DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

NOVEL COMPOSITIONS CONTAINING A DIRECT THROMBIN INHIBITOR

We, Alphamed Formulations Pvt. Ltd., having address at
Survey No. 225,Sampanbole Village, Shamirpet Mandal, RR Dist.
Hyderabad - 500078, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed.
:
FIELD OF INVENTION
The present invention relates to the field of oral pharmaceuticals. The invention specifically relates oral solid dosage forms and methods for the preparation of the same. The present invention further relates to the solid oral dosage forms of the drug Dabigatran Etexilate and the methods of the preparation of the same.
BACKGROUND OF INVENTION
The active ingredient of the present invention is Dabigatran Etexilate mesylate 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” and has an empirical chemical formula C34H41N7O5 • CH4O3S with a structural formula as follows:

The product is a known direct thrombin inhibitor. This product has been primarily indicated for the treatment of deep venous thrombosis and pulmonary embolism and prevents their recurrence in previously treated patients. It is also used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
WO 98/37075 (US 6,087,380) discloses Dabigatran product as a compound with thrombin inhibiting effect. The invention relates to new disubstituted bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E. The invention also relates to their tautomers, their stereoisomers, their mixtures, and their salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, thus represent valuable intermediate products for the production of the other compounds of the general formula (I). Furthermore, the compounds of the above general formula (I), in which E stands for a RbNH-C(=NH)-group, have valuable pharmacological properties, in particular in inhibiting thrombin and prolonging thrombin time.
US 7,932,273 specifically discloses the Form II of Dabigatran Etexilate mesylate with specific XRD data. The patent discloses ethyl3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in the crystalline modifications I, II, and the hemihydrate and the use thereof as a pharmaceutical composition.
The solubility of the active ingredient in water is only 1.8 mg/ml. Moreover, the active ingredient has a strong pH-dependent solubility that is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. There is therefore a need for oral pharmaceutical compositions of the active ingredient Dabigatran Etexilate that provide a release that is independent from the pH value of the stomach and thus, provide better bioavailability of the active ingredient.
IN 1879/MUM/2013 discloses a pharmaceutical composition comprising a first component comprising Dabigatran and a second component comprising an inorganic acidic excipient. It also relates to the method of preparing such compositions and using those compositions to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
US 2003/0181488 discloses a new administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof in combination with organic acid.
US 2012/0276206 discloses an improved method of manufacturing substantially spherical/ball-shaped tartaric acid starter pellets which are suitable for preparing active substance-containing medicament formulations, as well as the pellets as such that may be obtained in this way, and their use as starting material for the preparation of active substance-containing medicament formulations.
US 2013/0183384 discloses a multiple unit pellet system (MUPS) in the form of a tablet containing a pharmaceutically active ingredient, characterized in that the MUPS is an optionally coated immediate release pharmaceutical dosage form for oral administration. The pharmaceutically active ingredient was disclosed to be Dabigatran Etexilate mesylate .
WO 2013/124340 discloses compositions comprising a mixture of at least two types of particles wherein a) the first type of particles comprise Dabigatran Etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid, use of said compositions in the reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and/or in the prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery and processes for the preparation of said compositions.
It can be comprehended from the prior art that Dabigatran has a strong pH dependent solubility and thus is effected significantly in patients in whom the stomach pH value is changed by physiological variability, illness, or pre-medications.
It is also understood from the prior art that acids or their respective salts are used to address the solubility issue of Dabigatran. Moreover, it has been observed that Dabigatran is acid sensitive and hence, there is a need to overcome this incompatibility in the formulations containing the acids.
The present invention attempts to providea solution to the incompatibility with the use of acids or their respective salts in the pharmaceutical preparation of Dabigatran Etexilate.
OBJECTIVE OF INVENTION
The objective of the present invention is to provide a method of isolating Dabigatran Etexilate from acids or their respective salts by formulating them into separate solid dosage forms filled together into a capsule.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a capsule dosage form comprising a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises direct thrombin inhibitor.
Yet an embodiment of the present invention provides a capsule dosage form comprising a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises direct thrombin inhibitor; wherein the direct thrombin inhibitor is Dabigatran etexilate.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and in an outer capsule, i.e., capsule-in-capsule dosage form.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises acids or their salts thereof as particles, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises acids or their salts thereof as particles, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs, and
b) outer capsule comprises acids or their salts thereof as particles.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers,
b) outer capsule comprises acids or their salts thereof as particles.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, and
b) outer capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers,
b) outer capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers.
Still another embodiment of the present invention provides a method of preparation of the capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by extrusion and spheronization.
Still another embodiment of the present invention provides a method of preparation of the capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by extrusion and spheronization; and the particles filled into the inner capsule are coated using fluidized bed process.
Still another embodiment of the present invention provides a method of preparation of the capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by extrusion and spheronization; and the particles filled into the outer capsule are coated using fluidized bed process.
Still another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the inner and the outer capsules are made by extrusion and spheronization; and the particles filled into the inner and the outer capsules are coated using fluidized bed process.
Still another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by granulation.
Still another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by granulation; and the particles filled into the inner and the outer capsules are coated using fluidized bed process.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the capsules dosage form which is preferably administered through oral route. One embodiment of the present invention provides the pharmaceutically active ingredient to be Dabigatran etexilate which can be used as a free-base, salt form, polymorph, solvate, or hydrate thereof. The preferred polymorphic form of Dabigatran etexilate for the present invention is Form I.
One embodiment of the present invention provides the use of acids or their salts thereof, for the purpose of maintaining the acidic pH in the environment of the pharmaceutically active ingredient. This improves the solubility of Dabigatran etexilate as it is highly pH dependent for its solubilisation.
The acids used can be selected from, but not limited to, organic acids like tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and the like or combinations thereof including the hydrates and acid salts thereof used individually or in combination thereof; or inorganic acids like hydrochloric acid, sulphuric acid, phosphoric acid and the like including their respective hydrates and salts with hydrogen, ammonium, sodium, potassium, calcium, magnesium, and the like.
One embodiment of the present invention provides the capsule dosage form comprising two different types of solid dosage forms.
In yet another embodiment of the present invention, it is provided that the two different types of solid unit dosage forms are an inner capsule and an outer capsule. Further, the inner and outer capsule may comprise of different particles. Further, the inner capsule of the capsule-in-capsule dosage form comprises the pharmaceutically active ingredient and outer capsule comprises the acids or their salts thereof; or vice versa.
The particles in the present invention may be pellets, granules, microparticles, tablets, capsules, caplets, single-unit tablets, mini-tablets, powders and the like.
The present invention further provides that the capsule dosage form of Dabigatran includes pharmaceutically acceptable excipients. These excipients can be, but not limited to, binders, diluents, disintegrants, lubricants, plasticizers, surfactants, glidants, anti-tacking agents, pigments, flavours.
Examples of suitable binders include, but are not limited to celluloses such as microcrystalline cellulose, modified celluloses (such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose (or HPC), hydroxypropyl methylcellulose (or HPMC or hypromellose), hydroxyethylcellulose, hydroxyethyl methylcellulose, ethyl cellulose, cellulose gum, xanthan gum, sugars, starches such as corn or potato starch partially pregelatinized starches, polyvinyl acetate, polyvinyl alcohol-polyethylene glycol graft copolymer, copovidone, crospovidone, acrylic acid polymer, poloxamer, polycarbophil, polyethylene oxide, polyethylene glycol, and the like, combinations thereof and other material.
Examples of suitable diluents include, but are not limited to microcrystalline cellulose, coprocessed microcrystalline celluloses (such as Avicel CI-61 1 , Avicel RC-581, Avicel RC591, Avicel CE, Avicel DG, Avicel HFE), lactose, sucrose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dibasic calcium phosphate, kaolin, calcium sulphate, carrageenan, chitosan, pectinic acid, sodium alginate, magnesium aluminium silicate, calcium carbonate and the like, combinations thereof and other such materials.
The disintegrants may include, but not limited to, natural, modified or pregelatinized starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, calcium silicate clays, such as bentonite, microcrystalline cellulose, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, alginates, ion exchange resins, low substituted hydroxypropyl cellulose and the like, combinations thereof and other such materials.
Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, mineral oil and sodium stearyl fumarate, combinations thereof and other such.
The coating polymers may include, but are not limited to, cellulose derivatives that may be employed, include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, ethylcellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxymethyl cellulose, and the like or combinations thereof; Vinyl derivatives, copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol (Kollicoat IR), polyvinylpyrrolidone or combinations thereof; gums like gum arabic, alginates, guar gum, carrageenan, pectin, xanthan gum, gellan gum, and the like, or combinations;acrylic or methacrylic acid polymers, copolymers, esters or derivatives thereof like methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters butyl methacrylate, and methyl methacrylate ethyl acrylate, methyl methacrylate, copolymers of acrylate and methacrylates; sodium carboxymethylcellulose, or the like or any combinations thereof.
One embodiment of the present invention provides for the preparation of the single-unit tablets and particles; and the capsule-in-capsule dosage forms by the methods of granulation, extrusion and spheronization, and fluidized bed method.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES:
EXAMPLE 1:

S.No INGREDIENTS AMOUNT (mg)
Outer capsule (Size 0, HPMC) Composition
Intra-granular
1. Dabigatran etexilate mesilate 172.95
2. Microcrystalline cellulose PH 113 64.55
3. Sodium Starch Glycolate Type A 2.50
4. Hydroxypropyl cellulose EF 7.50
5. Isopropyl alcohol Qs
Extra-granular
6. Talc 1.25
7. Magnesium stearate 1.25
8. Empty Capsule Size 0
Inner capsule (Size 4, Gelatin) Composition
9. Tartaric acid 177.14
10. Acacia 8.86
11. Hydroxypropyl methylcellulose E5 4.46
12. Dimethicone 0.08
13. Talc 6.46
14. Ethanol Qs
15. Water Qs
16. Empty Capsule Size 4
Outer capsule fill weight 250.00 mg
Inner capsule fill weight 197.00 mg

Manufacturing procedure
Outer capsule:
Dabigatran etexilate mesilate, microcrystalline cellulose and sodium starch Glycolate were mixed and granulated using a solution of aqueous solution Hydroxypropyl cellulose in a granulator. The granules were dried and sized and blended with Sodium Starch Glycolate. The blend was lubricated with talc and magnesium stearate.
Inner capsule:
Aqueous solution containing tartaric acid, Acacia and talc was coated on tartaric acid pellets in bottom spray granulator. The obtained tartaric acid pellets were seal coated using Hydroxypropyl methylcellulose, Dimethicone, talc in ethanol and water. Seal coated pellets were filled size 4 capsules.
Capsule filling:
The size 4 capsule was placed in size 0 capsule followed by filled with the lubricated blend of outer capsule composition.
EXAMPLE 2:
S.No INGREDIENTS AMOUNT (mg)
Outer capsule (Size 0, HPMC) Composition
1. Sugar spheres 50.00
2. Hydroxypropyl methylcellulose E5 0.60
3. Dimethicone 0.02
4. Talc 0.90
5. Water Qs
6. Dabigatran etexilate mesilate 172.95
7. Hydroxypropyl cellulose EF 34.59
8. Talc 27.74
9. Isopropyl alcohol Qs
10. Empty Capsule Size 0
Inner capsule (Size 4, HPMC) Composition
11. Tartaric acid pellets 177.00
12. Empty Capsule Size 4
Outer capsule fill weight 286.80 mg
Inner capsule fill weight 177.00 mg

Manufacturing procedure
Outer capsule:
Sugar spheres were seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water in bottom spray granulator. The seal coated pellets were coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA in bottom spray granulator.
Inner capsule:
Tartaric acid pellets were filled in size 4 HPMC capsule.
Capsule filling:
The size 4 capsule was placed in size 0 capsule followed by filled with drug coated pellets.
EXAMPLE 3:
S.No INGREDIENTS AMOUNT (mg)
Outer capsule (Size 0, HPMC) Composition
1. Tartaric acid pellets 88.50
2. Empty Capsule Size 0
Inner capsule (Size 4, HPMC) Composition
3. Sugar spheres 25.00
4. Hydroxypropyl methylcellulose E5 0.30
5. Dimethicone 0.01
6. Talc 0.45
7. Water Qs
8. Dabigatran etexilate mesilate 86.48
9. Hydroxypropyl cellulose EF 17.29
10. Talc 13.87
11. Isopropyl alcohol Qs
12. Empty Capsule Size 4
Outer capsule fill weight 88.50 mg
Inner capsule fill weight 143.40 mg

Manufacturing procedure
Inner capsule:
Sugar spheres were seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water in bottom spray granulator. The seal coated pellets were coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA in bottom spray granulator. The drug coated pellets were filled in Size 4 capsule.
Capsule filling:
The size 4 capsule was placed in size 0 capsule followed by filled with tartaric acid pellets.
Dissolution profiles of the solid oral dosage forms of the present invention in comparison with Pradaxa® are given below :
The dissolution profile was performed in 900 ml of 0.01N HCl using USP-I rotating basket apparatus set at 100rpm.
Time (Min) Pradaxa®
(Australia reference)
(Lot: 406467) Example 1 Example 2 Example 3
% Drug release
10 18 11 19 1
15 76 17 26 11
20 95 23 33 41
30 99 31 48 51
45 99 47 63 60

Dated this Eighth (08th) day of March, 2016.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883

,CLAIMS:We Claim:
1. A capsule dosage form of a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs wherein direct thrombin inhibitor is isolated from acids, wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises one or more acids or their salts thereof and the other solid dosage form comprises direct thrombin inhibitor.
2. The capsule dosage form claimed in claim 1 wherein the direct thrombin inhibitor is Dabigatran etexilate.
3. The capsule dosage form claimed in claims 1 and 2 wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule.
4. The capsule dosage form claimed in claim 3 wherein
a) inner capsule comprises acids or their salts thereof as particles, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs.
5. The capsule dosage form claimed in claim 3 wherein
a) inner capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
6. The capsule dosage form claimed in claim 3 wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs, and
b) outer capsule comprises acids or their salts thereof as particles.
7. The capsule dosage form claimed in claim 3 wherein
a) inner capsule comprises Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers,
b) outer capsule comprises acids or their salts thereof as particles coated with pharmaceutically acceptable polymers.
8. The capsule dosage form claimed in claims 1 and 2 where in the composition comprises one or more acids, wherein one or more acids are selected from organic acids like tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and the like or combinations thereof and inorganic acids like hydrochloric acid, sulphuric acid, phosphoric acid and the like including their respective hydrates and salts with hydrogen, ammonium, sodium, potassium, calcium, magnesium thereof used individually or in combination thereof .
9. The capsule dosage form claimed in claims 1 to 3 wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein the particles filled into the inner and the outer capsules are made by granulation.
10. The capsule dosage form claimed in claims 1 further comprises excipients like binders, diluents, disintegrants, lubricants, plasticizers, surfactants, glidants, anti-tacking agents, pigments, flavours and like.