"PHARMACEUTICAL COMPOSITION OF DABIGATRAN ETEXILATE MESYLATE"
FIELD OF THE INVENTION:
The present invention relates to an oral pharmaceutical composition comprising Dabigatran etexilate mesylate and relates to process for the preparation of this pharmaceutical composition and is particularly useful as a medicament especially as anticoagulant.
BACKGROUND OF THE INVENTION:
Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Both free and clot-bound thrombin and thrombin-induced platelet aggregation are inhibited by the active moieties. It is indicated as a primary prevention of venousthromboembolic events in adult patients who have undergone elective total hip replacement surgery or total kneereplacement surgery.
Dabigatran etexilate mesylate was first approved by European Medicine Agency (EMA) on Mar 18, 2008, and then approved by the U.S. Food and Drug Administration (FDA) on Oct 19, 2010. It was developed and marketed as Pradaxa® by Boehringer Ingelheim Pharmaceuticals, Inc in the U.S. Dabigatran etexilate mesylate is available as capsule for oral use, containing 75mg, 1 lOmg or 150mg strength.
Dabigatran etexilate mesylate, is chemically known as (3-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-l-methyl-lHbenzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester, methanesulfonate. The structural formula is:

US 6,087,380 disclose Dabigatran or a physiologically acceptable salt thereof, which discloses compounds with a thrombin inhibiting effect and the effect of prolonging the thrombin time.
WO 03/74056 discloses an oral formulation of Dabigatran etexilate, which purport to provide pH-independent bioavailability of the active agent. The formulations contain a pharmaceutically acceptable organic acid having a water solubility of more than 1 g/250 ml at 20°C. Wherein the active ingredient layer is applied on an organic acid core while spatially separating the organic acid and active ingredient by an insulating layer.
US 2005/0038077 disclose a matrix tablet comprising Dabigatran etexilate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable organic acids and a pharmaceutically acceptable excipient or filler. However due to the presence of an organic acid in close contact with the active in a tablet composition without any special steps taken to separate the two from each other, can make the active highly susceptible to hydrolysis in the presence of humidity.
WO 2011/107427 discloses an oral pharmaceutical composition comprising Dabigatran etexilate or a pharmaceutically acceptable salt thereof and an inorganic acidic excipient, wherein the inorganic acidic excipient has a pH value in a 1 % aqueous solution of <6 and optionally after further processing steps compressing the mixture to tablets or filling the mixture into capsules.
WO 2013/110567 discloses an oral pharmaceutical composition comprising Dabigatran pharmaceutically acceptable salt or combinations thereof and as excipient at least one water soluble cyclodextrin agent.
WO 2013/124340 discloses a Dabigatran etexilate mesylate composition comprising a mixture of at least two types of particles and optionally at least one pharmaceutically > acceptable excipient. wherein a) the first type of particles comprise the active agent; b) the second type of particles comprise at least one pharmaceutically acceptable organic acid; and c) optionally at least one type of particles are coated with a protective coating layer.

discloses a pharmaceutical composition comprising: a) a first component comprising Dabigatran or a pharmaceutical^ acceptable salt thereof and one or more pharmaceutical^ acceptable excipient; and b) a second component comprising an organic acid; wherein the first component is in the form of a tablet and wherein the composition is in the form of a capsule.
The above attempts only provided compositions of Dabigatran etexilate mesylate, which are either tedious or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Therefore its need exists to prepare alternate compositions of Dabigatran etexilate that are stable, easy or convenient to prepare, provide the desired in vitro release and bioavailability.
Hence in view of above, the present inventors has developed a composition which reduce peak plasma fluctuations and minimize potential side effects with improved drug bioavailability with reduce inter and intra patient variability.
SUMMARY OF THE INVENTION
In one aspect of the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:
a. core comprising tartaric acid is coated with one or more water soluble
pharmaceutically acceptable polymers and plasticizers,
b. applying the active substance layer over the core comprising Dabigatran
' etexilate mesylate containing binder in an amount 10.5 % to 12.5 % by weight
of the total composition.
The details of the present invention are given in the below description with other features and advantages.
DETAILEDDESCRIPTION OF THE INVENTION
; The present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:

a. core comprising tartaric acid is coated with one or more water soluble
pharmaceutically acceptable polymers and plasticizers,
b. applying the active substance layer over the core comprising Dabigatran
etexilate mesylate containing binder in an amount 10.5 % to 12.5 % by weight
of the total composition.
The term "composition" or "pharmaceutical composition" or "dosage form" 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; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term 'stable' refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits. Further, the term 'stable' also optionally refers to formulations that contain polymorphically stable active ingredient.
According to the embodiment of the present invention, the content of tartaric acid in the core
is 25% to 70 %, preferably 35% to 50%.
According to the embodiment of the present invention, the core is in the form of granule, pellet or mini-tablet. Preferably, pellet.
According to the embodiment of the present invention, the water soluble pharmaceutically acceptable polymer is selected from hydroxypropyl methylcellulose, Povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and the copolymers of N-vinylpyrrolidine, vinyl acetate or combinations thereof.
According to the embodiment of the present invention, the plasticizer is selected from polyethylene glycol 6000, triethylcitrate, diethyl citrate, tributyl citratepropyleneglycol; preferably polyethylene glycol 6000.

According to the embodiment of the present invention, the content of the binder in the Dabigatran etexilate mesylate layer is 10.5 % to 12.5%, more preferably, 12% by weight of the total composition.
The Dabigatran etexilate mesylate layer may contain suitable plasticizers and separating agents.
According to the embodiment of the present invention, the pharmaceutical composition comprising Dabigatran etexilate mesylate is coated with film coating, wherein the film coating comprises film-forming agents and plasticizers.
In an embodiment of the present invention, the pellets are prepared by the method described as below
The tartaric acid containing seal core consists either crystals of tartaric acid or roughly spherical particles of the desired size containing large amounts of tartaric acid, which can be produced by methods known and established in pharmaceutical technology. The core material may be produced by spray drying or extrusion/spheronization.
The above pellets are coated with a dispersion containing Dabigatran etexilate mesylate and 10.5% to 12.5%) binder by weight of pellets coated layer in fluidized bed or coating pan.
The Dabigatran etexilate mesylate applied pellets are optionally coated with film coating.
Suitable solvent for the dispersion include isopropyl alcohol, acetone, ethanol, or dichloromethane or mixtures thereof.
The film coated pellets are filled into capsules. Capsules can be of any suitable size include #00, #0,#0el, #l,#lel, #2, #2el, #3 and #4.
The pharmaceutical composition is in the form of capsule. Capsules considered are soft gelatin, hard gelatin, polyethylene glycol, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, color, and water content. Preferably, hard gelatin capsules.

Diluent includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof.
Binders includes, but are not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose E3 LV, carbomers, Povidone, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate and the like.
Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
Lubricant includes, but are not limited to, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.
Plasticizers includes, but are not limited to propylene glycol, polyethylene glycol 6000, triethyl citrate, tributyl citrate, acetyl triethyl citrate, triacetin, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof.
Separating agent includes, but are not limited to talc, silicic acid. Preferably, talc.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Manufacturine process:
Seal coating:
1. Polyethylene 6000 is added to a mixture of isopropyl alcohol and dichloromethane under stirring to get a clear solution. To this solution added hydroxypropyl methyl cellulose.
2. Seal coating solution was sprayed on the tartaric acid pellets in fluid bed processor.

Drug loading:
3. Hydroxypropylmethyl cellulose E3 LV premium was dissolved in a mixture of isopropyl alcohol and dichloromethane under stirring to get clear solution
4. To this solution added Polyethylene 6000 and Dabigatran Etexilate Mesylate under stirred condition
5. Drug loading solution was sprayed on the seal coated pellets in fluid bed processor.
Lubrication:
6. Sodium Lauryl Sulphate and Talc were sifted through ASTM #60 sieve and added to
drug loaded pellets in low shear blender, blended.
Capsule Filling:
7. Lubricated Pellets were filled into the capsules
The dissolution performance for the composition was measured using a USP-1 rotating basket apparatus. Release times were measured by placing the capsule in a small wire basket with modified diameter of 24.5 mmplaced on the end of a rod spinning at 100 rpm. In dissolution media pH 2.0, aliquots were withdrawn from dissolution media up to 1 hour followed by subsequently analysis
Dissolution performance for the composition of Example 1.

We Claim:
1. A pharmaceutical compositions comprising:
a. core comprising tartaric acid is coated with one or more water soluble
pharmaceutically acceptable polymers and plasticizers,
b. applying the active substance layer over the core comprising Dabigatran etexilate
mesylate containing binder in an amount 10.5 % to 12.5 % by weight of the total
composition.
2. The pharmaceutical composition as claimed in claim 1, wherein the amount of binder is 11 %to 12%.
3. The pharmaceutical composition as claimed in claim 1, wherein the binder is hydroxypropyl methylcellulose E3 LV, hydroxyethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxym ethyl cellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
4. The pharmaceutical composition as claimed in claim 1, wherein the plasticizer is polyethylene glycol 6000, tri ethyl citrate, diethyl citrate, tributyl citratepropyleneglycol; preferably polyethylene glycol 6000.
5. The pharmaceutical composition as claimed in claim 1, wherein the water soluble pharmaceutically acceptable polymer is hydroxypropyl methylcellulose, Povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, the copolymers of N-vinylpyrrolidine, vinyl acetate or combinations thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein the content of tartaric
acid is 25 to 70 %.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of Capsules.