Claims:1. A pharmaceutical composition comprising:
a) i) core comprising tartaric acid
b) isolating layer coated over the core
c) active substance layer over the core comprising dabigatran etexilate or its pharmaceutical acceptable salts thereof and binder in an amount 13% to 40% by weight of the active substance layer.
2. The pharmaceutical composition according to claim 1, wherein the amount of binder is 20% to 30%.
3. The pharmaceutical composition according to claim 1, wherein the binder is gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate or combinations thereof.
4. The pharmaceutical composition according to claim 1, wherein the isolating layer comprising water soluble polymer.
5. The pharmaceutical composition according to claim 3, wherein the water-soluble polymer is gum arabic, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof.
6. The pharmaceutical composition according to claim 3, wherein the water-soluble polymer is gum arabic.
7. The pharmaceutical composition according to claim 1, wherein the content of dabigatran etexilate or its pharmaceutically acceptable salts thereof in the pharmaceutical composition is 5 to 60%.
8. The pharmaceutical composition according to claim 1, wherein the content of tartaric acid is 20 to 90%.
9. The pharmaceutical composition according to claim 1, wherein the active substance is dabigatran etexilate mesylate.
10. The pharmaceutical composition according to claim 1, wherein the composition is in the form of Capsules.
, Description:FIELD OF THE INVENTION
The invention relates to oral pharmaceutical compositions of dabigatran or a pharmaceutically acceptable salt thereof and process for the preparation of such compositions.

BACKGROUND OF THE INVENTION
Dabigatran etexilate mesylate, is chemically known as ß-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The structural formula is:

Dabigatran etexilate mesylate

Dabigatran etexilate is already known from PCT Publication No. WO 1998/37075, which discloses compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time.

Dabigatran is commercially available as immediate release oral capsules under the brand name Pradaxa® from Boehringer Ingelheim. Pradaxa capsules are supplied in 75, 110 and 150 mg strength. Each capsule contains dabigatran etexilate mesylate as the active ingredient: 172.95 mg dabigatran etexilate mesylate (equivalent to 150 mg dabigatran etexilate), 126.83 mg dabigatran etexilate mesylate (equivalent to 110 mg dabigatran etexilate), or 86.48 mg dabigatran etexilate mesylate (equivalent to 75 mg dabigatran etexilate).

Dabigatran etexilate mesylate is BCS class II drug having low aqueous solubility and high membrane permeability. The solubility of Dabigatran etexilate mesylate is pH dependent with high solubility in acidic media. The solubility in water is 1.8 mg/mL.
The pH dependent solubility of dabigatran etexilate mesylate leads to variations in bioavailability.

US Patent Application Nos. 20030181488 discloses a pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable organic acids with a solubility in water of >1g/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 Patent Application Nos. 2005038077 discloses a pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable organic acids with a solubility in water of >1g/250 mL at 20°C. 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.

PCT Publication No. WO 2011/107427 discloses an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and an inorganic acidic excipient. The composition as described comprises mixing dabigatran with the inorganic acidic excipient and optionally compressing the mixture to tablets or filling the mixture into capsules.

PCT Publication No. WO 2013/110567 discloses an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and at least one water soluble cyclodextrin agent as an excipient.

PCT Publication No. WO 2013/124340 discloses dabigatran etexilate compositions 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.

PCT Publication No. WO 2015/145462 discloses a pharmaceutical composition comprising: a) a first component comprising dabigatran or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; 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.

There exists a need to prepare alternate dabigatran etexilate compositions that are stable, easy or convenient to prepare and provide the desired bioavailability.

We herein after provide alternate pharmaceutical compositions comprising:
a) core comprising tartaric acid
b) isolating layer
c) active substance layer comprising dabigatran etexilate or its pharmaceutical acceptable salts thereof and binder in an amount 13 to 40% by the weight of the active substance layer.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition comprising:
a) core comprising tartaric acid
b) isolating layer coated over the core
c) active substance layer over the core comprising dabigatran etexilate or its pharmaceutical acceptable salts thereof and binder in an amount 13% to 40% by weight of the active substance layer.

Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include diluents, binders, disintegrants, surfactants, lubricants, glidants, plasticizers, anti-foaming agents, anti-tacking agents, opacifying agents, and the like.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The invention provides a pharmaceutical composition comprising:
a) core comprising tartaric acid
b) isolating layer coated over the core
c) active substance layer over the core comprising dabigatran etexilate or its pharmaceutical acceptable salts thereof and binder in an amount 13% to 40% by weight of the active substance layer.

In one embodiment, the content of tartaric acid in the core is 20% to 100%, preferably 30% to 95%.

In another embodiment, the tartaric acid containing core contains upto 10% by weight of suitable binder. Preferably, 2% to 8%.

In another embodiment, the core is in the form of granule, pellet or mini-tablet. Preferably, pellet.

In another embodiment, the isolating layer comprises pharmaceutically acceptable water soluble polymer.

The water soluble polymer is selected from gum arabic, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof. Preferably, gum arabic or hydroxypropylmethylcellulose.

The isolating layer may contain suitable plasticizers, separating agents and pigments.

In another embodiment, the active substance in the active substance layer is dabigatran etexilate mesylate.

Preferably, the content of the binder in the active substance layer is 13% to 35%, more preferably, 15% to 30% by weight of the active substance layer.

The active substance layer may contain suitable plasticizers, separating agents and pigments.

In another embodiment, the pharmaceutical composition comprising dabigatran or its pharmaceutically acceptable salts is coated with film coating.

The film coating comprises film-forming agents, plasticizers and optionally pigments.

The pellets may be prepared by the method described herein after:

The tartaric acid containing 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 isolating layer is applied over tartaric acid containing pellets with a dispersion containing pharmaceutically acceptable water soluble polymer and optionally plasticisers, separating agents and/or pigments in a fluidized bed or coating pan.

The above pellets are coated with a dispersion containing dabigatran etexilate mesylate and 13% to 40% binder by weight of active substance layer in fluidized bed or coating pan.

The active substance applied pellets are optionally coated with film coating.

Suitable solvent for the dispersion include water, ethanol, 2-propanol, acetone or methylene chloride or mixtures thereof.

The film coated pellets are filled into capsules. Capsules can be of any size. Examples of standard sizes include #000, #00, #0,#1, #2, #3, #4, and #5.

The pharmaceutical composition is in the form of capsule. Capsules considered are soft gelatin, hard gelatin, HPMC, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, colour, 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.

Binder includes, but are not limited to, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, 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, 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.

Plasticizer includes, but are not limited to propylene glycol, polyethylene glycol, 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.

Pigment includes, but are not limited to titanium dioxide or iron oxide pigments.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples
Table 1
S.No Ingredient Quantity/Capsule (mg)
Core
1 Tartaric acid pellets 154.41
2 Hydroxy propyl methyl cellulose, HPMC E5 4.50
3 Isopropyl alcohol qs
4 Methylene Chloride qs
Isolating layer
5 Gum Arabic 23.80
6 Talc 2.00
7 Water qs
Drug layer
9 Dabigatran etexilate mesylate 173.00**
10 Talc 14.40
11 Hydroxy propyl cellulose 67.50
12 Ethanol qs
Film Coating
14 Hydroxy propyl cellulose 10.00
15 Talc 0.39
16 Ethanol qs
Net fill weight 450.00
Capsule size 2
** Corresponds to 150 mg of the dabigatran etexilate base.

Manufacturing Process:
Core
1. Hydroxy propyl methyl cellulose is dissolved in Isopropyl alcohol under stirring. Then Methylene chloride is added under stirring.
2. The solution of step 1 is sprayed over tartaric acid pellets in the fluid bed processor.
Isolating layer
3. Gum Arabic is dissolved in purified water under stirring. Then talc is added to this solution with stirring.
4. The pellets of step 2 are coated with step 3 solution in the fluid bed processor.
Drug layer
5. Hydroxy propyl cellulose is dissolved in ethanol and then Dabigatran etexilate mesylate and talc are added to this solution under stirring.
6. The pellets of step 4 are coated with solution of step 5 in the fluid bed processor.
Film Coating
7. Hydroxy propyl cellulose is dissolved in ethanol and then talc is added to this solution.
8. The pellets of step 6 are coated with solution of step 7.
Capsule Filling
9. Film coated pellets of step 8 are filled into HPMC capsules of suitable size.