Co-micronized Rivaroxaban Pharmaceutical Compositions

The present invention relates to a pharmaceutical composition of rivaroxaban or a pharmaceutically acceptable salt thereof and a method for producing the same.

Background of the Invention

Rivaroxaban (5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-
oxazolidin-5-yl}methyl)-2-thiophenecarboxamide) is a low molecular weight, orally administrable anticoagulant indicated for reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis. It is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation. The rivaroxaban molecule and its method of use are first described in US patent No. 7157456, 7585860, 7592339. Different crystalline polymorphic forms are disclosed in various patents and patent applications like US 8188270, US 2010/0168111, WO 2012/004245 and WO2013041651.

Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media. This low solubility of the drug makes it difficult to prepare pharmaceutical formulation, which results in a poor bioavailability.

The prior art discloses various approaches for formulating rivaroxaban to increase the dissolution and oral bioavailability.

US 2008/0026057 discloses a solid, orally administrable pharmaceutical composition, comprising rivaroxaban in hydrophilized form. The rivaroxaban is provided as granules prepared by wet granulation with a granulating liquid.

US 2010/0151011 discloses rapid release solid pharmaceutical dosage form of rivaroxaban containing drug in amorphous form or thermodynamically metastable crystal modification form. Use of these modified forms increases the solubility and the oral bioavailability of rivaroxaban.

US 2011/0300214 discloses pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier.

US 2012/0231076 disclose process for producing a pharmaceutical composition of rivaroxaban. The process involves mixing rivaroxaban, a matrix former, and a disintegrant, melting the mixture, and granulating the melted mixture.

US 2013/0064888 discloses pharmaceutical dosage forms of rivaroxaban having a compressed inert core, an optional subcoat over the compressed inert core, a drug layer over the compressed core.

WO 2010/146179 discloses solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or dry granulation of the rivaroxaban with at least one excipient, co-milling rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient. The mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
The prior art describe various methods to enhance the dissolution and oral bioavailability of rivaroxaban but with many undesirable steps leads to disadvantages to overall formulation preparation. It is always desirable to formulate a simple formulation with simple process which will provide enhanced dissolution and bioavailability. It is the object of the invention is to provide an alternative pharmaceutical composition of rivaroxaban and its method of preparation which will enhance the dissolution and oral bioavailability of the drug.

Summary of invention
One embodiment of the invention relates to a pharmaceutical composition comprises rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant; wherein the rivaroxaban is co-micronized with the surfactant.

One embodiment of the invention relates to a pharmaceutical composition comprises is co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the rivaroxaban and surfactant is present in a molar ratio from about 0.1:1 to 1:0.1.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the surfactant is selected from the group consisting of sodium salts of fatty alcohol sulphates, sulphosuccinates, partial fatty acid esters of polyhydric alcohols, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene polypropylene glycol, fatty acid esters of sorbitan, a fatty acid esters of polyhydroxyethylene sorbitan, polyethylene glycol fatty acid esters, alkylene glycol fatty acid mono esters, hydrogenated castor oil and polyoxyethylene castor oil derivates, polyoxyethyleneglycerol oxystearate, sucrose fatty acid esters, vitamin E and its derivatives, phospholipids, glycerophospholipids, glyceroglycolipids, sphingophospholipids, sphingoglycolipids, docusate sodium, docusate calcium, docusate potassium, sodium dodecyl sulfate or sodium lauryl sulfate, dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof, ethoxylated triglycerides, quaternary ammonium salts, glycerol acetates, triethanolamine or mixtures thereof.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the surfactant is sodium lauryl sulfate.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the co-micronized rivaroxaban and surfactant mixture has a mean particle size less than 30μm, preferably less than 20um.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the composition comprises one or more of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule and a sachet.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, further comprises one or more pharmaceutically acceptable excipients.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the composition exhibits a dissolution profile such that at least 80% of rivaroxaban is released within 30 minutes; wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 900 ml of pH 4.5 acetate buffer + 0.5% sodium lauryl sulphate at 37± 0.5°C.

One embodiment of the invention relates a pharmaceutical composition comprises co-micronized rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant mixture, wherein the composition is prepared by a) co-micronizing rivaroxaban or a pharmaceutically acceptable salt thereof with one or more surfactant, b) mixing and granulating with other pharmaceutically acceptable excipients, and c) forming the mixture of step (b) into a pharmaceutical dosage form.

Detailed Description of the Invention

This invention relates to a pharmaceutical composition of rivaroxaban and the method of preparing the same. The pharmaceutical composition increases the dissolution and bioavailability of rivaroxaban. The composition of the invention can be administered to the patients who are in need of the drug for the treatment of reduction of risk of stroke, systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis or any other diseases known to be treated by rivaroxaban in the prior art.

In one embodiment, a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant; wherein the rivaroxaban is co-micronized with the surfactant.
The term "rivaroxaban" includes various forms of rivaroxaban such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Rivaroxaban can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "rivaroxaban" as used in the present invention.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The active ingredient, active agent and drug herein can be interchangeably used. As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

Surfactant otherwise called surface-active agents or solubilizing agents, help to solubilize the active agent either in composition or in-situ at the site of absorption or action. Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.

In the pharmaceutical composition of the invention, the rivaroxaban can be present in an amount relative to the surfactant, such that a molar ratio between the rivaroxaban and the surfactant is from about 0.1:1 to 1:0.1.

The co-micronization can be carried out by suitable means known in the art, which include but not limited to one or more of nano mill, ball mill, attritor mill, vibratory mill, sand mill, bead mill, jet mill, ultrasonication, and the like. A dry method of micronization is preferable.

The mean particle size of rivaroxaban and surfactant obtained after co-micronization may be less than 30um, preferably less than 20um, most preferably 15utn. In one of the embodiment of the invention relates to a pharmaceutical composition comprising co-micronized rivaroxaban and surfactant mixture, wherein the mean particle size of rivaroxaban and surfactant obtained after co-micronization is 0.1 to 10um.

Examples of suitable non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; alkyl polyglucosides; stearol ethoxylates; and alkyl polyglycosides.

Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.

More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.

Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Examples of suitable anionic surfactants include alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; and isethionate sulfonates.

Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; and sulfonxonium surfactants.
Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, and aminopropionic acid); imidazoline surfactants; amine oxides; and amidobetaines. Mixtures of surfactant may be used. In such mixtures there may be individual components which are liquid, provided that the carrier material overall, is a solid. The concentration of surface-active agent in the composition is from range of about 0.01 to about 20.0% by weight of the pharmaceutical composition, preferably about 0.1 to about 10%, more preferably of about 0.1 to about 5%.

Non limiting examples of surfactants are sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropylene glycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span® or Arlacel®, Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®60), polyoxyethylene (20) sorbitan monopalmitate (Tween®40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-l -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.

In another embodiment, a pharmaceutical composition comprising rivaroxaban and a non-ionic surfactant selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.

The pharmaceutical composition can be prepared by co-micronizing rivaroxaban and a surfactant, mixing, and granulating with other pharmaceutically acceptable excipients. The granules may be mixed with other suitable pharmaceutically acceptable excipients.

Suitable disintegrant can be used in the pharmaceutical composition can be selected from carboxymethylcellulose, crosslinked sodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), crosslinked polyvinylpolypyrrolidone (Plasone-XL®), microcrystalline cellulose, L-HPC (low- substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL® (International Specialty Products), magnesium aluminium silicate or mixtures thereof. Disintegrants are used to facilitate disintegration of the pellet upon administration and are typically present in an amount of about 1% to about 25%, with a preferred range of about 5% to about 10% by weight of the composition.

The suitable disintegrants for compositions of this invention are carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium available as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX, having a molecular weight of 90 000-700 000; crosslinked polyvinylpyrrolidones (PVP), e. g. crospovidones, e. g. Polyplasdone® XL and Kollidon® CL, in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns; modified starches especially sodium starch glycolate e.g. Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000-11000000. The most preferred disintegrant is Croscarmellose sodium. The composition according to the invention can comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.

The composition according to the invention can comprise diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.

The composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate. The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

Other excipients commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.

One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.

The pharmaceutical composition of the present invention can be present in the form of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule, a sachet and other dosage forms suitable for oral administration. Optionally, cores/tablets can be coated with conventional materials used for film coating, i.e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.

The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).

Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials form each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.
Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

A composition of coating suspension (calculated on dry material) is particularly preferred which comprises: 1-99% by weight of polymer, preferably 1- 95% of polymer; 1-50% by weight of plasticizer, preferably 1-40% of plasticizer; 0.1-20% of colourant/opacifier, preferably 0.1- 10% of colourant/opacifier, all the percentage are based on the total weight of coating material.

The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of rivaroxaban, the co-micronized rivaroxaban and surfactant mixture will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container.

The composition preparations of the invention can be produced by compressing a mixture of the drug substance which is co-micronized rivaroxaban and surfactant mixture of the invention with excipients. For example, one method for the production includes mixing the co-micronized rivaroxaban and surfactant mixture with the materials for the preparation by a suitable mixer, and directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders. Dry processing like direct compression and dry granulation are preferred method.

In another embodiment, the pharmaceutical composition is having dissolution profile of at least 80% of rivaroxaban is released within 30 minutes; wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 900 ml of pH 4.5 acetate buffer + 0.5% sodium lauryl sulphate at 37± 0.5°C.

The composition of the invention containing rivaroxaban is preferably administered 1 to 3 times a day in an amount of 0.8 to 100 mg/day. The exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.

The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein including treatment of reduction of risk of stroke, systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis or any other diseases known to be treated by rivaroxaban in the prior art.

In one embodiment, a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to the commercial form of rivaroxaban.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Example:

Procedure: Rivaroxaban and surfactant were mixed and co-micronized through a multimill. To the co-micronized mixture, Croscarmellose sodium, Hydroxypropylmethyl Cellulose, colloidal silicon dioxide and magnesium stearate were added, mixed and granulated using a roll compactor to obtain granules of a suitable size. Crospovidone and magnesium stearate were added to the granules and the resultant mixture was compressed into tablets using a suitable tooling.

We Claim:

1. A pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof and a surfactant; wherein the rivaroxaban is co-micronized with the surfactant.

2. The pharmaceutical composition of claim 1, wherein the rivaroxaban and surfactant is present in a molar ratio from about 0.1:1 to 1:0.1.

3. The pharmaceutical composition of claim 1, wherein the surfactant is selected from the group consisting of sodium salts of fatty alcohol sulphates, sulphosuccinates, partial fatty acid esters of polyhydric alcohols, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene polypropylene glycol, fatty acid esters of sorbitan, a fatty acid esters of polyhydroxyethylene sorbitan, polyethylene glycol fatty acid esters, alkylene glycol fatty acid mono esters, hydrogenated castor oil and polyoxyethylene castor oil derivates, polyoxyethyleneglycerol oxystearate, sucrose fatty acid esters, vitamin E and its derivatives, phospholipids, glycerophospholipids, glyceroglycolipids, sphingophospholipids, sphingoglycolipids, docusate sodium, docusate calcium, docusate potassium, sodium dodecyl sulfate or sodium lauryl sulfate, dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof, ethoxylated triglycerides, quaternary ammonium salts, glycerol acetates, triethanolamine or mixtures thereof.

4. The pharmaceutical composition of claim 1, wherein the surfactant is sodium lauryl sulfate.

5. The pharmaceutical composition of claim 1, wherein the co-micronized rivaroxaban and surfactant mixture has a mean particle size less than 30um.

6. The pharmaceutical composition of claim 1, wherein the co-micronized rivaroxaban and surfactant mixture has a mean particle size less than 20um.

7. The pharmaceutical composition of claim 1, wherein the composition comprises one or more of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule and a sachet.

8. The pharmaceutical composition of claim 1 further comprises one or more pharmaceutically acceptable excipients.

9. The composition of claim 1, wherein the composition exhibits a dissolution profile such that at least 80% of rivaroxaban is released within 30 minutes; wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 900 ml of pH 4.5 acetate buffer + 0.5% sodium lauryl sulphate at 37± 0.5°C.

10. The composition of claim 1, wherein the composition is prepared by a) co-micronizing rivaroxaban or a pharmaceutically acceptable salt thereof with one or more surfactant, b) mixing and granulating with other pharmaceutically acceptable excipients, and c) forming the mixture of step (b) into a pharmaceutical dosage form.