"ORAL 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, HOmg or 150mg strength.
Dabigatran etexilate mesylate, is chemically known as P-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. Where in 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.

WO 2015/145462 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. tartaric acid pellets is coated with coating dispersion (or) solution containing acacia
and anti-tacking agent in isopropanol and purified water;
b. seal coated pellets of step (a) is coated with coating dispersion (or) solution containing
one or more water soluble pharmaceutically acceptable polymers and anti-tacking
agent;
c. applying the active substance layer over the seal coated core of step (b), comprising
Dabigatran etexilate mesylate containing binder in an amount 10.03 % to 12.8 % by
total weight of (a), (b) and (c) in the composition, without using anti-tacking agent to
get drug load pellets; and
d. followed by top coating and lubrication.

The details of the present invention are given in the below description with other features and advantages.
DETAILED DESCRIPTION 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. tartaric acid pellets is coated with coating dispersion (or) solution containing acacia
and anti-tacking agent in isopropanol and purified water;
b. seal coated pellets of step (a) is coated with coating dispersion (or) solution containing
one or more water soluble pharmaceutically acceptable polymers and anti-tacking
agent;
c. applying the active substance layer over the seal coated core of step (b), comprising
Dabigatran etexilate mesylate containing binder in an amount 10.03 % to 12.8 % by
total weight of (a), (b) and (c) in the composition, without using anti-tacking agent to
get drug load pellets; and
d. followed by top coating and lubrication.
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, tartaric acid pellets is coated with coating dispersion (or) solution containing acacia and anti-tacking agent in isopropanol and purified water to get seal coated pellets
According to the embodiment of the present invention, the obtained coated pellets is again coating with dispersion (or) solution containing one or more water soluble pharmaceutically acceptable polymers and acceptable anti-tacking agent;
According to the embodiment of the present invention, applying the active substance layer over the above obtained seal coated core, comprising Dabigatran etexilate mesylate containing binder in an amount 10.03 % to 12.8 % by total weight of (a), (b) and (c) in the composition, without using anti-tacking agent to get drug load pellets.
According to the embodiment of the present invention, the pharmaceutical composition comprising the top coating on drug load pellets with coating dispersion (or) solution containing one or more water soluble pharmaceutically acceptable polymers and anti-tacking agent.
According to the embodiment of the present invention, the pharmaceutical composition comprising the lubrication of top coating drug loaded material comprising lubricant like talc and wetting agent like sodium lauryl sulphate.
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 active substance in the active substance layer is Dabigatran etexilate mesylate.
According to the embodiment of the present invention, the content of the binder in the Dabigatran etexilate mesylate layer is 10.03 % to 12.8 %, more preferably, 10.5 to 12.5 % by total weight of (a), (b) and (c) in the composition.

According to the embodiment of the present invention, the water soluble pharmaceutical^ acceptable polymer is selected from hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and the copolymers of N-vinylpyrrolidine, vinyl acetate or combinations thereof.
According to the embodiment of the present invention, the anti-tacking agent is talc.
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.
According to the embodiment of the present invention, the seal coating is applied over tartaric acid containing pellets with a dispersion (or) solution containing acacia and anti-tacking agent in isopropanol and purified water to get seal coated pellets.
According to the embodiment of the present invention, the again seal coating is applied over the obtained coated pellets with dispersion (or) solution containing one or more water soluble pharmaceutically acceptable polymers and anti-tacking agent.
According to the embodiment of the present invention, the above seal coated pellets coated with a dispersion containing the content of the binder in the Dabigatran etexilate mesylate layer is 10.03% to 12.8 %, more preferably, 10.5 to 12.5 % by total weight of (a), (b) and (c) in the composition, without using anti-tacking agent to get drug load pellets.
The drug load pellets are followed by coated with top coating and lubrication.
The suitable solvent for the dispersion include isopropyl alcohol, 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, binder is hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxymethylcellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
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, anti-tacking agent, 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, and mixtures thereof.
The addition of talc in drug layer coating formulations can result in sedimentation of the material during the spraying process, clogging of the spray nozzle, and incompatibilities with other materials in the coating.

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.

MANUFACTURING PROCESS:
2.1 Seal coating stage I:
1. Acacia powder is added to a mixture of isopropyl alcohol and purified water under
stirring to get clear solution. To this solution added talc powder and stir for 10 minutes.
2. The above seal coating solution (I) was sprayed over tartaric acid pellets in the Fluid
bed processor at inlet temperature of 50°C.
2.2 Seal coating stage II:
1. Hydroxy propyl methyl Cellulose is added to a mixture of isopropyl alcohol and dichloromethane under stirring to get a clear solution. To this solution added talc powder and stir for 10 minutes
2. The above seal coating solution (II) was sprayed on the seal coated (I) pellets in Fluid bed processor at inlet temperature of 50°C
2.3 Drug loading:
1. Hydroxy propyl cellulose is dissolved in isopropyl alcohol and then added Dabigatran Etexilate Mesylate under stirring to get a solution.
2. Drug loading solution is sprayed on the seal coated pellets (II) in fluid bed processor at inlet temperature of 40°C
2.4 Top coating:
1. Hydroxy propyl methyl cellulose E5 is dissolved in a mixture of isopropyl alcohol and dichloromethane under stirring to get a clear solution. To this solution added Talc powder and stir for 10 minutes
2. The above top coating solution was sprayed on the drug loaded pellets in fluid bed processor at inlet temperature of 40°C
2.5 Lubrication:

1. Sift talc and Sodium Lauryl Sulphate through ASTM #60 sieve and added to Top coated pellets in low shear blender, mix for 10 minutes
2.6 Capsule Filling:
Fill the Lubricated Pellets into the capsules of suitable size.
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

We Claim:
1. A pharmaceutical compositions comprising:
a. tartaric acid pellets is coated with coating dispersion (or) solution containing acacia
and anti-tacking agent in isopropanol and purified water;
b. seal coated pellets of step (a) is coated with coating dispersion (or) solution containing
one or more water soluble pharmaceutically acceptable polymers and anti-tacking
agent;
c. applying the active substance layer over the seal coated core of step (b), comprising
Dabigatran etexilate mesylate containing binder in an amount 10.03 % to 12.8 % by
total weight of (a), (b) and (c) in the composition, without using anti-tacking agent to
get drug load pellets; and
d. followed by top coating and lubrication.
2. The pharmaceutical composition as claimed in claim 1, wherein the amount of binder is 10.5% to 12.5%.
3. The pharmaceutical composition as claimed in claim 1, wherein the binder is hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxy ethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxymethylcellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
4. The pharmaceutical composition as claimed in claim 1, wherein the water soluble pharmaceutically acceptable polymer is hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxypropyl methylcellulose, Povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidine, vinyl acetate or combinations thereof.
5. The pharmaceutical composition as claimed in claim 1, wherein the content of tartaric acid is 25 to 70 %.

6. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of Capsules.
7. The pharmaceutical composition as claimed in claim 1, wherein the top coating on drug load pellets with coating dispersion (or) solution containing one or more water soluble pharmaceutically acceptable polymers and anti-tacking agent.
8. The pharmaceutical composition as claimed in claim 1, wherein the lubrication of top coating on drug loaded material comprising lubricant likes talc and wetting agent like sodium lauryl sulphate.
9. The pharmaceutical composition as claimed in claim 1 and 7, wherein the anti-tacking agent is talc.