FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for preparation of pharmaceutical compositions comprising droanedarone or a pharmaceutically acceptable salt thereof. The present invention also relates to method of administering the compositions comprising dronedarone in a subject in need thereof.

BACKGROUND OF THE INVENTION

Dronedarone is chemically known as N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide and is disclosed in US 5,223,510. Dronedarone is a benzofuran derivative and is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF). Dronedarone is marketed in the form of tablets under the trade name Multaq® in the United States.

US patent 7,323,493 discloses a solid pharmaceutical composition for oral administration comprising a benzofuran derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable salts thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients. US 7,323,493 also discloses a solid pharmaceutical composition in tablet form comprising a benzofuran derivative with antiarrhythmic activity selected from the group consisting of dronedarone and amiodarone, or a pharmaceutically acceptable salt thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant selected from poloxamers, optionally in combination with one or more pharmaceutical excipients, said nonionic hydrophilic surfactant being present in a proportion of from 5% to 15% by weight of the active principle in base form, provided that the pharmaceutical composition does not contain a polysorbate surfactant.
US patent 8,318,800 discloses a solid pharmaceutical composition for oral administration comprising dronedarone, or a pharmaceutically acceptable salt thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination fa with one or more pharmaceutical excipients wherein the nonionic hydrophilic surfactant is present in a proportion of from 1% to 50% by weight of the active principle in base form.

US patent publication 2007/0243257 discloses a solid pharmaceutical composition comprising a solid dispersion containing at least one active principle and a pharmaceutically acceptable polymer matrix, characterized in that said pharmaceutically acceptable polymer matrix comprises a blend of (i) polydextrose, in the form of a continuous polydextrose phase, and (ii) at least one polymer other than polydextrose, in the form of a continuous phase of this polymer, the proportion of said polydextrose being at least 20% by weight and the proportion of said at least one polymer other than polydextrose being at least 20% by weight, relative to the total weight of said pharmaceutically acceptable polymer matrix.

PCT publication WO 2011/113320 Al discloses a pharmaceutical composition, characterized in that it contains dronedarone or a pharmaceutically acceptable salt thereof as an active ingredient, one or more pharmaceutically acceptable amphiphilic lipid surface-active agent, one or more phospholipids, and in combination with one or more pharmaceutically acceptable excipients. PCT publication WO 2011/132167 Al discloses a method for preparing a composition of medicinal active ingredient comprising (a) a granular centre consisting of grains of active ingredient, agglomerated in the presence of binder, and (b) a layer of coating of said granular centre consisting of fatty matrix optionally comprising an adjuvant, preferably chosen from hydrophilic agents, surfactants or mixtures thereof, the method comprising the steps of: (El) preparing the granular centre by spraying an aqueous solution comprising the binder or by spraying the binder in the molten state onto the active ingredient alone or as a mixture with a diluent and/or a lubricant; (E2) coating by spraying, onto the granules, said fatty matrix pre-melted in a melting kettle at a temperature approximately 10 to 20°C above its melting point; (E3) cooling the composition obtained.

PCT publication WO 2011/135581 discloses a pharmaceutical composition of dronedarone or salts thereof, characterized in that said composition is devoid of surfactant. PCT publication WO 2011/135582 discloses a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants. PCT publication WO 2012/013088 Al discloses a solid dispersion comprising dronedarone or its pharmaceutically acceptable salts and carrier material, wherein the carrier material is selected from the group consisting of polyvidone, copovidone and hydroxypropyl cellulose, or a mixture thereof. PCT publication WO 2012/063005 A2 discloses a pharmaceutical composition comprising at least one active ingredient selected from (i) dronedarone base form, (ii) dronedarone in the form of a pharmaceutically acceptable salt, characterized in that it further comprises at least one amphiphilic lipid excipient of HLB value of between 2 and 20. PCT publication WO 2012/085284 A2 discloses a tablet comprising a pharmacologically effective amount of dronedarone or its pharmaceutically acceptable salt in an amount from about 40% to 90% in weight of the active moiety based on the total weight of the tablet, characterized in that dronedarone or its pharmaceutically acceptable salt is micronized, optionally co-micronized together with filler.

PCT publication WO 2012/105767 A2 discloses a composition comprising dronedarone or a pharmaceutically acceptable salt thereof and ethylene glycol/vinyl caprolactam/vinyl acetate graft polymer. PCT publication WO 2013/004830 Al discloses a pharmaceutical composition comprising from 81% to 92% by weight of dronedarone and/or at least one derivative thereof; 7 to 20% by weight of at least one excipient melt having a melting temperature or glass transition temperature greater than or equal to about 35°C and less than or equal to about 120°C; 0 to 20% by weight of at least one additional excipient, said excipient selected from disintegrants, lubricants and flow agents; the percentages being based on total weight of said pharmaceutical composition. PCT publication WO 2013/024411 Al discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients and further discloses a process for the preparation of a co-milled formulation of dronedarone comprising the step of co-milling dronedarone and one or more pharmaceutically acceptable excipients.

GB 2491380 patent discloses a dosage form comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid, an ionic surfactant or a mixture thereof, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone base exhibits a pharmacokinetic profile characterised by an AUCo-24 of about 500, more particularly 350 to 650 ng.hr/ml. Indian patent publication IN 3277/CHE/2010 A discloses a solid pharmaceutical composition for oral administration comprising a benzofuran derivative selected from the group consisting of dronedarone or a pharmaceutically acceptable salt, an anionic surfactant in combination with a solubility enhancer preferably betacyclodextrin and optionally in combination with one or more pharmaceutically acceptable excipients.

CN 100560067 patent discloses a pharmaceutical composition comprising 20% micronized dronedarone hydrochloride, 4% sodium lauryl sulphate, 4% of polyvinyl pyrrolidone, 50% of milk-sugar, 21.5% of Avicel®, 0.5% magnesium stearate, said micronized dronedarone hydrochloride has a mean diameter lower than or equal to 15 um. CN 102078307 patent discloses a pharmaceutical composition comprising dronedarone hydrochloride, characterized in that the composition consisting of dronedarone hydrochloride, microcrystalline cellulose, croscarmellose sodium, starch 1500, polyethylene glycol 4000, 1% solution of hydroxypropyl methylcellulose, saccharin sodium and magnesium stearate. CN 102349889 patent discloses a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof as active ingredient, phospholipid, acidic regulator and crystallization inhibitor, wherein the phospholipid is selected from the group consisting of soya lecithin and egg yolk lecithin, the acidic regulator is selected from the group consisting of malic acid, fumaric acid, tartaric acid, citric acid and succinic acid and said crystallization inhibitor is selected from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymer. CN 102579421 patent discloses a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer, said polymer is selected from the group consisting of polyethylene glycol 6000-vinyl caprolactam-vinyl acetate copolymer, polyvinyl pyrrolidone-vinyl acetate copolymers, ketone povidone, acrylic resins, cellulose derivatives or mixture thereof. CN 102614139 patent discloses a solid pharmaceutical composition comprising anti-arrhythmic activity benzofuran derivative or a pharmaceutically acceptable salt thereof, which is characterized in that the pharmaceutical composition contain one or more pharmaceutically acceptable crystallization inhibitor and one or more other excipients.

US 7323493 and US 8318800 patents suggest that solubility of dronedarone hydrochloride is pH dependent, with dronedarone showing maximum solubility at around pH values of 3 to 5, but very low solubility at pH about 6 to 7 where it tends to precipitate. Similarly in the gastrointestinal tract, it can be assumed that dronedarone hydrochloride solubilizes in the acidic conditions of stomach but risks precipitation at intestinal pH, and this property of dronedarone hydrochloride is responsible for its low bioavailability in vivo. The patents further suggest the use of nonionic hydrophilic surfactants with in a concentration range of 1.0-50% w/w by weight of the active principle in base form to overcome the solubility problem of dronedarone and improve its oral bioavailability. However, the patents do not disclose the effect of non-ionic hydrophobic surfactants and co-solvents on the solubility and bioavailability.

Hence, there exists a need to develop a pharmaceutical composition comprising dronedarone which shows at least comparable stability and bioavailability with respect to the marketed formulation in the form of tablets under the trade name Multaq®. The inventors of present invention have developed a composition comprising dronedarone hydrochloride, hydrophobic non-ionic surfactant in combination with co-solvent which shows at least comparable stability and in-vitro dissolution with respect to the marketed formulation.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof.
An aspect of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof, wherein the composition is substantially free of surfactant.

Another aspect of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof, wherein the composition is substantially free of non-ionic hydrophilic surfactant.

An aspect of the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant and one or more pharmaceutical acceptable excipient(s) thereof.

Yet another aspect of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutical^ acceptable salt thereof, a non-ionic hydrophilic surfactant in an amount less than about 1% w/w by weight of the active principle in base form and one or more pharmaceutically acceptable excipient(s) thereof.

Another aspect of the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.

An aspect of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a non-ionic hydrophilic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.

An aspect of the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.

Another aspect of the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent, an acidifying agent and one or more pharmaceutically acceptable excipient(s) thereof.

In an aspect the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of: (i) blending dronedarone with one or more pharmaceutically acceptable excipients, and (ii) formulating the blend of step (i) into a suitable dosage form.

An aspect of the present invention provides a method to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation.

DETAILED DESCRIPTION OF THE INVENTION

The term "particle size" unless indicated otherwise in the specification relates to particles of dronedarone free base as well as pharmaceutically acceptable salt, amorphous or various polymorphs or any isomer or derivative, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Dronedarone with specific "particle size" and distribution, or surface area would provide a fast dissolution of the active ingredient, would be easy to prepare and stable while maintaining the beneficial properties with respect to fast solubility and bioavailability. The amount of dronedarone used may be in the range of 30-90% by weight of the composition. In an embodiment, the polymorphic form is substantially retained in the formulation at the initial stage and during stability charge.

The term "composition" or "formulation" or "dosage form" or "medicinal preparation" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; meant for oral administration.

The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug (e.g. dronedarone), which is sufficient to elicit an appreciable biological response when administered to the patient.

The term "excipient" means a pharmacologically inactive component such as a diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. The phrase "medicinal package" unless indicated otherwise in the entire specification refers to bottle or blister pack or pouch or any corresponding packing known to a person skilled in the art in which the "dosage form" or the "medicinal preparation" is packed. The term "desiccant" unless indicated otherwise in the entire specification refers to a substance used to remove/suppress/decrease the odor/smell or to absorb moisture which prevents degradation/decomposition of the active agent(s). The desiccant may be placed in the internal space of the medicinal package, irrespective of any particular limit, so long as the amount is sufficient to remove the odorous material, that is, sufficient to suppress or reduce the smell. The amount of the desiccant can vary depending on kind or shape of the desiccant, distance from the medicinal preparation capable of giving out smells, amount of the compound giving out smells, type of formulation, volume of the space where the medicinal preparation and the desiccant are placed, amount of the existing or produced odorous material, preservation condition of the medicinal package. In another embodiment, the composition comprising dronedarone according to the present invention was found to be stable after storage at 40°C/75% RH for atleast three months.

As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a process" includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein throughout the entire specification, the phrase "substantially free" means that conventionally used surfactants are not present in the compositions. It should be appreciated by those skilled in the art that reference to "substantially free" in accordance with particular embodiments of the present invention does not exclude the presence of small amounts of surfactants. Thus, "substantially free" should be understood as meaning free of added surfactants, or in an amount less than about 1% w/w by weight of the active principle in base form.

The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof.
In an embodiment, the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof, wherein the composition is substantially free of surfactant.

In another embodiment, the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutical^ acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof, wherein the composition is substantially free of non-ionic hydrophilic surfactant.

In an embodiment, the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant and one or more pharmaceutically acceptable excipient(s) thereof.

Another embodiment of the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant in an amount less than about 1% w/w by weight of the active principle in base form and one or more pharmaceutically acceptable excipient(s) thereof.

In an embodiment, the present invention further relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.
In an embodiment, the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a non-ionic hydrophilic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.

In an embodiment, the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s) thereof.
In an embodiment, the present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent, an acidifying agent and one or more pharmaceutically acceptable excipient(s) thereof.

In another embodiment, the compositions according to the present invention may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous/non aqueous solvents), melt granulation, solid dispersion, direct compression, double compression, layering, high shear mixture granulation, fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like. Compaction of the blend into comprimates may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods, which includes jet milling, rolling milling, hammer milling, centrifugal-impact milling and sieving pebble milling, cutter milling or use of a mortar and pestle.

"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients are selected from but not limited to group comprising water soluble polymers, diluents, binders, disintegrants, antioxidants, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, co-solvents, buffering agents, acidifying agents, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

Diluents increase the bulk of the composition. Diluents according to the present invention are selected from but not limited to group comprising sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Starlac® (co-processed mixture of Starch and lactose), Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-95% by weight of the dosage form.

Binders hold the ingredients in the composition together. Exemplary binders are selected from but not limited to group comprising cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; polyvinylalcohol, polyvinyl alcohol based compositions such as Opadry® HP, Opadry® II white or Instacoat® and the like; hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers, and the like or combinations thereof. The binder may be used in the range of 1-30% by weight of the dosage form.

Disintegrants according to the present invention are selected from but not limited to group comprising water swellable substances, for example, cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums, and the like or combinations. The disintegrant may be used in the range of 1-30% by weight of the dosage form.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be nonionic, anionic, cationic, and zwitterionic surfactants. The surfactant may be used in the range of 0.001-10% by weight of the dosage form.

Non-ionic hydrophilic surfactants according to the present selected from but not limited to group comprising ethyleneoxide/propyleneoxide copolymers referred to herein below as poloxamers, such as poloxamer 124 sold under the brand name Synperonic® PE/L44; poloxamer 188 sold under the brand name Pluronic® F68 or Synperonic® PE/F68; poloxamer 237 sold under the brand name Pluronic® F87 or Synperonic® PE/F87; poloxamer 338 sold under the brand name Synperonic® PE/F108 or poloxamer 407 sold under the brand name Pluronic® F127, Synperonic® PE/F127 or Lutrol® F127. Polyethoxylated castor oils such as those sold under the brand name Cremophor® RH40. Ethoxylated polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 sold respectively under the brand names Tween®20, Tween®40, Tween®60 and Tween®80 or alternatively polyethylene hydroxystearates such as polyethylene hydroxystearate 660 sold under the brand name Solutol® HS15 and the like or combinations thereof.

Non-ionic hydrophobic surfactants according to the present invention selected from but not limited to group comprising d-alpha-tocopherol (vitamin E), polyoxyl 20 cetostearyl ether, polyoxyl 10 oleyl ether, polyoxyl lauryl ether, polyoxyl stearyl ether, macrogol 15 hydroxystearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan trioleate and the like or combinations thereof.

Anionic surfactants according to the present invention selected from but not limited to group comprising alkyl sulfates: ammonium lauryl sulfate, sodium lauryl sulfate (SDS, sodium dodecyl sulfate, another name for the compound); alkyl ether sulfates: sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), sodium myreth sulfate; sulfonates; docusates: dioctyl sodium sulfosuccinate; sulfonate fluorosurfactants: perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate; alkyl benzene sulfonates; phosphates: alkyl aryl ether phosphate alkyl ether phosphate; Carboxylates; alkyl carboxylates: fatty acid salts (soaps): sodium stearate; Sodium lauroyl sarcosinate; Carboxylate fluorosurfactants: perfluorononanoate, perfluorooctanoate (PFOA or PFO) and the like or combinations thereof.

Cationic surfactants according to the present invention selected from but not limited to group comprising based on pH-dependent primary, secondary or tertiary amines: primary amines become positively charged at pH < 1 0, secondary amines become charged at pH < 4; octenidine dihydrochloride; permanently charged quaternary ammonium cation; alkyltrimethyl ammonium salts: cetyl trimethylammonium bromide (CTAB) also known as hexadecyl trimethyl ammonium bromide, cetyl trimethylammonium chloride (CTAC); cetylpyridinium chloride (CPC); polyethoxylated tallow amine (POEA); benzalkonium chloride (BAC); benzethonium chloride (BZT); 5-bromo-5-nitro-l,3-dioxane; dimethyldiocta decylammonium chloride; dioctadecyldimethylammonium bromide (DODAB); zwitterionic (amphoteric): based on primary, secondary or tertiary amines or quaternary ammonium cation with sulfonates: CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate); sultaines: cocamidopropyl hydroxy sultaine; carboxylates; amino acids; betaines: cocamidopropyl betaine; phosphates; lecithin and the like or combinations thereof.

Co-solvents according to the present invention are selected from but not limited to group comprising polyethylene glycol, glycerin, propylene glycol, glycerol, ethylene glycol, alcohols and the like or combinations thereof.

Buffering agents according to the present invention are selected from but not limited to group comprising mixture of citric acid and sodium citrate, mixture of potassium hydrogen phthalate and sodium hydroxide, mixture of sodium acetate and acetic acid and the like or combinations thereof.

Acidifying agents according to the present invention are selected from but not limited to group comprising acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and the like or combinations thereof.

Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants are selected from but not limited to group comprising calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, sodium lauryl sulphate, vegetable oil, zinc stearate, and combinations comprising one or more of the foregoing lubricants. The lubricant may be used in the range of 0.01-5% by weight of the dosage form. Exemplary glidants include, but not limited to, talc, silicon dioxide, silicic acid, cornstarch and the like. The glidant may be used in the range of 0.01-5% by weight of the dosage form.

The dosage form according to the present invention may be uncoated or optionally coated with functional coating, film coating, moisture barrier coating or a protective coating composition. The coating composition mainly comprises of film forming polymers and one or more of plasticizers, opacifier, surfactant, anti tacking agents, coloring agent and the like. The coating according to the present invention is applied by solubilising or suspending the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylene chloride, 0.1N HC1 and the like or mixtures thereof. Varieties of commercially available cellulosic polymers exist and may include, for example, Spectracel® HPMC compositions (available from Sensient Technologies). Further, other commercially available coating materials are available marketed under the brand name Opadry® for example Opadry II Gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE; Opadry II Pink which contains: hypromellose type 2910 USP, titanium dioxide USP, lactose monohydrate NF, polyethylene glycol 3350 NF, triacetin USP, and FD&C Red #40; Opadry II Blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10; Opadry II Yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP; Opadry II Purple which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, D&C Red #27, polyethylene glycol 3350 NF, triacetin USP, and FD&C Blue #1 and the like. In an embodiment, the compositions of the present invention may additionally comprise of a colorant in order to produce a desirable color. Colors known to be 'FD&C certified may be used to provide coloring to the product and are within the purview of the present invention. Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used, which is typically an FD&C or D&C dye, e.g., an approved dye selected from the so-called 'coal-tar' dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a 'lake' thereof, i.e. an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the 'GRAS' (Generally Regarded as Safe) category.

In an embodiment, dronedarone according to the present invention haves an average particle size D5o in the range of 1-200 microns. The term "D50" unless indicated otherwise in the specification is defined as the size value corresponding to cumulative size distribution at 50%, which represents the size of particles below which 50% of the sample lies. The known particle size analysis methods are suitable for determining the particle size, for example, particle size measurement using light-scattering methods such as by Malvern or Horiba. In another embodiment, the composition according to the present invention comprises dronedarone in the range of 50 to 1000 mg. In yet another embodiment, the composition according to the present invention comprises dronedarone and surfactant in the ratio of 40:1 to 5:1.

In another embodiment, the composition comprising dronedarone can be packed in any suitable packaging material known in the art such as, but not limited to, HDPE bottles and Clear PVC/PVDC Plain Aluminium Foil Blister.

In another embodiment, the composition comprising dronedarone according to the present invention was found to be stable after storage at 40°C/75% RH for atleast three months.

An embodiment of the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of: (i) blending dronedarone with one or more pharmaceutically acceptable excipient(s), and (ii) formulating the blend of step (i) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),

(iii) blending the prepared granules of step (i) with one or more pharmaceutically acceptable
excipient(s), and
(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a non-ionic hydrophilic surfactant in an amount less than about 1% w/w by weight of the active principle in base form and one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),
(iii) blending the prepared granules with one or more pharmaceutically acceptable excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a surfactant other than non-ionic hydrophilic surfactant and one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a non-ionic hydrophobic surfactant and one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a co-solvent and one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a non-ionic hydrophilic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s),
(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable
excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of: (i) blending dronedarone with a surfactant other than non-ionic hydrophilic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s), (ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s),

(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable
excipient(s), and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) blending dronedarone with a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipients,

(ii) granulating the blend of step (i),

(iii) blending the prepared granules with one or more pharmaceutically acceptable excipients, and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

(i) preparing a solution comprising a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent and one or more pharmaceutically acceptable excipient(s),

(ii) adsorbing the solution of step (i) on dronedarone and blending with one or more pharmaceutically acceptable excipient(s),

(iii) granulating the blend of step (ii),

(iv) blending the prepared granules of step (iii) with one or more pharmaceutically acceptable
excipient(s), and

(v) formulating the blend of step (iv) into a suitable dosage form.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising dronedarone, which comprises the steps of:

preparing a solution comprising a non-ionic hydrophilic surfactant, a non-ionic
hydrophobic surfactant, a co-solvent, an acidifying agent and one or more pharmaceutically
acceptable excipient(s),

(ii) adsorbing the solution of step (i) on dronedarone and blending with one or more
pharmaceutically acceptable excipient(s),

(iii) granulating the blend of step (ii),

(iv) blending the prepared granules of step (iii) with one or more pharmaceutically acceptable excipient(s), and

(v) formulating the blend of step (iv) into a suitable dosage form.

In another embodiment, the composition comprising dronedarone according to the present invention can be used to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF). In yet another embodiment, the present invention relates to use of dronedarone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of atrial fibrillation. In an embodiment, the present invention relates to dronedarone or a pharmaceutically acceptable salt thereof for use in treating atrial fibrillation.

In another embodiment, the composition comprising dronedarone according to the present invention comprises water content in the range of 1-10%.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

* Lost in processing q.s.: quantity sufficient
Manufacturing process:

i) Poloxamer and glycerin were dissolved in purified water and adsorbed on to dronedarone hydrochloride, ii) Maize starch, crospovidone, lactose monohydrate and hydroxypropyl methylcellulose were added to the material of step (i), iii) The material of step (ii) was granulated using purified water and the wet mass was dried, milled and sifted, iv) The granules of step (iii) were blended with hydroxypropyl methylcellulose, crospovidone, lactose monohydrate and colloidal silicon dioxide, v) The blend of step (iv) was lubricated with magnesium stearate and compressed to form tablets. Coating of tablets vi) The compressed tablets of step (v) were finally coated with the coating solution.

Examples 2.3 & 4

The compositions given in Examples 2, 3 and 4 were prepared using the similar procedure described in Example 1.


* Lost in processing q.s.: quantity sufficient
Manufacturing process:

i). Poloxamer, sorbitan monolaurate, polyethylene glycol and citric acid were dissolved in purified water and adsorbed on to Dronedarone HC1. ii). Lactose monohydrate, hydroxypropyl methylcellulose, maize starch and crospovidone were added to the material of step (i) and granulated with purified water alone.

iii). Lactose monohydrate, crospovidone and colloidal silicon dioxide were added to the dried and milled granules of step (ii). iv). The blend of step (iii) was further lubricated using magnesium stearate and compressed into tablets, v). The compressed tablets of step (iv) were finally coated with the coating solution.

Table-1 shows the comparative dissolution profile of dronedarone hydrochloride tablets according to the present invention (Examples 1 & 2) and Multaq® Tablets carried out in 1000 ml medium (pH 4.5 phosphate buffer) using Apparatus USP II (Paddle), at 75 rpm speed after storing at 40°C/75% RH for 3 months.

Table 1

We claim:

1. A pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) thereof characterized in that the composition is substantially free of surfactant.

2. The composition according to claim 1, wherein the composition is substantially free of non-ionic hydrophilic surfactant.

3. The composition according to claim 1, wherein a surfactant is selected from group comprising of a non-ionic hydrophilic surfactant and a non-ionic hydrophobic surfactant.
4. The composition according to claim 3, wherein non-ionic hydrophilic surfactant is in an amount less than about 1% w/w by weight of the active principle in base form.

5. The composition according to claim 1, wherein the composition comprises a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant and a co-solvent.

6. The composition according to claim 1, wherein the composition comprises a non-ionic hydrophilic surfactant and a co-solvent.

7. The composition according to claim 1, wherein the composition comprises a non-ionic hydrophobic surfactant and a co-solvent.

8. The composition according to claim 1, wherein the composition comprises a surfactant selected from group comprising of a non-ionic hydrophilic surfactant, a non-ionic hydrophobic surfactant, a co-solvent and an acidifying agent.

9. The composition according to claims 1 to 8, wherein the pharmaceutically acceptable excipients are selected from group comprising water soluble polymers, diluents, binders, disintegrants, antioxidants, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, co-solvents, buffering agents, acidifying agents, suspending agents, dispersing agents, film formers, flavors and printing inks.

10. A process for preparing a pharmaceutical composition comprising dronedarone according to claim 1, which comprises the steps of:

i) blending dronedarone with a non-ionic hydrophilic surfactant in an amount less than about 1% w/w by weight of the active principle in base form and one or more pharmaceutically acceptable excipient(s), ii) granulating the blend of step (i), iii) blending the granules prepared in step (ii) with one or more pharmaceutically acceptable excipient(s), and iv) formulating the blend of step (iii) into a suitable dosage form.