WO2015011724A2

WO2015011724A2 - A novel omega -3 fatty acid composition with a plant extract

Info

Publication number: WO2015011724A2
Application number: PCT/IN2014/000483
Authority: WO
Inventors: Thevar Ganesan Munyandi; Kalimuthu Selvakumar
Original assignee: Kms Health Center Pvt Ltd
Priority date: 2013-07-22
Filing date: 2014-07-22
Publication date: 2015-01-29
Also published as: WO2015011724A3

Abstract

A composition comprising omega-3 fatty acid, a plant extracts at least one surfactant and a process to process to prepare such composition is disclosed. The composition disclosed herein has enhanced bioavailability of omega -3 fatty acids and is substantially free of food effects.

Description

A novel Omega -3 fatty acid composition with a Plant extract FIELD OF INVENTION

This invention relates to omega-3 fatty acid composition of enhanced bioavailability comprising omega-3 fatty acids, a plant extract and at least one surfactant.

This invention also relates to omega-3 fatty acid composition substantially free of food effects comprising Omega-3 fatty acids, a plant extract and at least one surfactant.

This invention also relates to process of preparing composition comprising omega-3 fatty acids, a plant extract and at least one surfactant.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS Omega -3 fatty acids:

Omega-3 fatty acids, also called n-3 poly unsaturated fatty acids (PUFA), have long been suspected of having beneficial effects in humans, particularly with regards to reducing the risk of coronary heart disease, reducing obesity, improving diabetic parameters including blood glucose levels, and improving other parameters of the metabolic syndrome. These fatty acids have a number of beneficial effects, among which is lowering elevated blood triglyceride levels down to more clinically acceptable values (Harris et. al., "Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives" Atherosclerosis. 2008 March; 197(1): 12-24).

Omega-3 fatty acids may improve cognitive function and delay the onset of Alzheimer's disease, Omega-3 fatty acids delivers ingredients essential for eye development and which may protect against age related macular degeneration and help dry eye syndrome and also contains essential fatty acids which may improve the nutrition of the skin and associated inflammatory conditions.

Omega -3 fatty acids may also help in reducing pain, stiffness and inflammation associated with arthritis and other joint conditions. Omega-3 fatty acids have also been shown to be important in pregnant women and infants, where their depletion may lead to visual or central nervous system problems Omega-3 fatty acids cannot be manufactured in the human body and are therefore called essential fatty acids. They need to be obtained from the diet of an individual. The two major health promoting omega-3 polyunsaturated fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are naturally found in certain cold-water fatty fish such as salmon, tuna, and mackerel. They can also be derived in the body from alpha-linolenic acid (ALA), which is an omega-3 fatty acid found in certain seeds and plant-based oils. However, the body is very inefficient at converting ALA into EPA and DHA. This table lists several different names for the most common omega-3 fatty acids found in nature.

Because of the wide range of known health benefits related to omega-3 fatty acids, a number of international organizations and agencies proposed recommendations for omega-3 fatty acids, as well as fish intake for health promotion and prevention of various chronic diseases. Although the intake of omega-3 fatty acids has proven to be crucial, it has been found that omega-3 fatty acids are deficient in the typical Western diet. The omega-3 deficiency situation is even worse among the poor and malnourished.

One approach to alleviating omega-3 fatty acid deficiencies is through dietary supplementation, which is a convenient way to add them to the diet. Nutritional supplements are especially useful in individuals who struggle to meet their nutrient needs because of inadequate dietary intakes. Various forms of omega-3 fatty acids and uses thereof, including in pharmaceutical, nutritional or dietary supplement products is known in art. One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Lovaza®. Such a form of omega-3 fatty acid is described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.

WO2013103902 discloses DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form

WO2013148136 describes composition comprising Omega-3 fatty acid esters, free of Omega-3 free fatty acids

U.S. Patent Nos. 7652068 discloses highly purified omega-3 fatty acid formulations containing greater than 85% omega-3 fatty acids by weight.

The bioavailability and thus the therapeutic efficacy of an omega-3 fatty acid formulation is affected by the form in which it is administered. The amount of absorption of omega-3 fatty acid in gastro intestinal tract depends upon the chemical and physical form of the fish oil.

There are several omega-3 fatty acid supplements available. Current dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters have a food effect, with poor absorption when taken while fasting or with a low fat meal. One such drug sold under trade name OMYTRYG® when administered under fasted condition, on average the peak (Cmax) and total (AUC0-72h) exposure were lower by up to 20 to 80-fold, respectively, for total plasma EPA, and lower by up to 2 to 4-fold, respectively, for total plasma DHA, in comparison to those observed under fed condition (high-fat high-calorie meal). Therefore, OMTRYG should be taken with food.

Therefore a need arises for compositions with enhanced bioavailability of omega-3 fatty acids and which can be administered without food effects

Plants Extracts:

In recent years, the use of various plant extract for the prevention of disease, alleviating the effects thereof, or for treating diseases have been gradually increasing in all societies. Throughout the human history, there have been and still are attempts for treating many diseases by using some plant extracts. According to the records of the World Health Organization (WHO), a large proportion of the world's population (70-80%) makes use of plant extracts for therapeutic or prophylactic purposes. Additionally, around 25% of prescription drugs in developed countries are composed of plant based active agents (vinblastine, reserpine, quinine, aspirin, etc.) (Farnsworth et al.,1985). Particularly following the end of the 1990s, the discovery of new areas of use for medical and aromatic plant extracts and the increasing demand for natural products have increased the use potential thereof day by day.

Many plant derivatives and domestic remedies have been screened for their hypolipidemic action. More than 70 medicinal plants have been documented to have significant hypolipidemic action. During the last decade, an increase in the use of medicinal plants has been observed in metropolitan areas of developed countries. Medicinal plants play a major role in hypolipidemic activity. The advantages of herbal medicines reported are effectiveness, safety, affordability and acceptability

Extracts from plants such as Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleiferd), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata) are known for antidiabetic, hypolipidemic, antibacterial, antioxidant, antiulcerogenic, hepatoprotective, gastroprotective, and chemopreventive properties. Various studies have been documented for these plant extracts having Antihyperlipidimic activities. Amla (Emblica officinalis), family: euphorbiaceac (Jeevangi Santoshkumar., et al :A study of anti-hyperlipidemia, hypolipedimic and anti-atherogenic activity of fruit of emblica officinalis (amla) in high fat fed albino rats); Green coffee bean {Coffea arabica), family: Rubiaceae (Gaafar M. Ahmed., et al: Effect of green and degree of roasted arabic coffee on hyperlipidemia and antioxidant status in diabetic rat); Drumstick tree or Horseradish tree (Moringa oleifera), family: Moringaceae (Rajanandh MG., et al: Moringa oleifera Lam. A herbal medicine for hyperlipidemia: A pre- clinical report); Guggul or Mukul myrrh tree {Commiphora wightii), family: burseraccac (Singh RB., et al: Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia.); Frankincense (Boswellia seratd), family: Burseraceae (Dashti GH.,et al : The effect of frankincense extract on accumulation of fatty streaks in coronary arteries of high-cholesterol fed male rabbits)

Attempts were to make to include these plant extacts in our Omega-3 fatty acid preparation to have a synergistic effect and/or additive effect to antihyperlipedimic property of omega-3 fatty acids.

The compositions comprising omega-3 fatty acid and plant extract should have good physical stability; the physical properties of this composition should be made ideal to provide high patient compliance. However, it is quite difficult to provide the above described conditions in the formulations comprising plant extract. Due to some characteristic chemical, biological and physical properties of the plant extract used in the formulation, some problems are encountered in obtaining a formulation comprising said substances as well as having a good physical stability and ideal physical properties in terms of patient compliance. Physical properties and physical stability of the formulation are directly affected by the characteristic features of the plant extracts comprised therein.

Under the light of the foregoing, it would be desirable to provide a formulation, as well as a process for the preparation of this formulation, comprising combinations of plant extracts, being capable to retain the physical stability for a long time, and having ideal physical properties in terms of patient compliance.

These plant extracts may prevent oxidative degradation of Omega-3 fatty acid that occurs over time can result in an unpleasant aftertaste following administration.

SUMMARY AND OBJECTIVES OF THE INVENTION:

This invention relates to a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant suitable for oral administration.

More particularly, the invention relates to a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, where in the composition is substantially free of food effects.

Yet another object of the invention, upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., C_max and AUC, or max, AUC, and T_max) under fed conditions which is similar to, the absorption profile of the same composition administered under fasting conditions. In some embodiments, the mammal is a human.

Yet another objective of the invention relates to a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein exhibits enhanced bioavailability

Yet another objective of the invention relates to a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein the said composition forms micelles in aqueous medium having D90 less than lOOnm

Another objective of the invention relates to the process of preparing a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration. Another objective of the invention relates to method of administering a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.

Another aspect of the invention provides a composition suitable for prophylactic or therapeutic treatment known for omega-3fatty acids for a subject in need thereof, said composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.

Another aspect of the invention provides an omega-3 fatty acid composition comprising Plant extracts wherein the plant extracts may provide synergistic and/ or additive effect on antihyperlipidemic property of omega-3 fatty acids.

BRIEF DESCRIPTION OF THE DRAWINGS

A clear understanding of some of the features of the invention summarized above may be carried out by reference to the appended drawings, which illustrate the objective of the invention, although it will be understood that such drawings depict observation with one of the preferred embodiments of the invention and, therefore, are not to be considered as limiting its scope with regard to other embodiments which the invention is capable of contemplating. Accordingly:

FIG. 1 is an illustration of the particle size of the self-emulsified droplets in gastric environment.

FIG. 2 is an illustration of the comparative oral pharmacokinetic profile of the omega-3 fatty acid present in fish oil with omega-3 fatty acid given as novel preconcentrate formulation.

FIG. 3 is an illustration of the comparative oral pharmacokinetic profile of "EPA" concentration in Fast state and Fed state of Omega-3 fatty acid KMS formulation.

FIG. 4 is an illustration of the comparative oral pharmacokinetic profile of EPA concentration in fast state with omega-3 fatty acid KMS formulation vs lovaza DETAILED DESCRIPTION OF THE INVENTION:

Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular materials disclosed herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "or" means "and/or".

The terms "comprising", "having", "including", and "containing" are to be construed as open- ended terms (i.e., meaning "including, but not limited to").

The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass ±10% of a specified amount, frequency or value.

The term "formulation" and "composition" may be used interchangeably herein.

The term "omega-3 fatty acids" includes natural and synthetic omega-3 fatty acids, as well as pharmaceutically-acceptable esters, free acids, triglycerides, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al, U.S. Pat. No. 6,245,811, each hereby incorporated by reference), precursors, salts, and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long-chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters. The omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof according to the present disclosure can be used in their pure form and/or as a component of an oil, for example, as marine oil (e.g., fish oil and purified fish oil concentrates), algae oils, microbial oils and plant-based oils.

The term "Fatty acid oil", "omega -3 fatty acid", "Fish oil" or "active ingredient" may be used interchangeably therein unless the content clearly dictates otherwise.

The term "plant", "plant extracf'or "Herbal extract" " may be used interchangeably therein unless the content clearly dictates otherwise.

As used herein, the term "plant extract" means an extract, juice, or concentrate from any part of a plant, such as the seed, leaf, fruit, flower, stem, root, tuber, bark, etc.,

The term "food effect" refers to a somewhat unpredictable phenomenon that can influence the absorption of active ingredients from the gastrointestinal tract following oral administration. A food effect can be designated negative when absorption is decreased, or positive when absorption is increased and manifested as an increase in oral bioavailability (as reflected by total exposure).

Alternatively, "food effects" can refer to changes in maximum concentration, or the time to reach maximum concentration, independently of overall absorption. As a result, some active ingredients have to be taken in either fasted or fed conditions to achieve the optimum effect. However, many drugs are unaffected by food, and thus, can be taken in either a fasted or a fed condition.

The presence or absence of a food effect may be quantified by making Area under the Curve (AUC) and/or C_max measurements according to methods well known in the art. Typically AUC measurements and C_max measurements are made by taking timed biological fluid samples and plotting the serum concentration of Omega-3 fatty (or the active agent thereof) against time. The values obtained represent a number of values taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/or C_max values, one can determine whether Omega-3 fatty exhibits a food effect.

The term ^MC_max" refers to maximum concentration of omega-3 fatty acids in blood or serum following the ingestion of a dose of omega-3 fatty acids.

The term "T_max" refers to the time following ingestion required for the level of omega-3 fatty acids in blood or serum to reach C_max., the term "AUC" refers to the area under the curve of a plot of the blood/serum concentration of omega-3 fatty acids against time from the time omega-3 fatty acids is ingested until the concentration is below the detection limit. "AUC" is a measure of the total patient exposure to omega-3 fatty acids.

Bioavailability is a measurement of the rate and extent to which a drug reaches the systemic circulation

The term "bioavailability" disclosed here in refers to "relative bioavailability" between composition of present invention comprising omega-3 fatty acid Plant extracts and an unformulated Omega-3 fatty acid.

The term "preconcentrate" here in refers to a composition which when diluted with aqueous solution forms dispersions

As used herein, the term "aqueous medium" refers to any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1 N HC 1. COMPOSTIONS:

In one embodiment composition is provided wherein composition comprises omega-3 fatty acids, a plant extract and atleast one surfactant suitable for oral administration.

In another embodiment composition with enhanced bioavailability of omega -3 fatty acids comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.

In another embodiment composition substantially free of food effects comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.

In one embodiment Omega-3 fatty acids used herein may be derived from either marine source or plant source.

In one embodiment Omega-3 fatty acids may be derived from a marine species, such as a fish oil or crustacean. Examples of fish known to have high levels of omega-3 fatty acids include so-called "oily fish" such as salmon, tuna, swordfish, halibut, tilefish, cod fish (including cod liver oil), anchovies, and sardines. Several crustaceans are also known to have high levels of omega-3 fatty acids, including krill, a crustacean in the Antarctic (the source of krill oil) and the New Zealand green-lipped mussel, (also known as Perna canaliculus) but not limited to them

In one embodiment Omega-3 fatty acids may be may be derived from a vegetable source, in particular seed oils, including perilla seeds (Linnaean name Perilla frutescens); chia seeds (Salviahispanica); flax seeds (Linum usitatissimum); lingon berry seeds (Vaccinium vitis-idaea); and rape seeds (Brassicanapus), more commonly called canola oil but not limited to them

In one embodiment the composition comprises about 10% to about 98% (w/w) of omega-3 fatty acids in total composition. Preferably about 20% w/w of omega-3 fatty acids, More preferably about 30% w/w of the omega-3 fatty acids.

In one embodiment Omega-3 fatty acids used herein is preferably either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both In one embodiment Omega -3 fatty acids comprising "EPA" and "DHA" used herein may be of esterified, triglyceride, phospholipid or free fatty acid forms

In one embodiment Omega-3 fatty acids comprising "EPA" and "DHA" used herein is preferably in esterified form.

In one embodiments of the present disclosure, the weight ratio of EP A:DHA of the fatty acid oil mixture ranges from about 1 : 10 to about 10:1, from about 1 :8 to about 8: 1, from about 1 :6 to about 6:1, from about 1 :5 to about 5: 1 , from about 1:4 to about 4:1, from about 1 :3 to about 3:1, or from about 1 :2 to about 2:1. More preferably from about 1 :3 to about 3: 1

In one embodiment the content of EPA and DHA, taken together, is atleast above 10% w/w; atleast above 20%w/w; atleast about 30%w/w; atleast about 40% w/w; atleast about 50%w/w of omega -3 fatty acids in the total composition. Preferably about 50% w/w of omeg-3 fatty acids in total composition.

In one embodiment the content of EPA alone is atleast above 10% w/w of the total composition. Preferably above 20% w/w of the total composition; more preferably above 30% w/w of the total composition.

In one embodiment the content of DHA alone is atleast above 5% w/w of omega-3 fatty acids in the total composition. Preferably above 10%w/w of the total composition; more preferably above 15% w/w of the total composition.

In one embodiment the composition comprises a plant extract; wherein the plant extract is select from the group consisting of extracts from Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleifera), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata) In one embodiment the plant extract may exert additive effect and/or synergistic effect on antihyperlipidemic activity of omega- 3 fatty acids.

In one embodiment plant extract comprises about 1 % to about 50 %( w/w), of the total composition.

In one embodiment the plant extract is preferably Amla (Phyllanthus emblica).

In one embodiment plant extract comprises about 1 % to about 50 % (w/w), of the total composition; wherein the plant extract is Amla.

In one embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant. SURFACTANTS:

A surfactant may, for example, lower the surface tension of a liquid or the surface tension between two liquids. For example, surfactants according to the present disclosure may lower the surface tension between the fatty acid oil mixture and an aqueous solution. Chemically speaking, surfactants are molecules with at least one hydrophilic part and at least one hydrophobic (i.e., lipophilic) part. Surfactant properties may be reflected in the hydrophilic- lipophilic balance (HLB) value of the surfactant, wherein the HLB value is a measure of the degree of hydrophilic versus lipophilic properties of a surfactant. The HLB value normally ranges from 0 to 20, where a HLB value of 0 represents high hydrophilic character, and a HLB of 20 represents high lipophilic character. Surfactants are often used in combination with other surfactants, wherein the HLB values are additive. The HLB value of surfactant mixtures may be calculated as follows:

HLBA (fraction of surfactant A) + HLB_B (fraction of surfactant B) = HLB_A+B mixture In certain embodiments, said surfactant is selected from the group consisting of nonionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, or combinations thereof.

In one embodiment non-ionic surfactants are selected from a group having a hydrophobic group and a reactive hydrogen atom, for example aliphatic alcohols, acids, amides and alkyl phenols, with alkylene oxides, especially ethylene oxide either alone or in combination with propylene oxide.

Examples of nonionic surfactant compounds include, but are not limited to, Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol, ethylene glycol fatty acid esters, poly(ethylene glycol) fatty acid esters, propylene glycol fatty acid esters (propylene glycol monolaurate), poly(propylene glycol) fatty acid esters, glycol fatty acid esters, trimethylolpropane fatty acid esters, pentaerythritol fatty acid esters, glucoside derivatives, glycerin alkyl ether fatty acid esters, trimethylolpropane oxyethylene alkyl ethers, fatty acid amides, alkylolamides, alkylamine oxides, lanolin and its derivatives, castor oil derivatives, hardened castor oil derivatives, sterols and its derivatives, polyoxyethylene alkyl ethers, polyoxyethylene alkyl allyl ethers, polyoxyethylene alkylamine, polyoxyethylene fatty acid amides, polyoxyethylene alkylolamides, polyoxyethylene diethanolamine fatty acid esters, polyoxyethylene trimethylolpropane fatty acid esters, polyoxyethylene alkyl ether fatty acid esters, polyoxyethylene polyoxypropylene glycols, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene polyhydric alcohol ethers, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, Carbomer, or combinations thereof.

Examples of are typically the Polyoxyethylene Sorbitan Fatty Acid Esters, polysorbates. Polysorbates are a class of oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common brand names for polysorbates include Tween®. Tween-20, Tween-60 and Tween-80, for example, are available from AkzoNobel (Strawinskylaan 2555 1077 ZZ, Amsterdam, the Netherlands). Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate ), polysorbate 60(polyoxyethylene (20) sorbitan monostearate ), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).

Examples of Polyoxyethylene Castor Oil Derivatives include Polyoxyl 5 castor oil(PEG-5 castor oil; polyoxyethylene 5 castor oil.), Polyoxyl 9 castor oil(PEG-9 castor oil; polyoxyethylene 9 castor oil), Polyoxyl 15 castor oil(PEG-15 castor oil; polyoxyethylene 15 castor oil), Polyoxyl 35 castor oil(Cremophor EL; Kolliphor EL; PEG-35 castor oil; polyethoxylated castor oil; polyoxyethylene 35 castor oil), Polyoxyl 40 castor oil(PEG-40 castor oil; polyoxyethylene 40 castor oil), Polyoxyl 40 hydrogenated castor oil(Cremophor RH 40; PEG-40 hydrogenated castor oil; polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated castor oil), Polyoxyl 60 castor oil(PEG-60 castor oil; polyoxyethylene 60 castor oil), Polyoxyl 60 hydrogenated castor oil(PEG-60 hydrogenated castor oil; polyoxyethylene 60 hydrogenated castor oil), Polyoxyl 100 castor oil(PEG-100 hydrogenated castor oil; polyoxyethylene 100 hydrogenated castor oil), Polyoxyl 100 hydrogenated castor oil(polyoxyethylene 100 hydrogenated castor oil), Polyoxyl 200 castor oil(polyoxyethylene 200 castor oil; PEG-200 castor oil;), Polyoxyl 200 hydrogenated castor oil(PEG-200 hydrogenated castor oil; polyoxyethylene 200 hydrogenated castor oil).

Examples of Sorbitan Esters (Sorbitan Fatty Acid Esters) include Sorbitan monoisostearate (Arlacel 987; Crill 6; sorbitan isostearate), Sorbitan monolaurate (sorbitan laurate; sorbitani lauras; Span 20), Sorbitan monooleate(Arlacel 80), Sorbitan monopalmitate(Span 40.),Sorbitan monostearate (Span 60),Sorbitan sesquiisostearate, Sorbitan sesquioleate (Arlacel C; Arlacel 83; Crill 43),Sorbitan trilaurate (Span 25),Sorbitan trioleate (Span 85), Sorbitan tristearate (Span 65)

Examples of Polyoxylglycerides include but not limited to Caprylocaproyl polyoxylglycerides (Labrasol; macro golglyceridorum caprylocaprates; PEG 400 caprylic/ capric glycerides), Lauroyl polyoxylglycerides(Gelucire 44/14; hydrogenated coconut oil PEG 1500 esters),Linoleoyl polyoxylglycerides (Corn oil PEG 300 esters; LabrafilM2125CS), Oleoyl polyoxylglycerides (Apricot kernel oil PEG 300 esters), Stearoyl polyoxylglycerides(Gelucire 50/13; hydrogenated palm oil PEG 1500 ester)

In one embodiment anionic surfactants are selected from a group include, but are not limited to, N-acyl-L-glutamic acid diethanolamine, N-acyl-L-glutamic acid triethanolamine, sodium N- acyl-L-glutamate, sodium alkanesulfonate, ammonium alkyl (C_12> C₁₄, Ci₆) sulfate, alkyl (Cn, C , C15) sulfuric acid triethanolamine, alkyl (C » , C13, C15) sulfuric acid triethanolamine, alkyl (C₁₂ to C₁₄) sulfuric acid triethanolamine, liquid alkylsulfuric acid triethanolamine, sodium alkyl (Ci₂, C₁₃) sulfate, liquid sodium alkylsulfate, sodium isoethionate, sodium lacto-isostearate, disodium undecylenoylamido ethyl sulfosuccinate, triethanolamine sulfooleate, sodium sulfooleate, disodium oleamide sulfosuccinate, potassium oleate, sodium oleate, morpholine oleate, oleoyl sarcosine, oleoyl methyltaurine sodium salt, potassium-containing soap base, liquid base for potassium soap, potassium soap, carboxylated polyoxyethylene tridodecyl ether, sodium salt (3 ethyle oxide "E.O.") of carboxylated polyoxyethylene tridodecyl ether, triethanolamine N-hydrogenated tallow fatty-acyl-L-glutamate, sodium N-hydrogenated tallow fatty-acyl- L-glutamate, sodium hydrogenated coconut fatty acid glyceryl sulfate, sodium diundecylenoylamido ethyl sulfosuccinate, sodium stearyl sulfate, potassium stearate, triethanolamine stearate, sodium stearate, sodium N-stearoyl-L-glutamate, disodium stearoyl- L- glutamate, stearoyl methyltaurine sodium salt, sodium dioctyl sulfosuccinate, liquid sodium dioctyl sulfosuccinate, liquid disodium polyoxyethylene monooleylamido sulfosuccinate (2 E.O.), disodium polyoxyethylene lauroyl ethanolamide sulfosuccinate (5 E.O.), disodium lauryl sulfosuccinate, diethanolamide cetyl sulfate, sodium cetyl sulfate, soap base, sodium cetostearyl sulfate, triethanolamine tridecyl sulfate, potassium palmitate, sodium palmitate, palmitoyl methyltaurine sodium salt, liquid castor oil fatty acid sodium salt (30%), ammonium polyoxyethylene alkyl ether sulfate (3 E.O.), liquid diethanolamine polyoxyethylene alkyl (CI 2, CI 3) ether sulfate, liquid triethanolamine polyoxyethylene alkyl ether sulfate (3 E.O.), triethanolamine polyoxyethylene alkyl (CI 1, CI 3, CI 5) ether sulfate (1 E.O.), triethanolamine polyoxyethylene alkyl (CI 2, CI 3) ether sulfate (3 E.O.), liquid sodium polyoxyethylene alkyl ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 1, C13, C15) ether sulfate (1 E.O.), sodium polyoxyethylene alkyl (CI 1 to CI 5) ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 2, CI 3) ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 2 to CI 4) ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (C12 to C₁₅) ether sulfate (3 E.O.), disodium polyoxyethylene alkyl (CI 2 to CI 4) sulfosuccinate (7 E.O.), sodium polyoxyethylene undecyl ether sulfate, liquid sodium polyoxyethylene octyl phenyl ether sulfate, ammonium polyoxyethylene oleyl ether sulfate, disodium polyoxyethylene lauryl sulfosuccinate, sodium polyoxyethylene nonyl phenyl ether sulfate, sodium polyoxyethylene pentadecyl ether sulfate, triethanolamine polyoxyethylene myristyl ether sulfate, sodium polyoxyethylene myristyl ether sulfate, sodium polyoxyethylene myristyl ether sulfate (3 E.O.), liquid sodium polyoxyethylene lauryl ether acetate (16 E.O.), ammonium polyoxyethylene lauryl ether sulfate (2 E.O.), triethanolamine polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene lauryl ether sulfate, diethanolamine myristyl sulfate, sodium myristyl sulfate, potassium myristyl sulfate, sodium N- myristoyl- L-glutamate, sodium myristoylmethylaminoacetate, liquid myristoyl methyl- -alanine sodium salt, myristoyl methyltaurine sodium salt, medicinal soaps, triethanolamine/magnesium coco alkyl sulfate, triethanolamine N-coconut oil fatty-acyl-L- glutamate, sodium N-coconut oil fatty-acyl-L-glutamate, sodium coconut oil fatty acid ethyl ester sulfonate, coconut oil fatty acid potassium salt, liquid coconut oil fatty acid potassium salt, sodium N-coconut oil fatty/hydro genated fatty-acyl-L-glutamate, coconut oil fatty acid sarcosine, coconut oil fatty acid sarcosine triethanolamine salt, coconut oil fatty acid sarcosine sodium salt, coconut oil fatty acid triethanolamine salt, liquid triethanolamine salt of cocbnut oil fatty acid, coconut oil fatty acid sodium salt, coconut oil fatty acid methyl alanine sodium salt, liquid coconut oil fatty acid methyl alanine sodium salt, coconut oil fatty acid methyltaurine potassium salt, coconut oil fatty acid methyltaurine sodium salt, sodium laurylamino dipropionate, liquid sodium laurylamino dipropionate (30%), sodium lauryl sulfoacetate; sodium lauryl benzenesulfonate, lauryl sulfate, ammonium lauryl sulate, potassium lauryl sulfate, diethanolamine lauryl sulfate, triethanolamine lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, monoethanolainine lauryl sulfate, potassium laurate, lauric acid triethanolamine, liquid lauric acid triethanolamine, sodium laurate, lauric acid/myristic acid triethanolamine, lauroyl-L-glutamic acid triethanolamine, sodium N- lauroyl-L-glutamate, lauroyl sarcosine, lauroyl sarcosine potassium, liquid lauroyl sarcosine triethanolamine salt, lauroyl sarcosine sodium, liquid lauroyl methyl-.beta. -alanine sodium salt, lauroyl methyltaurine sodium salt, liquid lauroyl methyltaurine sodium salt, or combinations thereof. In another embodiment surfactants also include, but are not limited to the bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurolithocholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid and salts thereof, e.g., sodium, potassium, lithium), natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethyl ene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium or combinations thereof.

In one embodiment atleast one surfactant preferably selected from group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.

More preferably atleast one surfactant is selected from group of Polyoxyethylene glycol sorbitan alkyl esters such as Tween 20, Tween 60 Tween80.

More preferably atleast one surfactant is selected from group of Sorbitan Fatty Acid Esters such as Span 20, Span 60. More preferably atleast one surfactant is selected from a group of Polyoxyethylene Castor Oil derivatives such as PEG-35 castor oil, PEG-40 castor oil.

In one embodiment the total amount of surfactants present in the composition do not exceed 50% w/w of the total composition.

In one embodiment the value of HLB of the Surfactants present is in the composition should be from about 8 - 18. More preferably above 12.

In one embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant optionally may contain co surfactants and other pharmaceutically acceptable excipients

OTHER PHARMACEUTICAL EXCIPIENTS: Co- Surfactant

In some embodiments, compositions of the present disclosure further comprise at least one co- surfactant. As used herein the term "co-surfactant" means a substance added to the compostion in combination with the at least one surfactant to affect, e.g., increase or enhance, emulsification and/or stability of the compostion, for example to aid in forming an emulsion. In some embodiments, the at least one co-surfactant is hydrophilic.

Examples of co-surfactants suitable for the present disclosure include, but are not limited to, short chain alcohols comprising from 1 to 6 carbons (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g., propylene glycol, glycerol, polyethylene glycols such as PEG 600 and PEG 400), glycol ethers such as tetraglycol and glycofurol (e.g., tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as N-methylpyrrolidone (e.g., Pharmasolve®) and 2-pyrrolidone (e.g., Soluphor® P), and bile salts, for example sodium deoxycholate. Further examples include ethyl oleate. Additional oils

In some embodiments, Synergistic composition further comprise at least one additional oil, such as medium chain triglyceride (MCT) oil and long chain triglyceride (LCT) oil

PARTICLE SIZE:

In another embodiment composition can be a preconcentrate or an emulsion.

In another embodiment the composition produce dispersions when contacted with aqueous medium

In another embodiment the preconcentrates produce dispersions when contacted with aqueous medium generating self-nanoemulsifying drug delivery systems (SNEDDS), self- microemulsifying drug delivery systems (SMEDDS), or self emulsifying drug delivery systems (SEDDS).

In another embodiment the compostion is preferably self-nanoemulsifying drug delivery systems (SNEDDS)

In another embodiment composition the composition forms micelles in aqueous medium having D₉₀ less than 500nm, D₉₀ less than 300nm, more preferably D₉₀ less than lOOnm.

In another embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium.

In one embodiment particle size are preferably between 20nm to about 90nm.

In on embodiment the aqueous medium may be any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1N HC1.

BIOAVAILABILITY:

Absorption of omega-3 fatty acids from the gastrointestinal tract involves the conversion of large fat globules to the smaller size micellar droplets by action of bile salts. The smaller droplets are then acted upon by pancreatic lipase that coverts the triglyceride within fat to fatty acids that traverse easily through the phospholipid bilayer. Thus absorption of omega-3 fatty acid from gastrointestinal tract depends widely upon its emulsification and conversion to smaller droplets.

The self-emulsifying composition of this invention comprising omega-3 fatty acids, a plant extract and atleast one surfactant which rapidly form an oil-in-water emulsion when introduced into the aqueous media under mild agitation. The digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification in vivo. The self-emulsification process occurs spontaneously. The spontaneous formation of micro/nano emulsion advantageously presents the drug in a dissolved form and the resultant small droplets size provides a large interfacial surface area for drug release and absorption. Main mechanisms include increasing membrane fluidity to facilitate transcellular absorption, opening tight junction to allow paracellular transport, inhibiting P-gp and/or CYP450 to increase intracellular concentration and residence time by surfactants, and stimulating lipoprotein/chylomicron production by lipid.

In one embodiment of the invention, upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., Cmax and AUC, or Cmax, AUC, and Tmax) under fed conditions which is similar, or bioequivalent to, the absorption profile of the same composition administered under fasting conditions. In some embodiments, the mammal is a human.

In another embodiment the synergistic composition comprising omega-3 fatty acid extract and a Plant extract; where in the composition is substantially free of food effect. After rapid and complete hydrolysis of omega-3 fatty acids in the intestine, the free fatty acids are absorbed / transported into the intestinal enterocytes; rapidly re esterified, and enters the systemic circulation via the thoracic duct as chylomicrons. Following transit through the thoracic duct, the chylomicrons enter the plasma. The normal half-life of a chylomicron in the circulation is approximately 10 minutes. Lipoprotein lipase, present on the endothelial surfaces of capillary beds, hydrolyzes the triglyceride core of the chylomicron, liberating the fatty acids for tissue uptake.

The absorption of omega-3 fatty acids into the systemic circulation can be directly measured by determining the plasma levels of their free form and the total levels after liberating the free fatty acid form from its esterified form (chylomicrons).

In addition, the fatty acid composition of the serum phospholipids correlates with levels incorporated in membranes (e.g., erythrocyte, monocyte, and thrombocyte membranes) (See, e.g. Katan, MB, et al., J Lipid Res. 1997; 38:2012-22 and Tremoli, E et al., Am J Clin Nutr. 1995; 67:607-13). The omega-3 fatty acid composition of erythrocyte and thrombocyte membranes, in turn, correlates with whole body content of these compounds. Analysis of blood phospholipids is, therefore, an appropriate way to assess the performance of products intended to increase total body stores of omega-3 fatty acids. Analysis of plasma phospholipids has been described, e.g. by Harris, W. et al. Clinical Biochemistry 43 (2010) 338-340; Harris, W. et al., American Journal of Clinical Nutrition 2007; 86: 1621-5; Cao, J. et al., Clinical Chemistry 52:12 2265-2271 (2006); Harris, W. et al., Preventive Medicine 39 (2004) 212-220; and Park, Y. et al., Journal of Lipid Research 44, 2003 455-463.

Thus, when investigating the absorption of omega-3 fatty acids comprising EPA and DHA (e.g., from omega-3-acid ethyl esters comprising EPA and DHA ethyl esters), the increase of EPA and DHA in plasma or in serum phospholipids may be used as a measure of absorption. These measures of absorption may be used as a measure of oral bioavailability.

In one embodiment the of substantially composition is substantially free of food effect such that when administered orally the difference between AUCo-_t value for EPA in the blood plasma of the human under a fed state and AUC _0-t value under a fasted state when administered orally to a human is not more than 15%, wherein t is 24 hours from the administration of the pharmaceutical composition.

In one embodiment the of the composition is substantially free of food effect such that when administered orally the difference between C_max value for EPA in the blood plasma of the human under a fed state and C_max value under a fasted state when administered orally to a human is not more than 10%, wherein t is 24 hours from the administration of the pharmaceutical composition.

Other embodiments of the invention provide for a method of enhancing bioavailability of an omega-3 fatty acid in a subject in need of treatment with an omega-3 fatty acid, comprising orally administering an emulsion or self- emulsifying composition of this invention to the subject, wherein the oral absorption and/or oral bioavailability is enhanced compared to the oral absorption and/or oral bioavailability unformulated omega-3 fatty acid.

In some embodiments, an increase in absorption is exhibited by an increase in AUC of the total omega-3 fatty acids measured.

In some embodiments, the omega-3 fatty acids which is measured are EPA and/or DHA.

In some embodiments, the blood serum level of total EPA and/or DHA is increased; preferably the blood serum level of total EPA and/or DHA is increased by at least about 2, 3 or 4- fold compared to the blood serum level of total EPA and/or DHA of unformulated omega-3 fatty acid. More preferably atleast 2 fold Increase in total EPA and/or DHA compared to of unformulated omega-3 fatty acid.

MANUFACTURING PROCESS:

In another embodiment the composition relates to process of preparing composition comprising omega-3 fatty acid, a plant extract and atleast one surfactant. The method of preparing involves mixing the plant extract with Surfactant, to the mixture optionally cosurfactants was added and mixed. The mixture obtained was added slowly to the oil containing omega-3 fatty acids and homogenized if needed.

In one embodiment the pharmaceutical composition of the present invention is filled into capsules. Preferred capsules are gelatin capsules which may be soft or hard. The soft gelatin capsule is a capsule which is manufactured and filled in one single operation. The hard gelatin capsule consists of two pieces, a cap and a body, one fitting inside the other. The hard gelatin capsules are produced empty and filled in a separate operation step.

In a one embodiment of the invention, the pharmaceutical composition is filled into capsules such as Soft gelatin capsules, but capsules from alternative materials such as methylcellulose- based shells, and hard gelatin capsules may also be used.

In one embodiment the liquid composition optionally converted into solid form through but not limited to process such as spray drying, Melt granulation, Adsorption to solid carriers, Melt extrusion/extrusion spheronization. The solid particles obtained can be filled into hard gelatin capsules or can be manufactures as tablets with suitable excipients.

METHOD OF ADMINISTRATION:

Another objective of the invention relates to method of administering a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.

In one embodiment composition is formulated as both ready-to-use aqueous solutions and or a Non-aqueous preconcentrate.

In another embodiment composition may be diluted with suitable solutions immediately before administration.

In one embodiment composition of present invention is filled into single dosage forms suitable for oral administration, such as capsules, drinking ampoules and dose cushions, or may be formulated as other suitable oral dosage forms such as chewable soft pills and chewy-base lozenges.

In an alternative embodiment of the invention, the pharmaceutical composition may be dissolved in e.g. a glass of water, thus allowing the pre-concentrate to form an emulsion which may be taken as an oral solution. The compositions intended for dissolution prior to administration may be filled e.g. into soft gelatin capsules, plastic or aluminum cushions, or plastic or glass ampoules. This feature is particularly advantageous for high dose compositions which would require a large capsule, for patients who have difficulty in swallowing capsules, and for pediatric patients.

In another embodiment, pre-concentrate filed in soft gelatin capsules transforms into an oil-in- water emulsion upon contact with the gastrointestinal fluids, whereby the omega-3 fatty acid is released. Thus, the composition will form an in situ oil-in-water emulsion in the gastrointestinal tract (GI tract).

USE:

In another embodiment the synergistic composition provide both, Plant extracts and Omega-3 fatty acids together in a stable form.

Yet another embodiment is to have a composition, plant extracts which protects the highly labile omega-3 fatty acid molecules from oxidation and also from the damaging effect of light and air. In one embodiment the composition of present invention is stable for the FDA recommended period In another embodiment the omega-3 fatty acid in this composition is very palatable, and would minimize or eliminate an unpleasant smell and/ or an unpleasant aftertaste, and/or burping in the patient.

In view of the teachings presented herein, other modifications and variations of the present inventions will be readily apparent to those of skill in the art. The foregoing discussion and description are illustrative of some embodiments of the present invention, but are not meant to be limitations on the practice thereof.

The invention will be more fully understood by the following examples which are illustrative but not limiting of compositions in accordance with the present invention.

EXAMPLE: 1

Illustrates the composition containing omega-3 fatty acids with varying amounts of EPA and DHA , surfactants , plant extracts and other excipients in Table 1- 11 and process of preparing such compostions.

EPA: DHA ratio in fish oil in each composition mentioned in the parenthesis in each table alongside of fish oil.

TABLE: 1

Ingredients Ex -1 E -2

% w/w % w/w

Fish oil (35: 25) 94.33 57.14

Amla Extract - 0.57

Polysorbate 20(Tween 20) - 3.8

Polysorbate 80(Tween 80) 0.94 26.66

Polyethylene Glycol (PEG 600) - 1.90

Purified water 4.71 4.76

Total 100 100 TABLE: 2

Ingredients Ex-3

% w/w

Fish oil (55:20) 78.95

Polysorbate 80 (Tween 80) 10.09

Sorbitan monolaurate (Span 20) 10.09

Polyethylene Glycol (PEG 600) 0.88

Total 100

TABLE: 3

Ingredients Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9

% w/w % w/w % w/w % w/w % w/w % w/w

Fish oil (35: 25) 70.72 97.06 74.25 59.40 49.5 70.72

Amla Extract 28.29 1.94 24.75 39.60 49.5 28.28

Polysorbate 80 (Tween 80) 1 1 1 1 1 1

Total 100 100 100 100 100 100 TABLE: 4

Ingredients Ex-10 Ex-11 Ex-12

% w/w % w/w % w/w

Fish oil (35: 25) 37.75 44.47 60

Amla Extract 15.10 - 6

Polysorbate 20 (Tween 20) 13.97 16.46 4

Polysorbate 80 (Tween 80) 29.39 34.62 28

Polyethylene Glycol (PEG 600) 3.78 4.45 2

Total 100 100 100

TABLE: 5

Ingredients Ex-13 Ex-14

% w/w % w/w

Fish oil (10:40) 67.70 67.74

Polysorbate 80 (Tween 80) 29.30 25.26

Polyethylene Glycol (PEG 600) 3 3

Purified water - 4

Total 100 100 TABLE: 6

Ingredients Ex-15

% w/w

Fish oil (10:60) 67.74

Polysorbate 60 (Tween 60) 9.68

Polysorbate 80 (Tween 80) 19.35

Tricaprylin (MCT) 3.23

Total 100

TABLE: 7

Ingredients Ex-16 Ex-17 Ex-18 Ex-19 Ex-20 Ex-21

% w/w % w/w % w/w % w/w % w/w % w/w

Fish oil (35: 25) 83.33 46.47 60.61 50 50 50

Plant Extract

Guggul extract - 4.65 - - - ^■ -

Boswellia serata - - 6.06 - - -

Moringa Extract - - - 5 - -

Moringa oleifera 16.67 - - - -

Moringa oil - - - - 10 -

Green Coffee bean extract - - - - - 5

Surfactant

Polysorbate 20 (Tween 20) - - - - 10 -

Polysorbate 80 (Tween 80) - - - 35 25 35

Polysorbate 60 (Tween 60) - 2.32 3.03 - - -

Other excipients

Sodium alginate 30.30 - -

Carbomer - 46.47 - - - -

(Pemelun TF₂ (0.25 % solution))

NaOH 18% Solution - 0.08 - - - -

Polyethylene Glycol (PEG 600) - - - - 5 -

Purified water - - - 10 - 10

Total 100 100 100 100 100 100 TABLE: 8

Ingredients Ex-22 Ex-23 Ex-24 Ex-25 Ex-26 Ex-27

% w/w % w/w % w/w % w/w % w/w % w/w

Fish oil (52:22) 54.55 54.55 54.55 63.67 67.05 68.81

Amla Extract 5.45 5.45 5.45 2 3.83 3.67

Polysorbate 80(Tween 80) 37.36 - 5.45 16.18 9.96 9.54

Polyethylene Glycol(PEG 600) 2.64 - - 5.45 5.75 5.5

Polyoxyl 35 castor oil (KoUiphor EL) - 40 27.73 12.73 13.41 12.84

Polyoxylglycerides(Labrasol) - - 1.36 - -

Total 100 100 100 100 100 100

TABLE: 9

Ingredients Ex-28 Ex-29 Ex-30 Ex-31 Ex-32

% w/w % w/w % w/w % w/w % w/w

Fish oil (52:22) 75 74.69 74.38 75.19 74.35

Amla Extract 5 4.98 4.96 4.96 4.90

Polysorbate 80(Tween 80) 7.5 7.47 7.44 7.52 7.43

Polyethylene Glycol(PEG 600) 1.67 1.66 1.65 1.50 1.49

Polyoxyl 35 castor oil (KoUiphor EL) 10.83 10.79 10.74 10.83 10.71

Lauroglycol - 0.41 0.83 - 1.12

Total 100 100 100 100 100 TABLE: 10

Ingredients Ex-33 Ex-34 Ex-35

% w/w % w/w % w/w

Fish oil (52:22) 74.07 75 74.07

Amla Extract 4.94 5 4.94

Polysorbate 80 (Tween 80) 8.23 7.5 7.41

Sorbitan monolaurate (Span 20) - - 11.52

Polyethylene Glycol (PEG 600) 1.65 1.67 0.82

KoUiphor EL 11.11 10.83 -

Lipase Filterate - - 1.23

Total 100 100 100 TABLE: 11

Ingredients Ex-36 Ex-37 Ex-38 Ex-39 Ex-40

% w/w % w/w % w/w % w/w % w/w

Fish oil (52:22) 75 72.58 77.59 75 78.95

Amla Extract 5 4.83 5.17 5 -

Polysorbate 80 (Tween 80) · 7.5 9.27 8.62 7.5 10.09

Sorbitan monolaurate (Span 20) 11.67 9.27 7.76 7.5 10.09

Polyethylene Glycol (PEG 600) 0.83 0.81 0.86 1.25 0.88

Total 100 100 100 100 100

Method of preparing the composition containing ingredients from table 1-11:

Step 1: A plant extract if present in the composition is mixed with a surfactant

Step 2: To the mixture obtained in step 1 other excipients present in the compostion is added and mixed

Step 3: To the mixture obtained in step 2, fish oil was added slowly and mixed.

Step 4: The mixture obtained from step 3 was homogenized if needed. Relative bioavailability studies:

EXAMPLE: 2

Illustrates relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 under fasting and fed condition; to demonstrate the food effect on this formulation

TABLE 12- Relative bioavailability studies of KMS formulation in fast and fed state.

# Geometric mean *Median Results in Table 12 shows that oral pharmaceutical composition containing 1.2g of omega -3 fatty acid Capsules prepared according to Example 34 has increase AUCo-t and C_max to about 13.65% and 10.25% respectively, under fed condition compared to fasting condition.

However, the effect of food on bioavailability (both AUC_0-t and C_max) of oral pharmaceutical composition containing 1.2g of omega-3 fatty acid capsules prepared according to Example 34 is found to be modest and is not of clinically significance

Relative bioavailability of KMS formulation in fast and fed state is illustrated in FIG: 3 EXAMPLE: 3

Illustrates relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 and lovaza® (omega-3 -acid ethyl esters) capsules 1 g of Glaxosmithkline, RTP, NC 27709 (four capsules as single dose) in health, adult, human subjects under fed condition. TABLE 13: Relative bioavailability in fed condition

# Geometric mean * Median Results in Table 12 shows that oral pharmaceutical composition 1.2g of omega -3 fatty acid Capsules prepared according to Example 34 has increase AUC_0-t and C_max to about 15.12% and 22.69% respectively, under fed condition compared to Lovaza®. EXAMPLE 4:

Relative bioavailability in fasting condition

Relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 and lovaza® (omega-3-acid ethyl esters) capsules 1 g of Glaxosmithkline, RTP, NC 27709 (four capsules as single dose) in health, adult, human subjects under fasting condition is studied.

The statistical analysis was not performed as there are no EPA concentrations obtained for lovaza of under fasting conditions. EPA concentration of lovaza® vs KMS formulation in fasting condition is illustrated in FIG: 4

EXAMPLE 5:

Enhanced bioavailability

A comparative pharmacokinetic study of the novel preconcentrate formulation suggested in the invention against polyunsaturated fatty acid with similar omega-3 fatty acid content was carried out in Sprague dawley rats at unimolar dose i.e similar amount of omega-3 fatty acid was administered to the different groups treated with preconcentrate formulation and the unformulated fatty acid. The design of study offered a weight to weight comparison of the omega-3 fatty acid bioavailability given as novel formulated preconcentrate and unformulated fatty acid. The collection of the blood carried out at defined time interval and plasma separated from it by centrifuging at 4000 rpm speed for 10 min. The plasma samples were analyzed using a validated LC-MS/MS method. TABLE 14:

Results in Table 14 shows more than 2 times improvement in C_max and AUC for the preconcentrate formulation prepared according to our invention.

Enhanced bioavailability is illustrated in FIG: 2.

Claims

claim:

1. A novel composition of enhanced bioavailability comprising

(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition

(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total compostion

wherein the composition forms particle size D₉₀ less than lOOnm when contacted with aqueous medium; wherein the said composition can be taken with or without food.

2. A novel composition of claim 1, wherein Omega -3 fatty acids comprising "EPA" and "DHA" used herein may be of esterified, triglyceride, phospholipid or free fatty acid forms. More preferably in preferably in esterified form.

3. A novel composition of claim 1, where in concentration of EPA alone is atleast above 10% w/w of the total composition.

4. A novel composition of claim 1, where in concentration of DHA alone is atleast above 10% w/w of the total composition.

5. A novel composition comprising omega-3 fatty acids of claim 1, where in the weight ratio of EPA:DHA in omega-3 fatty acid oil mixture ranges from about 1 :10 to about 10:1, from about 1 :8 to about 8:1, from about 1 :6 to about 6:1, from about 1:5 to about 5:1, from about 1 :4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2:1.

6. A weight ratio of EPA: DHA in omega-3 fatty acid oil mixture of claim 5, is preferably from about 1 :6 to about 6:1

. A novel composition of claim 1, where in omega -3 fatty acid further may contain other polyunsaturated fatty acids such as a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters or combinations thereof.

8. A novel composition of claim 1, wherein a nonionic surfactant selected from a group of group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.

9. A novel composition of claim 1 , where in nonionic surfactant is preferably selected from group of Polyoxyethylene glycol sorbitan alkyl esters such as Tween 20, Tween 60, Tween 80 etc.

10. A novel composition of claim 1, where in nonionic surfactant is preferably selected from group of Sorbitan Fatty Acid Esters such as Span 20, span 60 etc.

11. A novel composition of claim 1, where in nonionic surfactant is preferably selected from group of Polyoxyethylene Castor Oil derivatives such as PEG-35 castor oil, PEG-40 castor oil etc.

12. A novel composition of claim 1, optionally contains additional Surfactant selected from a nonionic surfactants, cationic surfactants, anionic surfactants, zwitterion surfactants, or combinations thereof.

13. A novel composition of claim 1, has an HLB value between 8-18.

14. An HLB value of novel composition of claim 13, is preferably above 12.

15. A novel composition of claim 1, further comprises a therapeutically effective amount of plant extract where in plant extract is selected from Amla (Phyllanthus emblica), Green coffee bean {Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleifera), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata)

16. A novel composition comprising plant extract of claim 15, where in plant extract comprises about 1 % to about 50 % (w/w), of the total composition.

17. A plant extract of claim 16, where in plant extract is preferably Amla (Phyllanthus emblica).

18. A novel composition of enhanced bioavailability comprising

(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition;

(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition;

wherein the composition forms particle size D₉₀ less than lOOnm when contacted with aqueous medium;

wherein the difference between AUC_0-t value for EPA in the blood plasma of the human under a fed state and AUC ₀._t value under a fasted state when administered orally to a human is not more than 15%, wherein t is 24 hours from the administration of the pharmaceutical composition;

wherein the difference between C_max value for EPA in the blood plasma of the human under a fed state and C_raax value under a fasted state when administered orally to a human is not more than 10%, wherein t is 24 hours from the administration of the pharmaceutical composition.

19. A novel composition substantially free of food effects comprising (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition;

wherein the blood serum level of total EPA of novel composition is increased, at least about 2 fold to the blood serum level of total EPA of omega-3 fatty acid alone.

20. A process of preparing novel composition comprising mixing (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition and (b atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition and optionally homogenizing the mixture if needed.

21. A method of administering a composition comprising (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition (b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition; wherein the composition is either ready-to-use aqueous solutions and or a non-aqueous preconcentrate.

22. A method of administering a composition according to claim 21, wherein a non-aqueous preconcentrate may be diluted with suitable solutions immediately before administration.

23. A method of administering a composition according to claim 21, wherein a non-aqueous preconcentrate is filled into single dosage forms suitable for oral administration, such as capsules, drinking ampoules and dose cushions, or may be formulated as other suitable oral dosage forms such as chewable soft pills and chewy-base lozenges.

24. A method of administering a composition according to claim 21, wherein a non-aqueous pre-concentrate filed in soft gelatin capsules ; where in, the composition will form an in situ oil-in-water emulsion in the gastrointestinal tract (GI tract).

25. A method of treating and/or preventing hyperlipidemia and/or hypercholesterolemia, age related macular disorders, dry eye syndrome, Alzheimer's disease; pain, stiffness and inflammation associated with arthritis and other joint conditions comprises administering a composition comprising (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition (b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition to a subject in need thereof.

26. A method of treating and/or preventing hyperlipidemia and/or hypercholesterolemia, age related macular disorders, dry eye syndrome, Alzheimer's disease; pain, stiffness and inflammation associated with arthritis and other joint conditions as in claim 25 further comprises a plant extract; wherein the plant extract exerts additive effect and/or synergistic effect to omega-3 fatty acids.

27. A novel self emulsifying composition comprising

(c) Optionally a plant extract selected from a group of Amla {Phyllanthus emblica), Green coffee bean (Coffea arabicd), Drumstick tree or Horseradish tree (Moringa oleiferd), Guggul or Mukul myrrh tree (Commiphora wightii), Frankincense

(Boswellia serata)

wherein the composition forms particle size D₉₀ less than lOOnm when contacted with aqueous medium wherein the composition is substantially free of food effects with enhanced bioavailability

8. A self-emulsifying composition capable of forming an oil-in-water emulsion upon dilution with an aqueous solution, having particle size D₉₀ less than lOOnm comprising

(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition; ¹

Wherein the non-ionic surfactant is selected from a group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.

Where in the said composition can be taken with or without food.