Field of the invention

The present invention relates to a capsule 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 and at least one organic acid or at least one inorganic acid wherein the capsule has two compartments which are separated from each other by a layer.

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 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 the 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, an 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 an organic acid.

There is still a need to prepare formulations of dabigatran etexilate that are stable, cost- effective, easy to prepare, provide the desired in vitro release, improved dissolution profile and bioavailability. We have found an easy way to separate the organic acid or the inorganic acid formulation from the dabigatran etexilate formulation by using a capsule which has two compartment. It also provides good stability and improvement in dissolution profile.

Detailed Description of the Invention

The main object of the present invention is to provide capsule formulations comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid in a unit dosage form having good stability and effective dissolution profile.

Another object of the present invention is to obtain a stable dabigatran etexilate formulation with high bioavailability.

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

The present invention provides a stable combination despite the incompatibilities of two component, dabigatran etexilate and organic/inorganic acid, in a single dosage unit. In one embodiment, a capsule formulation comprises a dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid, wherein the capsule has two compartments. The two compartments are separated from each other by a layer.

In one embodiment of the present invention, the capsule comprises two formulations ;a formulation in one of compartments comprising the active agent and at least one pharmaceutically acceptable excipients is called the first formulation, a formulation in the other of compartments comprising at least one organic acid or at least one inorganic acid, and at least one pharmaceutically acceptable excipient is called the second formulation.

According to this embodiment of the present invention, the capsule comprises two formulations;

-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 and at least one pharmaceutically acceptable excipient

-the second formulation comprises at least one organic acid or at least one inorganic acid, and at least one pharmaceutically acceptable excipient.

According to one embodiment of the present invention, the first formulation is present in one compartment, the second formulation is present in another compartment.

According to one embodiment of the present invention, the amount of dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof in first formulation is between 5.0% and 80.0% or between 5.0% and 50.0% or between 5.0% and 30.0%, or between 10.0% and 80.0 or between 20.0% and 80.0 or between 30.0% and 80.0 or between 40.0% and 80.0 by weight.

According to one embodiment of the present invention, said organic acid or inorganic acid is in the form of pellets or granule or minitablet.

Suitable organic acid 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, citric acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.

According to one embodiment of the present invention, the organic acid is citric acid or tartaric acid or mixtures thereof.

Suitable inorganic acid is selected from the group comprising hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, hydroiodic acid, sulfurous acid, hyposulfurous acid, pyrosulfuric acid, dithionous acid, thiosulfurous acid, peroxydisulfuric acid, or mixtures thereof.

In one embodiment, optionally, the organic acid pellets or inorganic acid pellets are coated with an isolation solution.

Preparation isolation solution:

Formula 1 :

HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.

Formula 2:

HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.

Formula 3:

HPMC is added to purified water and mixed in homogenizer. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenizer.

According to one embodiment of the present invention, the amount of organic acid pellets or inorganic acid pellets in second formulation is between 30.0% and 55.0% or between 30.0% and 50.0% or between 35.0% and 55.0% or between 40.0% and 55.0% by weight.

According to this embodiment of the invention, the weight ratio of dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof in first formulation to organic acid pellets or inorganic acid pellets in second formulation is 0.01 -2.0. This ratio provides improved dissolution profile in the capsule.

According to one embodiment of the present invention, formulations in the two compartments are in the form of mini tablets or pellets or granules. 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.

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 "granules" as used herein refers to agglomerates of particles.

According to one embodiment of the present invention, the first formulation is in the form of mini tablets or pellets or granules, the second formulation is in the form of mini tablets or pellets or granules.

The forms of the two formulations in a capsule may be as follows;

- The first formulation is in the form of mini tablet, the second formulation is in the form of mini tablet.

- The first formulation is in the form of pellet, the second formulation is in the form of mini tablet.

- The first formulation is in the form of granule, the second formulation is in the form of mini tablet.

- The first formulation is in the form of mini tablet, the second formulation is in the form of pellet.

- The first formulation is in the form of pellet, the second formulation is in the form of pellet.

- The first formulation is in the form of granule, the second formulation is in the form of pellet.

- The first formulation is in the form of mini tablet, the second formulation is in the form of granule.

- The first formulation is in the form of pellet, the second formulation is in the form of granule.

- The first formulation is in the form of granule, the second formulation is in the form of granule. In one embodiment, the first formulation and the second formulation comprise at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, binders, lubricants, glidants, coating agents, solvents or mixtures thereof.

Suitable fillers are selected from the group comprising microcrystalline cellulose, microcrystalline cellulose pellet, lactose monohydrate, starch, sucrose, glucose, dextrose, maltodexrin, natural and synthetic gums, gelatin, pregelatinized starch or mixtures thereof.

According to one embodiment of the present invention, the amount of filler in a formulation is between 5.0% and 50.0% by weight, preferably between 10.0% and 20.0% or between 25.0% and 45.0% by weight.

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

Suitable disintegrants are selected from the group comprising croscarmellose sodium, cross- linked polyvinilpyrrolidone (crospovidone), povidone, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.

According to one embodiment of the present invention, the amount of disintegrant in a formulation is between 0.5% and 15.0% by weight, preferably between 0.5% and 10.0% or between 6.0% and 12.0% by weight.

According to one embodiment of the present invention, the disintegrant is croscarmellose sodium.

Suitable binders are selected from the group comprising hydroxypropyl methyl cellulose, polyvinylpyrrolidone, pullulan, glyceryl behenate, polycarbophil, cellulose acetate phthalate, hydroxypropyl starch, tragacanth gum, cetostearyl alcohol, polyethylene glycol, polyvinyl alcohol, sucrose, sodium alginate, cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

According to one embodiment of the present invention, the amount of binder in a formulation is between 0.1% and 30.0% by weight, preferably between 6.0% and 10.0% or between 0.1% and 5.0% by weight.

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

Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, 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 are selected from the group comprising colloidal silicon dioxide, talc, aluminium silicate, silica or mixtures thereof.

According to one embodiment of the present invention, the glidant is colloidal silicon dioxide or talc or mixtures thereof.

The coating agent is formed of a water soluble polymeric pharmaceutically acceptable agent. Suitable coating agent is selected from the group comprising hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and derivatives, ethylcellulose and ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), methyl cellulose (MC), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-b-propylene oxide), polyoxyethylene (POE), poly vinyl pyrrolidone (PVP), polyethylenimine (PEI), poly(N-vinylpyrrolidone/vinyl acetate), polyvinylpyrollidone PVP K-90, polyacrylic acid and copolymers, poly(vinylamine) hydrochloride, poly(acrylic acid sodium salt), poly(methacrylic acid), poly(methylacrylic acid sodium salt), poly(ethylene/acrylic acid), poly(2-hydroxyethyl methacrylate/methacrylic acid), poly(2-hydroxypropyl methacrylate), polyacrylamides (PAM), poly(acrylamide/acrylic acid), polymethacrylamide, poly(N- isopropylacrylamide) (PNIPAM), poly(styrenesulfonic acid) sodium salt, poly(2-oxazoline), poly (2-ethyl-2-oxazoline), poly (3-chloro-2-hydroxypropyl- 2-methacryl-oxyethyl- dimethyl, 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, poly(4-vinylpyridine N-oxide), poly(4-vinylpyridine), poly(styrenesulfonic acid/maleic acid) sodium salt, poly(N-vinyl acetamide), poly(N-vinyl acetamide-co-sodium acrylate), poly(vinylsulfonic acid) sodium salt, polyelectrolytes; agar, alginates, casein and caseinates, carrageenan, chitosan, cucurbit[n]uril hydrate, curdlan, dextran, gelatin, gellan gum, guar gum and derivatives, gum carrageenan, gum arabic and other tree and shrub exudates, locust bean gum, maltodextrins, methocel, pectin, pullulan, resin, sodium alginate, starch and starch derivatives, xanthan gum or mixture thereof.

Suitable solvents are selected from the group comprising water, propanol, 1 -butanol, 2- butanol, ethyl acetate, ethyl ether, heptane, pentane, 1 -pentanol, 1 -propanol, 2-propanol, methylene chloride, acetone, ethanol, dichloromethane, n-hexane, dioxane or mixtures thereof.

According to one embodiment of the present invention, the first formulation is in the form of mini tablet. 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, croscarmellose sodium, hydroxypropyl methyl cellulose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate. Optionally, the mini tablet is coated with a coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

According to one embodiment of the present invention, the first formulation is in the form of pellets. 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, microcrystalline cellulose pellet, talc, 2-propanol, water and coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

According to one embodiment of the present invention, the second formulation is in the form of mini tablet. The second formulation comprises organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose, colloidal silicon dioxide and magnesium stearate. The mini tablet is coated with a coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent. Example 1 : The first formulation comprising dabigatran etexilate is in the form of mini tablet and the second formulation comprising organic acid or inorganic acid is in the form of mini tablet

Optionally, the mini tablet comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof is coated with a coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent. The total amount of a water soluble polymeric pharmaceutically acceptable agent is between 1 .0% - 5.0% by weight of the total of first formulation.

For first formulation, dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50°C and sieved. The colloidal silicon dioxide is sieved by sieving and added to the dried granules and stirred. Magnesium stearate is added to the dried granules and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets. For second formulation, the production method of the second formulation is dry granulation; organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and a half of the colloidal silicon dioxide and a half of magnesium stearate are mixed for 10 min. The mixed powder is passed through the compactor or the slug-briquette is pressed. Powder passed through the compactor or tablets made of briquettes are broken and sieved. The other half of the magnesium stearate and the other half of the colloidal silicon dioxide are added to this mixture. Mix for 5 minutes and then minitablets are pressed. The minitablets obtained are coated with coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

Then, the first formulation and second formulation fill into a capsule. Example 2: The first formulation comprising dabigatran etexilate is in the form of mini tablet and the second formulation comprising organic acid or inorganic acid is in the form of mini tablet

For first formulation, dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50°C and sieved. The colloidal silicon dioxide is sieved by sieving and added to the dried granules and stirred. Magnesium stearate is added to the dried granules and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.

For second formulation, the production method of the second formulation is dry granulation; organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and a half of the colloidal silicon dioxide and a half of magnesium stearate are mixed for 10 min. The mixed powder is passed through the compactor or the slug-briquette is pressed. Powder passed through the compactor or tablets made of briquettes are broken and sieved. The other half of the magnesium stearate and the other half of the colloidal silicon dioxide are added to this mixture. Mix for 5 minutes and then minitablets are pressed. The minitablets obtained are coated with coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

Then, the first formulation and second formulation fill into a capsule.

Example 3: The first formulation comprising dabigatran etexilate is in the form of mini tablet and the second formulation comprising organic acid or inorganic acid is in the form of mini tablet

For first formulation, dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50°C and sieved. The colloidal silicon dioxide is sieved by sieving and added to the dried granules and stirred. Magnesium stearate is added to the dried granules and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets. The mini tablet comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof is coated with a coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

For second formulation, the production method of the second formulation is dry granulation; organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and a half of the colloidal silicon dioxide and a half of magnesium stearate are mixed for 10 min. The mixed powder is passed through the compactor or the slug-briquette is pressed. Powder passed through the compactor or tablets made of briquettes are broken and sieved. The other half of the magnesium stearate and the other half of the colloidal silicon dioxide are added to this mixture. Mix for 5 minutes and then minitablets are pressed. The minitablets obtained are coated with coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

Then, the first formulation and second formulation fill into a capsule.

Example 4: The first formulation comprising dabigatran etexilate is in the form of pellet and the second formulation comprising organic acid or inorganic acid is in the form of mini tablet

q.s.: quantity sufficient For first formulation,

-Coating microcrystalline cellulose pellets with active agent suspension (dabigatran suspension)

a. Preparation of dabigatran suspension

Solving coating agent in 2-propanol or 2-propanol-water mixture.

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 talc to the mixture to form dabigatran suspension.

b. Coating microcrystalline cellulose pellets with the dabigatran suspension.

For second formulation, the production method of the second formulation is dry granulation; organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and a half of the colloidal silicon dioxide and a half of magnesium stearate are mixed for 10 min. The mixed powder is passed through the compactor or the slug-briquette is pressed. Powder passed through the compactor or tablets made of briquettes are broken and sieved. The other half of the magnesium stearate and the other half of the colloidal silicon dioxide are added to this mixture. Mix for 5 minutes and then minitablets are pressed. The minitablets obtained are coated with coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent. Then, the first formulation and second formulation fill into a capsule.

Example 5: The first formulation comprising dabigatran etexilate is in the form of granule processed with wet granulation and the second formulation comprising organic acid or inorganic acid is in the form of mini tablet

For first formulation, dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50°C. The colloidal silicon dioxide is sieved by sieving and added to the dried granules and stirred. Magnesium stearate is added and mixed 1 -2 more minutes.

For second formulation, the production method of the second formulation is dry granulation; organic acid pellets or inorganic acid pellets, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and a half of the colloidal silicon dioxide and a half of magnesium stearate are mixed for 10 min. The mixed powder is passed through the compactor or the slug-briquette is pressed. Powder passed through the compactor or tablets made of briquettes are broken and sieved. The other half of the magnesium stearate and the other half of the colloidal silicon dioxide are added to this mixture. Mix for 5 minutes and then minitablets are pressed. The minitablets obtained are coated with coating agent which is formed of a water soluble polymeric pharmaceutically acceptable agent.

Then, the first formulation and second formulation fill into a capsule.