DESCRIPTION

Field of the Invention

The present invention relates to a capsule-in-capsule composition comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof characterized in that one of the capsules is filled with a liquid formulation.

Background of the Invention

Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. Dabigatran was first disclosed in WO98/37075, which claimed compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the name 1 -methyl-2-[N-[4-(N-n- hexyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-ylcarboxylic acid-N-(2- pyridyl)-N-(2 ethoxycarbonylethyl)amides.

Dabigatran etexilate, a novel direct thrombin inhibitor, is a prodrug of dabigatran and is a non-peptide thrombin inhibitor. The structural formula is:

Formula 1 : Dabigatran etexilate

Dabigatran is currently available as dabigatran etexilate mesylate, under the trade name Pradaxa from Boehringer Ingelheim is used for the reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

The solubility of dabigatran etexilate mesylate in water is 1.8 mg/mL and dependent on the pH value. To increase the solubility of dabigatran etexilate, EP1658056B1 suggests a tablet formulation containing dabigatran etexilate and an organic acid with a solubility in water of > 1 g / 250 ml at 20°C.

Dabigatran etexilate is also less stable in acidic environment. To avoid stability problem, many solutions were offered in the prior art. EP2740471 B1 discloses a pharmaceutical composition contains the following main components: a core material comprising an inorganic acid layer, an active substance layer and an insulating layer between inorganic acid layer and active substance layer. EP2588090A2 discloses a process for the preparation of an oral dosage comprising a spherical core coated with tartaric acid, a isolating layer on the coated tartaric acid layer and a layer comprising dabigatran etexilate on the isolating layer. WO2015145462A1 discloses a pharmaceutical composition comprising a first component in the form of tablet comprising dabigatran and a second component in the form of capsule comprising organic acid.

There is still a need to prepare alternate compositions of dabigatran etexilate that are desired stability and improved dissolution profile. We have found an easy way to provide the desired stability at a composition comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof. Thus, it also provides improvement in dissolution profile.

Detailed Description of the Invention

The main object of the present invention is to provide a capsule-in-capsule composition comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof which one of the capsules is filled with a liquid formulation. Thereof, capsule-in-capsule comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof provides desired stability and effective dissolution profile.

Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.

As used here in, ‘capsule-in-capsule’ means a form is comprising a first capsule and a second capsule which is located within the first capsule.

According to one embodiment of the present invention, a capsule-in-capsule composition comprises ; a) First capsule has first formulation which comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or a liquid formulation. b) Second capsule has second formulation which comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or a liquid formulation.

In one embodiment, a capsule-in-capsule form comprises a first capsule and a second capsule which is located within the first capsule, wherein the first capsule comprising a first formulation held between the first and second capsule and comprising a second formulation held in the second capsule, and wherein the first formulation or the second formulation comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or a liquid formulation.

According to one embodiment of the present invention, dabigatran etexilate in the form of the free base is used.

According to one embodiment of the present invention, the first formulation comprises dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, the second formulation comprises a liquid formulation.

According to one embodiment of the present invention, the first formulation comprises a liquid formulation, the second formulation comprises dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof.

According to one embodiment of the present invention, the composition provides stability in a single dosage unit. Especially, using LFHC technology (liquid filled hard capsule) in liquid formulation has surprisingly provided the stability of the composition. To prepare a capsule with LFFIC at capsule-in-capsule form is very proper especially when considering the features of dabigatran and this method eliminates both incompatibility and stability problems encountered in the prior art.

According to one embodiment of the present invention, a liquid formulation comprises solubility enhancing agents. Suitable solubility enhancing agent is selected from the group comprising polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), glycerin, propylene glycol, ethanol, gelucire, cremophor (EL, RH 40, RH 60), isostearyl diglyceryl succinate (Imvitor) (191 , 308, 742, 780 K, 928, 988), transesterified ethoxylated vegetable oil (labrafil), lauroglycol, polaxamer, polyethylene glycol sorbitan, sodium lauryl sulfate or mixtures thereof.

According to one embodiment of the present invention, the solubility enhancing agent is polyethylene glycol (PEG).

According to one embodiment of the present invention, the solubility enhancing agent is polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate or mixtures thereof.

According to one embodiment of the present invention, the first formulation or second formulation is comprising in the form of mini tablets or granules or pellets or powder or beads or liquid or mixtures thereof.

According to one embodiment of the present invention, the first formulation is comprising in the form of mini tablets or granules or pellets or powder or beads or mixtures thereof.

The term “pellets” refers to small particles with approximately uniform shapes and sizes produced by an extrusion process. A “small particle” refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).

The term “mini tablet”, as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm. The mini tablets have round shape and smooth surface to ease coating process.

In one embodiment, the first formulation or the second formulation further comprises at least one pharmaceutically acceptable excipient selected from fillers, disintegrants, binders, anti caking agents, lubricants, glidants, coating agents, solvents or mixtures thereof. Preferably, only the first formulation further comprises at least one pharmaceutically acceptable excipient selected from fillers, disintegrants, binders, anti-caking agents, lubricants, glidants, coating agents, solvents or mixtures thereof. Suitable fillers is selected from the group comprising microcrystalline cellulose, microcrystalline cellulose pellet, mannitol, spray-dried mannitol, lactose, 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.

According to one embodiment of the present invention, the filler is microcrystalline cellulose or microcrystalline cellulose pellet or mixtures thereof.

According to one embodiment of the present invention, the amount of fillers is between 5.0% and 50.0% by weight of the first formulation.

According to one embodiment of the present invention, the amount of fillers is between 5.0% and 25.0%, between 10.0% and 50.0%, between 15.0% and 50.0%, between 10.0% and 40.0% by weight of the first formulation.

Suitable disintegrant is selected from the group comprising cross-linked carboxymethyl cellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), povidone, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, polyacrylate potassium, sodium alginate, sodium starch glycolate, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodecyl sulphate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.

According to one embodiment of the present invention, the disintegrant is cross-linked carboxymethyl cellulose (croscarmellose sodium).

According to one embodiment of the present invention, the amount of disintegrant is between 1 .0% and 15.0%, between 5.0% and 15.0% by weight of the first formulation.

Suitable binder is selected from the group comprising hydroxypropyl methyl cellulose, glyceryl behenate, polycarbophil, polyvinyl acetate and its copolymers, cellulose acetate phthalate, hydroxypropyl starch, cetostearyl alcohol, acacia mucilage, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, sodium alginate, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carrageenan, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

According to one embodiment of the present invention, the binder is hydroxypropyl methyl cellulose.

According to one embodiment of the present invention, the amount of binders is between 5.0% and 30.0% by weight of the first formulation.

According to one embodiment of the present invention, the amount of binders is between 5.0% and 15.0%, between 10.0% and 30.0% by weight of the first formulation.

Suitable anti-caking agent is selected from the group comprising talc, calcium phosphate, tribasic, calcium silicate, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate or mixtures thereof.

According to one embodiment of the present invention, anti-caking agent is talc.

According to one embodiment of the present invention, the amount of anti-caking agent is between 2.0% and 30.0% by weight of the first formulation.

Suitable lubricants is selected from the group comprising magnesium stearate, calcium stearate, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, glyceryl palmito stearate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.

According to one embodiment of the present invention, the lubricant is magnesium stearate.

Suitable glidants is selected from the group comprising colloidal silicon dioxide, aluminium silicate, silica or mixtures thereof.

According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.

Suitable solvents is selected from the group comprising 2-propanol, water, ethyl alcohol or mixtures thereof.

According to an embodiment of the present invention, the capsule-in-capsule comprises at least one coating agent which having water-soluble polymer.

Suitable water-soluble polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and derivatives, ethylcellulose and ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), methyl cellulose (MC), polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyethylene oxide-b-propylene oxide), polyoxyethylene (POE), polyethylenimine (PEI), poly(N-vinylpyrrolidone/vinyl acetate), polyvinylpyrollidone PVP K-90, poly(vinylamine) hydrochloride, poly(2-hydroxypropyl methacrylate), polyacrylamides (PAM), polymethacrylamide, poly(N-isopropylacrylamide) (PNIPAM), poly(2-oxazoline), poly(2-ethyl-2-oxazoline), poly (3-chloro-2-hydroxypropyl-2- methacryloxyethyldimethyl-ammonium chloride), poly(2-vinyl-1-methylpyridinium bromide), poly(2-vinylpyridine), polyamines, poly(2-vinylpyridine N-oxide), poly(N-vinylpyrrolidone/2- dimethylaminoethyl methacrylate) dimethyl sulfate quaternary, sodium alginate, starch or mixture thereof.

According to an embodiment of the present invention, the water-soluble polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC) or mixtures thereof.

Dabigatran etexilate is able to maintain its stability against heat and light under hardened conditions, while moisture is degraded. In order to protect the dabigatran etexylate in a capsule from the moisture of the other capsule, the second capsule can be coated with at least one coating comprising water-soluble polymer. The weight of at least one coating is between 1.0% and 20.0% or between 5.0% and 20.0% in the composition. It is used in such a small proportion provides an advantage in terms of stability without causing any delay in resolution.

According to one embodiment of the present invention, the capsule-in capsule composition is free of an organic acid and inorganic acid.

In this application, the term ‘organic acid or inorganic acid’ refers to the following excipients which is selected from the group comprising citric acid, tartaric acid, gallic acid, orotic acid, p- coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid, adipic acid.

The pharmaceutical combination of the present invention is prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation. Example 1 : First formulation is in the form mini tablet, second formulation comprising a liquid formulation

Example 2: First formulation is in the form mini tablet, second formulation comprising a liquid formulation A process for example 1 or 2;

For first capsule, a) Mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose and croscarmellose sodium, b) Granulating with water, c) Drying and sieving, d) Adding colloidal Silicon dioxide, then mixing, e) Adding magnesium stearate, then mixing, f) Pressing to form mini-tablet, g) Filling the mini-tablets into first capsule.

For the second capsule, h) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, i) Filling the liquid mixture into the second capsule

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.

Example 3: First formulation is in the form pellet, second formulation comprising a liquid formulation q.s.: quantity sufficient Example 4: First formulation is in the form pellet, second formulation comprising a liquid formulation q.s.: quantity sufficient

A process for example 3 or 4;

For first capsule, a) Dissolving at least one coating agent in 2-propanol-water and then mixing, b) Adding dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and then, adding talc and obtained a suspension c) Coating microcrystalline cellulose pellets with the suspension on step b), d) Filling the pellets into first capsule.

For the second capsule, e) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, f) Filling the liquid mixture into the second capsule

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.

Example 5: First formulation is in the form granule, second formulation comprising a liquid formulation Example 6: First formulation is in the form granule, second formulation comprising a liquid formulation

A process for example 5 or 6;

For first capsule, a) Mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium, b) Granulating the mixture with water, c) Drying and sieving, d) Adding magnesium stearate, then mixing, e) Filling the mixture into first capsule.

For the second capsule, f) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, g) Filling the liquid mixture into the second capsule

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.

Example 7: First formulation comprising a liquid formulation, second formulation is in the form mini tablet Example 8: First formulation comprising a liquid formulation, second formulation is in the form mini tablet

A process for example 7 or 8;

For the first capsule, a) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, b) Filling the liquid mixture into the second capsule

For second capsule, c) Mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose and croscarmellose sodium, d) Granulating with water, e) Drying and sieving, f) Adding colloidal Silicon dioxide, then mixing, g) Adding magnesium stearate, then mixing, h) Pressing to form mini-tablet, i) Filling the mini-tablets into second capsule.

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.

Example 9: First formulation comprising a liquid formulation, second formulation is in the form pellet Example 10: First formulation comprising a liquid formulation, second formulation is in the form pellet

A process for example 9 or 10; For the first capsule, a) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, b) Filling the liquid mixture into the second capsule For second capsule, c) Dissolving at least one coating agent in 2-propanol-water and then mixing, d) Adding dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and then, adding talc and obtained a suspension e) Coating microcrystalline cellulose pellets with the suspension on step b), f) Filling the pellets into second capsule.

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.

Example 11 : First formulation comprising a liquid formulation, second formulation is in the form granule Example 12: First formulation comprising a liquid formulation, second formulation is in the form granule

A process for example 11 or 12;

For the first capsule, a) Mixing PEG, polyvinylpyrrolidone and sodium lauryl sulfate, b) Filling the liquid mixture into the second capsule

For second capsule, c) Mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium, d) Granulating the mixture with water, e) Drying and sieving, f) Adding magnesium stearate, then mixing, g) Filling the mixture into second capsule.

Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.