WO2016146608A1

WO2016146608A1 - Pharmaceutical compositions of dronedarone and essential fatty acids

Info

Publication number: WO2016146608A1
Application number: PCT/EP2016/055501
Authority: WO
Inventors: Ali TÜRKYILMAZ; Gülay Yelken; Sevgi Gökcek; Melike Eceoglu
Original assignee: Sanovel Ilac Sanayi Ve Ticaret A.S.
Priority date: 2015-03-16
Filing date: 2016-03-15
Publication date: 2016-09-22
Also published as: TR201503136A2

Abstract

The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt in combination with essential fatty acids or their esters or mixtures thereof and at least one pharmaceutically acceptable excipient.

Description

PHARMACEUTICAL COMPOSITIONS OF DRONEDARONE AND ESSENTIAL FATTY

ACIDS Field of Invention

The background of the invention

Dronedarone is a noniodinated benzofuran derivative with antiarrhythmic properties. It is an amiodarone analog that differs structurally from amiodarone in that the iodine moiety was removed and a methane sulfonyl group was added. These modifications reduce thyroid and other adverse effects and makes dronedarone less lipophilic, with a shorter half-life. The chemical name of dronedarone is N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1 - benzofuran-5-yl]methanesulfonamide and it has the structure shown in the following formula I.

Formula I : Dronedarone Formula II: Dronedarone hydrochloride Dronedarone hydrochloride (shown in formula II) is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF. It was approved by the FDA on 2009 and marketed under the brandname MULTAQ™. Recommended dose is one tablet of 400 mg twice a day with morning and evening meals. Following oral administration in fed conditions, dronedarone is well absorbed (at least 70 %) from intestines to blood. Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal.

In prior art, dronedarone and pharmaceutically acceptable salts thereof are described in EP 0 471 609 B1 . US 7 323 493 B1 discloses tablet formulations of dronedarone HCI. There are also several patent applications which dronedarone composition formulations, but none of them includes essential fatty acids.

Essential fatty acids (EFAs) are carboxylic acids that humans cannot synthesize but requires for the health. The term "essential fatty acid" refers to fatty acids required for biological processes. Because they cannot be synthesized within the human body, they must be obtained from the diet. There are two families of essential fatty acids: omega-3 (n-3) and omega-6 (n-6) fatty acids. As these fatty acids are not saturated with hydrogen (H) atoms (and contain more than one double bond between the atoms) they are also called ' polyunsaturated fatty acids ' (PUFAs).

The European Food Safety Authority, the American Heart Association, and other scientific and regulatory bodies confirm that essential fatty acids, especially omega 3 fatty acids are important for cardiovascular health. Omega 3 fatty acid consumption lowers plasma triglycerides, blood pressure, slows growth rate of atherosclerotic plaque and decreases risk of arrhythmias and also improves myocardial filling, efficiency and vascular function and also lower inflammation.

Especially, fish and fish oils contain essential fatty acids and in the treatment of cardiac arrhythmia especially in atrial fibrillation, fish or fish oil or essential fatty acid capsules are recommended in combination with antiarithmics. However, in prior art, there is no formulation which combines dronedarone and essential fatty acids in one dosage form. Instead of one per se use, combining more than one molecule in one dosage form increases the patients' quality of life and patients' compliance. Therefore, a composition of dronedarone and essential fatty acids in one suitable pharmaceutical dosage form is needed in the art.

On the other side, there are many challenges while combining two or more molecules in a dosage form such as dissolution, compatibility and stability problems. Each drug molecule has different dissolution and solubility properties. They may follow different absorption and distribution pathways after administration. For that reason, it is not easy to combine drug molecules in a same dosage form with desired dissolution profiles. They also may react with each other or with other used excipients and that may cause undesired instability problems. Moreover, due to solubility differences, many problems may be encountered during the process. Therefore, it is well known that even drugs used in the same therapeutic area or even for treating the same indication cannot always be combined into safe and efficacious dosage forms with the expectation of at least additive therapeutic effects.

Thus, a need occurs in the art which combines fatty acids and dronedarone in a same dosage form and overcome all problems above. In this present invention, dronedarone and essential fatty acids are combined in one dosage form and an effective and safe treatment of cardiovascular diseases is achieved.

Detailed description of the invention

The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with essential fatty acids or their esters or mixtures thereof and at least one pharmaceutically acceptable excipient.

According to one embodiment, said essential fatty acid is selected from the group comprising omega 3 fatty acids, omega 6 fatty acids or mixtures thereof. According to this embodiment, said essential fatty acid is omega 3 fatty acid.

In this embodiment, said omega 3 fatty acid is selected from the group comprising hexadecatrienoic acid, alpha linolenic acid, gamma linolenic acid, dihomo gamma linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, docosahexaenoic acid, heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid, tetracosapentenoic acid, tetracosahexaenoic acid, arachidonic acid, nervonic acid or mixtures thereof.

According to this embodiment, said esters of omega 3 fatty acid are their methyl esters or ethyl esters.

According to one embodiment, omega 3 fatty acid is present in an amount of between 0.1 to 95.0 %, preferably between 0.1 to 80.0 % and more preferably 0.1 to 70.0 % by weight of total formulation. According to this embodiment, omega 3 fatty acid is present in an amount of between 30 to 2500 mg, preferably 30 to 1000 mg, preferably 30 to 500 mg and more preferably it is 30 to 250 mg. According to one embodiment, dronedarone or a pharmaceutically acceptable salt used in this present invention is dronedarone hydrochloride (HCI).

According to this embodiment, dronedarone hydrochloride is present in an amount of between 3.0 to 95.0 %, preferably between 10.0 to 90.0 % and more preferably it is 15.0 to 70.0 % by weight of total formulation.

In this embodiment, dronedarone hydrochloride present in an amount of between 50 to 1200 mg, preferably 100 to 800 mg and more preferably it is 200 to 800 mg. In this present invention, dronedarone HCI is used as an antiarrithmic in combination with omega 3 fatty acids, for use in the treatment of cardiovascular diseases, especially for cardiac arrhythmia and to prevent serious or life-threatening side effects in patients.

In one embodiment, a pharmaceutical dosage form comprising dronedarone HCI in combination with omega 3 fatty acid has been developed providing a stable pharmaceutical combination with safe and effective dissolution profiles for each drug molecule.

In this embodiment, it has been found that in spesific ratio of dronedarone HCI to omega 3 fatty acid which is between 0.010 - 35.0(w/w), preferably 0.1 - 30.0 (w/w) and more preferably 0.1 - 25.0 (w/w) helps the formulation easily processed into a dosage form, in desired weight which can easily be swallowed by the patients.

According to this embodiment, in this present invention, pharmaceutical composition formulated in one dosage form provides desired dissolution profile for both dronedarone HCI and omega 3 fatty acid.

According to one embodiment of this invention, the pharmaceutical composition is in the form of solid, liquid or semisolid dosage form. In this embodiment, these pharmaceutical compositions are administrated oral, parenteral, intranasal, sublingual, transdermal, transmucosal, ophthalmic, intravenous, pulmonary, intramuscular or rectal administration, and preferably for oral administration. According to this embodiment, the pharmaceutical composition is in the form of tablets, bilayer tables, capsules, softgel capsules, pellets, microcapsules, tablet in tablets, in-lay tablets, mini tablets, multilayer tablets, buccal tablets, sublingual tablets, effervescent compositions, effervescent tablets, immediate release tablets, modified release tablets, orally disintegrating tablet, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, pills, powders, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, sterile ocular solutions, aerosols, sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, sachets; films, orally administrable films, solutions, solids; elixirs, tinctures, suspensions, syrups, colloidal dispersions, dispersions, emulsions.

Dronedarone and omega 3 fatty acids have different solublity properties. Therefore, combining essential fatty acids with dronedarone HCI in a same dosage form is not easy. Many problems may be encountered while developing a stable dosage form comprising dronedarone HCI and omega 3 fatty acids.

In this present invention, all problems have been overcome and a pharmaceutical composition has been developed which combines dronedarone HCI and omega 3 fatty acid. According to this embodiment, said pharmaceutical composition is formulated in the form of tablet or bilayer tablet or capsule or softgel capsule pellet or in-lay tablet or tablet in tablet.

According to the challenges mentioned above the selection of the excipients thus essential. According to this embodiment, at least one pharmaceutically acceptable excipient is selected from the group comprising surfactants, buffering agents, stabilizers, binders, diluents, dispersing agents, lubricants, glidants, disintegrants, plasticizers, preservatives, sweeteners, flavoring agents, coloring agents, oils or mixtures thereof.

In one embodiment, surfactant is used in this present invention to overcome solubility difference of dronedarone HCI and omega 3 fatty acid. It is surprisingly found that by using surfactant, dronedarone HCI and omega 3 fatty acid can be combined in a tablet or bilayer tablet or capsule or or softgel capsule pellet or in-lay tablet or tablet in tablet.

According to this embodiment, the surfactant is selected from the group comprising sodium lauryl sulphate, magnesium lauryl sulfate, dioctylsulfosuccinate, polysorbates, cetostearyl alcohol, polyoxyethylene alkyl esters, glycerylmonolauratesaponins, sorbitanlaurate and mixtures thereof, preferably it is sodium lauryl sulphate. In this embodiment, said pharmaceutical composition is formulated in the form of a tablet or bilayer tablet or capsule or softgel capsule or pellet or in-lay tablet or tablet in tablet comprising dronedarone HCI and omega 3 fatty acids.

In further embodiment, said pharmaceutical composition may comprise softgel microcapsules loaded by omega 3 fatty acid. Omega 3 fatty acid soft gel microcapsules comprise gelatin or glycerol or water or mixtures thereof. In further embodiment, said pharmaceutical composition may comprise dronedarone HCI pellets.

In an embodiment of the present invention said dronedarone HCI pellets comprises mannitol or pregelatinized starch or carbomer or croscarmellose sodium or polyvinylpyrrolidone (PVP) or polymethacrylates or polyvinyl alcohol or sugar pellet or microcrystalline cellulose (MCC) pellet or hydroxypropyl cellulose or or silicon dioxide or magnesium stearate coloring agent or mixtures thereof.

According to this embodiment, said dronedarone HCI pellets used in this present invention comprises a coating. In further, coating is inert coating that prevents chemical and physical interaction of dronedarone HCI. Coating ensures the stability of dronedarone HCI and omega 3 fatty acid. Another important reason is that the formulations of the drug molecules with different release properties can be provided in the same dosage form. Thus, desired release profiles are achieved for each drug molecules for a safe and effective treatment of cardiovascular diseases.

In this embodiment of this present invention, dronedarone HCI pellets comprises a coating is selected from the group comprising starch, lactose, sugar alcohol (D-mannitol, erythritol, etc.), lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose, cellulose acetate phthalate, methacrylic acid copolymers (Eudragit L types (methacrylic acid, ethyl acrylate copolymers), Eudragit RL and RS types (copolymer of ethyl acrylate, methyl methacrylate and ammonia methacrylate), Eudragit-S types (Methacrylic acid, methyl methacrylate copolymer)), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid co-polymer type C and mixtures thereof. Suitable buffering agents may comprise but not limited to alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, sorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, and preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate or mixtures thereof.

Suitable stabilizers may comprise but not limited to citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof. Suitable binders may include but not limited to xanthan gum, pregelatinized starch, polyvinylpyrrolidone, polymethacrylates or derivatives, polyethylene glycol, polyvinyl alcohol, starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, alginic acid, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

Suitable diluents may comprise but not limited to mannitol, lactose, microcrystalline cellulose, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof. Suitable dispersing agents may comprise but not limited to calcium silicate, magnesium aluminum silicate or mixtures thereof.

Suitable lubricants may comprise but not limited to magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof. Suitable glidants may comprise but not limited to silicon dioxide, talc, aluminium silicate, colloidal silicon dioxide, starch or mixtures thereof. Suitable disintegrants may comprise but not limited to pregelatinized starch, cross-linked polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.

Suitable plasticizers may comprise but not limited to polyethylene glycols of different molecular weights, propylene glycol, glycerine, triethyl citrate (TEC), triacetin, diethyl phthalate (DEP), dibutyl phthalate (DBP), tributhyl citrate (TBC), castor oil, dibutyl sebacate (DBS), diacetylated monogglycerides or mixtures thereof.

Suitable preservatives may comprise but not limited to methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene, boric acid, sorbic acid, benzyl alcohol, benzalconium chloride, parahydroxybenzoic acids or butylated hydroxyanisole or mixtures thereof.

Suitable antioxidants may include but not limited to butyl hydroxyanisole, butyl hydroxytoluene, ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid, sodium ascorbate, sodium bisulfate, sodium metabisulfate, monothioglycerol, cysteine, sodium thioglycolate, acetone sodium bisulfite, sodium bisulfate, sodium dithionite, gentisic acid ethanolamine, monosodium glutamate, sodium formaldehyde sulfoxylate, alpha tocopherol, or the mixtures thereof.

Suitable sweeteners may comprise but not limited to aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.

Suitable opacifiers may comprise but not limited titanium dioxide, silicon dioxide, talc, calcium carbonate, behenic, cetyl alcohol or mixtures thereof. Suitable flavoring agents may comprise but not limited to menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.

Suitable coloring agents may comprise but not limited to ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.

Suitable oils comprise but not limited to soybean oil, fish oil, krill oil, seal oil, borage oil, flax seed oil, evening primrose oil, hemp seed oil, pumpkin seed oil, grape seed oil, germ oil, safflower oil, squalene oil, squalane, sesame seed oil, arachidonic acid, conjugated linoleic acid, rosemary oil, lemon oil, peppermint oil, terrapin oil, pomegranate seed oil, sea buckthorn fruit oil, sunflower oil, chia oil, goji berry oil, sea buckthorn oil, jasmine oil, sweet almond oil, ginger oil, parsley seed oil, orange oil, halibut liver oil, wheat germ oil, aloe vera oil, garlic oil, avocado oil, castor oil, saw palmetto extract oil, olive oil, mineral oil, median chain tryglycerin, lavender oil, phosphatidylipids, rice bran oil, macadamia nut oil, arachis oil, phytosterol, phytotanol, castor bean oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, evening primrose oil, rice bran oil, borage oil, sunflower oil, soybean oil, palm oil, corn oil and safflower oil or a mixtures thereof.

Example 1 : Tablet

Ingredients Amount (%)

Dronedarone HCI 3.00 - 95.00

Omega 3 fatty acid or their 0.10 - 95.00

esters or mixtures

Microcrystalline cellulose 5.00 - 90.00

(MCC)

Sodium lauryl sulphate 0.10 - 15.00

Copovidone

(polyvinylpyrrolidone- vinyl 0.10 - 25.00

acetate copolymer)

Magnesium stearate 0.10 - 3.00 Production process: Dronedarone HCI, omega 3 fatty acid, MCC, sodium lauryl sulphate and copovidon are sieved and mixed. Then, magnesium stearate is added and mixed. Tablet compression is performed. Example 2: Bilaver tablet

Production process: Dronedarone HCI, mannitol and crospovidon are mixed. Omega 3 fatty acid, MCC, sodium lauryl sulphate and crospovidon are mixed seperately. Each mixture are mixed with silicon dioxide then magnesium stearate. Then, Bilayer tablet compression is performed.

Example 3: Pellet (coating)

Ingredients Amount (%)

Dronedarone HCI 3.00 - 95.00

Omega 3 fatty acid or their 0.10 - 95.00

esters or mixtures

Polyvinylpyrrolidon (PVP) 0.10 - 25.00

Sodium lauryl sulphate 0.10 - 15.00 Sugar pellet 5.00 - 90.00

Polymethacrylate 0.10 - 40.00

Silicon dioxide 0.10 - 2.00

Magnesium stearate 0.10 - 3.00

Production process: Alcoholic PVP solution is prepared with Dronedarone HCI, omega 3 fatty acid and sodium lauryl sulphate seperatly. Sugar pellets are seperataly coated with these solutions. Alcoholic solution of polymethacrylate is prepared and Dronedarone HCI pellets and omega 3 fatty acid pellets are coated with this solution separately. Pellets are first mixed with silicon dioxide and then magnesium stearate. Then, pellets mixed and filled into the capsules.

Example 4: Softqel capsule

Production process: Dronedarone HCI, sodium lauryl sulphate and antioxidants are mixed until homogen mixture is observed. This solid powder mixture is mixed with omega 3 fatty acid and soybean oil for the inner phase of the capsule. Glycerol, gelatin and water are mixed until homogen mixture is observed. Alginate, coloring agent, opacifier andflavoring agent are added to this mixture.

Final mixture is adhere to the spaces with vacuum, gelatin lines are taken to the spaces of the cylindirs. Filling, shaping, capping process is performed. And then, capsules are cut and dried.

Example 5: Dronedarone HCI pellets in omeqa-3 fatty acid softqel capsule

Production process: Dronedarone HCI and carbomer are mixed and passed through the extruder while melting. Then, the mixture is cooled and sieved.

Dronedarone HCI and mannitol are mixed together then by spraying carbomer solution a wet mass is formed. Pellets produced from this wet mass by extrusion/spheronization pelletizing technique. The pellets are mixture is mixed with omega 3 fatty acid, antioxidant and sodium lauryl sulphate for the inner phase of the capsule. Glycerol, gelatin and water are mixed until homogen mixture is observed. Coloring agent, opacifier and flavoring agent are added to the mixture. Final mixture is adhere to the spaces with vacuum, gelatin lines are taken to the spaces of the cylindirs. Filling, shaping, capping process is performed. And then, capsules are cut and dried.

Example 6: Omeqa-3 softqel microcapsules in dronedarone HCI capsule

Production process: Glycerol, gelatin and water are mixed until homogen mixture is observed. Final mixture is adhere to the spaces with vacuum, gelatin lines are taken to the spaces of the cylindirs. Omega 3 fatty acid is filled into the microcapsules and shaping, capping process is performed. And then, microcapsules are cut and dried.

Dronedarone HCI, mannitol, crospovidon and pregelatinize starch are mixed until homogen mixture is observed. Total mixture and softgel microcapsules are filled into capsules.

Example 7: Omeqa-3 softqel microcapsule and dronedarone HCI pellets in capsule

Ingredients Amount (%)

Softgel microcapsules

Omega 3 fatty acid or their 0.10 - 95.00

esters or mixtures

Gelatin 30.00 - 90.00

Glycerol 5.00 - 50.00 Water q.s.

Dronedarone HCI pellets

Dronedarone HCI 3.00 - 95.00

Mannitol 5.00 - 90.00

Pregelatinized starch 5.00 - 90.00

Poloxamer 0.10 - 30.00

Coating 0.10 - 3.00

Dronedarone HCI, poloxamer, pregelatinized starch and mannitol are mixed together then by coating solution a wet mass is formed. Pellets produced from this wet mass by extrusion/spheronization pelletizing technique.

Dronedarone HCI pellets are filled into capsules with softgel microcapsules.

Claims

1 . A pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with essential fatty acids or their esters or mixtures thereof and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1 , wherein essential fatty acid is selected from the group comprising omega 3 fatty acids, omega 6 fatty acids or mixtures thereof.

3. The pharmaceutical composition according to claim 2, wherein essential fatty acid is omega 3 fatty acid.

4. The pharmaceutical composition according to claim 2 or 3, wherein omega 3 fatty acids are selected from the group comprising hexadecatrienoic acid, alpha linolenic acid, gamma linolenic acid, dihomo gamma linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, docosahexaenoic acid, heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid, tetracosapentenoic acid, tetracosahexaenoic acid, arachidonic acid, nervonic acid or mixtures thereof.

5. The pharmaceutical composition according to claim 1 , wherein omega 3 fatty acid is present in an amount of between 0.1 to 95.0 %, preferably between 0.1 to 80.0 % and more preferably 0.1 to 70.0 % by weight of total formulation.

6. The pharmaceutical composition according to claim 1 , wherein omega 3 fatty acid is present in an amount of between 30 to 2500 mg, preferably 30 to 1000 mg, preferably 30 to 500 mg and more preferably it is 30 to 250 mg.

7. The pharmaceutical composition according to claim 1 , wherein dronedarone or a pharmaceutically acceptable salt is dronedarone hydrochloride.

8. The pharmaceutical composition according to claim 1 or 7, wherein dronedarone hydrochloride is present in an amount of between 3.0 to 95.0 %, preferably between 10.0 to 90.0 % and more preferably it is 15.0 to 70.0 % by weight of total formulation.

9. The pharmaceutical composition according to claim 8, wherein dronedarone hydrochloride present in an amount of between 50 to 1200 mg, preferably 100 to 800 mg and more preferably it is 200 to 800 mg.

10. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is in the form of solid, liquid or semisolid dosage form.

1 1 . The pharmaceutical composition according to claim 10, wherein said pharmaceutical composition is in the form of of tablets, bilayer tables, capsules, softgel capsules, pellets, microcapsules, tablet in tablets, in-lay tablets, mini tablets, multilayer tablets, buccal tablets, sublingual tablets, effervescent compositions, effervescent tablets, immediate release tablets, modified release tablets, orally disintegrating tablet, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, pills, powders, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, sterile ocular solutions, aerosols, sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, sachets; films, orally administrable films, solutions, solids; elixirs, tinctures, suspensions, syrups, colloidal dispersions, dispersions, emulsions.

12. The pharmaceutical composition according to claim 10, wherein said pharmaceutical composition is formulated in the form of tablet or bilayer tablet or capsule or softgel capsule or pellet or in-lay tablet or tablet in tablet.

13. The pharmaceutical composition according to claim 1 , wherein at least one pharmaceutically acceptable excipient is selected from the group comprising surfactants, buffering agents, stabilizers, binders, diluents, dispersing agents, lubricants, glidants, disintegrants, plasticizers, preservatives, sweeteners, flavoring agents, coloring agents or mixtures thereof.

14. The pharmaceutical composition according to claim 13, wherein the surfactant is selected from the group comprising sodium lauryl sulphate, magnesium lauryl sulfate, dioctylsulfosuccinate, polysorbates, cetostearyl alcohol, polyoxyethylene alkyl esters, glycerylmonolauratesaponins, sorbitanlaurate and mixtures thereof, preferably it is sodium lauryl sulphate.

15. The pharmaceutical composition according to claim 12, wherein said pharmaceutical composition comprises microcapsules loaded by omega 3 fattyacid.

16. The pharmaceutical composition according to claim 15, omega 3 fatty acid soft gel microcapsules comprises gelatin or glycerol or water or mixtures thereof.

17. The pharmaceutical composition according to claim 12, said pharmaceutical composition comprises dronedarone HCI pellets.

18. The pharmaceutical composition according to claim 17, dronedarone HCI pellets comprises mannitol or pregelatinized starch or carbomer or croscarmellose sodium or polyvinylpyrrolidone (PVP) or polymethacrylates or polyvinyl alcohol or sugar pellet or microcrystalline cellulose (MCC) pellet or hydroxypropyl cellulose or or silicon dioxide or magnesium stearate coloring agent or mixtures thereof as pharmaceutically acceptable excipients.

19. The pharmaceutical composition according to any preceding claims, for use in treatment of cardiovascular diseases and especially for cardiac arrhythmia.