnesium oxide is 0.033% at day 0; 0.163% after subjected to 40°C / 75% RH for 3 months; 0.212% after subjected to 40°C / 75% RH after 6 months; 0.141% after subjected to 25°C / 60% RH for 6 months.18) The formulation as claimed in claim 1 , wherein the viscosity of the formulation ranges from 40-60 cps; wherein shelf-life period of the formulation is for about 24 months.19) A method for preparation of a palatable liquid oral formulation; wherein the method comprises of: a) mixing of icosapent ethyl and tocopherol under stirring;b) combining miglyol 812 to mixture [from step (a)] under stirring to form a uniform continuous phase; c) adding docusate sodium to the continuous phase [from step (b)]; homogenizing for 10- 30 minutes at 2000 to 5000 RPM to obtain a clear solution; d) adding rosuvastatin calcium, colloidal silicon dioxide, and magnesium oxide to the solution [from step (c)] under stirring; homogenizing for another 10-30 minutes at 2000 to 5000 RPM to obtain a suspension; e) incorporating of sucralose into the suspension [from step (d)]; homogenizing for 5 minutes at 2000-5000 RPM; f) mixing peppermint oil into the suspension [from step (e)] under stirring for 5-10 minutes; g) obtaining a palatable liquid oral suspension; and packing the formulated suspension into containers.20) A method for assessing organoleptic properties of a palatable liquid oral formulation; wherein the method comprises of: a) selecting a panel of subjects to evaluate organoleptic properties including, but not limited to taste, mouth feel, and flavour; b) administering the oral formulation to the subjects; c) preparing a feedback form for the subjects; d) requesting subjects to assign scores to the organoleptic properties based on a predefined scoring system, wherein the scoring system utilizes qualitative and quantitative scales; e) collecting, recording, and storing the scores provided by the subjects; and f) analysing the collected scores to determine the acceptability, preference, and quality of the formulation.21) The method as claimed in claim 20, wherein the oral formulation comprises of 60- 76.57% of icosapent ethyl, 0.2 % of tocopherol, 0.20-0.80% of rosuvastatin calcium, 1.00- 1.65% of colloidal silicon dioxide, 0.80- 1.07% of magnesium oxide, 0.50- 0.77% of docusate sodium, 6.00- 7.66% of miglyol 812, 6.00- 7.66% of peppermint oil and 2.00- 3.82% of sucralose.22) The method as claimed in claim 20, wherein the scoring system involves a five -point scale for each property.23) The method as claimed in claim 20, wherein the acceptance of palatability is about 96%; wherein the acceptance of mouth feel property is about 84%; wherein the acceptance of flavour property is about 80%.

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