CLIAMS:We Claim:

1. An oral pharmaceutical composition comprising plurality of units comprising first component of dabigatran etexilate or salts thereof and a second component of at least one organic acid, wherein the organic acid from the second component begins to release its content before the release of dabigatran etexilate or salts thereof starts from first component of dabigatran etexilate or salts thereof.

2. The oral pharmaceutical composition of claim 1, wherein the composition is in the form of a capsule.

3. The oral pharmaceutical composition of claim 1, wherein the unit comprises sugar spheres coated with a layer of dabigatran etexilate or salts thereof and a binder as a first component, which layer is surrounded by a layer comprising at least one organic acid, wherein both the layers are separated by a layer of a film forming polymer.

4. The oral pharmaceutical composition of claim 1, wherein the sugar spheres are coated with a film forming polymer.

5. The oral pharmaceutical composition of claim 1, wherein the dimension of units is more than 0.5 mm and less than 2.0 mm.

6. The oral pharmaceutical composition of claim 1, wherein the units are in the form of pellets.

7. The oral pharmaceutical composition of claim 1, wherein the ratio of amount dabigatran or salts thereof to the amount of organic acid is in the range of about 1:0.1 to about 1:10.

8. The oral pharmaceutical composition of claim 1, wherein the dosage form exhibits release of more than about 80% of dabigatran etexilate or salts thereof in 30 minutes, when measured in 900 mL of 0.01N HCl at 37ºC using USP Type I dissolution apparatus at 100 rpm.

9. The oral pharmaceutical composition of claim 1, wherein the dosage form retains at least 90% w/w of the potency of dabigatran or salt thereof when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

10. The oral pharmaceutical composition of claim 1, wherein the composition is prepared by a process, which process comprises steps of:
(a) dispersing dabigatran or salts thereof with a solution or dispersion of at least one binder in alcoholic or non-alcoholic vehicle;
(b) spraying dispersion from step (a) over sugar spheres to form pellets of dabigatran or salts thereof;
(c) dispersing or dissolving one or more binders and organic acid in a alcoholic or non-alcoholic vehicle.
(d) spraying the dispersion or solution of step (c) over sugar spheres to form pellets of organic acid.
(e) filling the units from step (b) and (d) in capsule.

,TagSPECI:4. Description

The present invention provides oral pharmaceutical composition comprising dabigatran etexilate or salts thereof. In particular, the composition comprises plurality of units comprising first component of dabigatran etexilate or salts thereof and a second component of at least one organic acid, wherein the organic acid begins to release its content from second component before the release of dabigatran etexilate or salts thereof starts from first component. Further, the invention also provides process for preparation of the immediate release oral pharmaceutical composition. The composition may provide therapeutically effective plasma concentration to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation when administered to a patient in need thereof.

Dabigatran is an anticoagulant that works by the clotting protein thrombin. Dabigatran is used to prevent blood clots from forming because of a certain irregular heart rhythm (atrial fibrillation). Preventing these blood clots helps to reduce the risk of a stroke. It is administered in capsule form. Side effects can include bruising and minor bleeding, nausea, and abdominal or stomach pain.

Dabigatran etexilate is a low-molecular-weight prodrug that exhibits no pharmacological activity. After oral administration, dabigatran etexilate is converted to its active form, dabigatran, a potent, competitive, and reversible direct inhibitor of the active site of thrombin, the final effector in blood coagulation. The ability to inhibit fibrin-bound thrombin is an important theoretical advantage of dabigatran over the heparins because bound thrombin can continue to trigger thrombus expansion.

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties. It’s chemical name is β-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 the following structural formula:

Dabigatran etexilate is approved in the United States and is available in capsule form which is marketed under the name of Pradaxa®. The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate. Pradaxa® is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Solubility of dabigatran etexilate mesylate is strongly pH dependent with increased solubility at acidic pH. Therefore it is formulated together with tartaric acid to reduce the variability of dabigatran etexilate absorption. 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. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability, illness, or premedications (for example, PP inhibitors).

A single Pradaxa® capsule contains hundreds of tiny pellets, the exact number depending on the dose strength of the capsule. A dabigatran etexilate coating is applied onto a tartaric acid core to form such tiny pellets (~1-mm diameter). In this way, dabigatran etexilate absorption becomes independent of gastrointestinal tract acidity and is not materially affected by co-administration of a proton pump inhibitor.

The incorporation of pH modifiers, e.g. organic acids, into an oral dosage form modulates the microenvironmental pH and thereby enhances the drug solubility and drug dissolution. In addition, pH-independent drug release can be achieved.

After oral administration, dabigatran etexilate is rapidly absorbed and quickly and completely hydrolyzed to its active moiety, dabigatran, by nonspecific ubiquitous esterases in the gut, plasma, and liver. Because bioconversion of dabigatran etexilate begins in the gut, the drug enters the portal vein as a combination of prodrug and active compound. The absolute bioavailability after oral administration of dabigatran etexilate is only ~ 6.5%, so relatively high doses must be given to ensure that adequate plasma concentrations are achieved.

Patent application JP 58-134033 disclosed a drug composition for oral medication with improved solubility obtained by adding an acidic substance to cinnarizine. The acidic substance (e.g. tartaric acid, citric acid etc.) is added to cinnarizine, to give a drug composition tablet, etc. When it is orally administered, it is hardly affected by the change in pH value in the stomach; it shows stable solubility in the digestive organs.

US patent application US20120301541 discloses a compressed core for a pharmaceutical dosage form comprising a mixture of (a) at least one pharmaceutically acceptable organic acid, and (b) at least one pharmaceutically acceptable excipient is described. Such compressed core is useful for the preparation of pharmaceutical compositions containing a drug in which dissolution of the drug is favored in acidic environments. The application suggested that it may be preferable to include a subcoat layer between the core containing the pharmaceutically acceptable acid and the drug layer particularly for providing a physical barrier to protect certain active agents, including dabigatran, from undesirable interactions with the acid in the core.

PCT application number WO2009/118321 discloses a process for the preparation of approximately spherical/ball- shaped tartaric acid pellets suitable for the manufacture of drug formulations containing active ingredients, the pellets so obtained as such, and the use thereof as a starting material for the production of drug formulations containing active ingredients. The process is characterized in that in a first step the tartaric acid pellets are produced by powder layering, which are sprayed in a second step with an ethanolic isolation suspension which comprises hydroxypropylmethyl cellulose (HPMC).

US patent application number US 20030183779 discloses a new administration form for the oral application of dabigatran etexilate and the pharmacologically acceptable salts thereof. In particular, the invention describes the roughly bead shaped/spherical core region of the pellet containing/consisting of the pharmaceutically acceptable organic acid which was coated with a layer, the so-called insulating layer, which separates the acid core from the layer containing the active substance. The insulating layer is in turn surrounded by the equally spherically shaped layer of active substance which may in turn be enclosed in a coating which increases the abrasion resistance and shelf life of the pellets. According to the application such type of formulation has two advantages, one being the spatial separation of the organic acid and active substance by the insulating layer and second is the fact that the organic acid does not go into solution until after the preparation has been taken and then produces an acid microclimate in which the active substance can dissolve.

As the solubility of dabigatran etexilate or salts thereof is pH dependent, inventors of the present invention found that release of organic acid after dabigatran release may lead to interpatient variability due to variable acidic conditions in some cases as fasting or fed condition and achlorhydria.

Thus, there exists an enduring need to develop an improved simple pharmaceutical composition of dabigatran etexilate which will provide an alternative to existing formulations and overcome the associated problems.

Therefore, the inventors of the present invention felt the need to develop an alternative pharmaceutical composition where organic acid part begins to release its content before the release of dabigatran or salts thereof starts.

The inventors of the present invention have surprisingly found that it is possible to devise a composition which comprises plurality of units comprising component of dabigatran etexilate or salts thereof and a component of at least one organic acid, wherein the organic acid component begins to release its content before the release of dabigatran etexilate or salts thereof starts from component of dabigatran etexilate or salts thereof.

In one general aspect, there is provided an oral pharmaceutical composition comprising plurality of units which comprises of first component of dabigatran etexilate or salts thereof and a second component of at least one organic acid.

In another general aspect, the release of organic acid begins from second component before the release of dabigatran etexilate or salts thereof starts from first component.

In another general aspect, there is provided an oral pharmaceutical composition in the form of a capsule.

In another general aspect, there is provided a unit comprising cores of dabigatran etexilate or salts thereof and a binder as a first component and a coating of a layer comprising at least one organic acid over said cores as a second component, wherein the first and second components are separated by a layer of film forming polymer. The second component may be further coated with a film forming polymer.

In another general aspect, there is provided a unit comprises inert cores coated with a layer comprising dabigatran etexilate or salts thereof as a first component and a coating of a layer comprising at least one organic acid surrounding said coating as a second component, wherein the first and second components are separated by a layer of film forming polymer. The second component may be further coated with a film forming polymer.

In another general aspect, there is provided a composition, wherein inert cores are in the form of sugar spheres coated with a layer of a film forming polymer.

In another general aspect, there is provided a composition, wherein there are three film forming layers (i) first layer over sugar spheres, (ii) over layer of dabigatran or salts thereof and (iii) a layer surrounding the organic acid layer.

In another general aspect, there is provided a composition comprising plurality of separate units of dabigatran etexilate or salts thereof and plurality of units of at least one organic acid, wherein units of organic acid begins to release its content before the units of dabigatran or salts thereof start releasing its content.

In another general aspect, the amount of dabigatran or salts thereof to the amount of organic acid is selected such that corresponding ratio of dabigatran or salts thereof to organic acid is in the range of from about 1:0.1 to 1:20, preferably from about 1:1 to 1: 5.

In another general aspect, there is provided a composition comprising dabigatran etexilate or salts thereof which exhibits release of more than about 80% of dabigatran etexilate or salts thereof in about 30 minutes, when measured in 900 mL of 0.01N HCl at 37ºC using USP Type I dissolution apparatus at 100 rpm.

In another general aspect, there is provided a process for the preparation of a composition, which process comprises of following steps:
(a) dispersing or dissolving dabigatran etexilate or salts thereof with a solution or dispersion of at least one binder in alcoholic or non-alcoholic vehicle;
(b) coating the dispersion or solution of step (a) over inert cores;
(c) coating a layer of film forming polymer over the drug coated cores of step (b);
(d) dispersing or dissolving one or more binders and an organic acid in an alcoholic or non-alcoholic vehicle;
(e) coating the dispersion or solution of step (d) over coated cores of step (c);
(f) coating a layer of film forming polymer over coated cores of step (e); and
(g) filling the units of step (e) in capsule.

In another general aspect, there is provided a process for the preparation of a composition, which process comprises of following steps:
(a) dissolving hypromellose and talc in ethanol and spray coating on sugar spheres to form seal coated sugar spheres;
(b) dissolving dabigatran etexilate mesylate, hydroxypropyl cellulose and talc in ethanol;
(c) coating the solution of step (b) over seal coated sugar spheres of step (a);
(d) dissolving hypromellose, dimethicone and talc in ethanol and spray coating on drug coated sugar spheres of step (c);
(e) dissolving tartaric acid, hypromellose and talc in ethanol and spray coating on coated sugar spheres of step (d);
(f) dissolving hypromellose and talc in ethanol and spray coating on sugar spheres of step (e); and
(g) filling the units of step (f) in capsule.

In another general aspect, there is provided a process for the preparation of a composition, which process comprises of following steps:
(a) preparing cores comprising dabigatran etexilate or salts thereof and at least one pharmaceutically acceptable excipient;
(b) coating a layer of film forming polymer over the cores of step (a);
(c) dispersing or dissolving one or more binders and an organic acid in an alcoholic or non-alcoholic vehicle.
(d) coating the dispersion or solution of step (c) over the cores of step (b);
(e) coating the layer of film forming polymer over the cores of step (d); and
(f) filling the units of step (e) in capsule.

In another general aspect, there is provided a method of reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation by administering the composition of dabigatran or salts thereof as substantially described throughout the specification.

The composition may contain one or more pharmaceutically acceptable excipients selected from the class of organic acids, binder, diluents, disintegrants, glidants, lubricants and antioxidants.

In another general aspect, there is provided a composition of dabigatran etexilate or salts thereof, characterized in that the dosage form retains at least 90% w/w of the potency of dabigatran etexilate or salt thereof when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

The present invention provides an oral pharmaceutical composition comprising plurality of units comprising first component of dabigatran etexilate or salts thereof and second component of at least one organic acid. The composition is formulated in such a way that organic acid part begins to release its content before the release of dabigatran or salts thereof start.

The term “dabigatran” used throughout the specification refers to not only dabigatran per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. The preferred ester is etixilate and the preferred salt is mesylate.

The term "units" as mentioned throughout the present invention refers to cores, pellets, beads, granules, minitablets having dimensions more than 0.5 mm and less than 2.0 mm. The pellets may be prepared by methods known to person skilled in the art such as granulation, extrusion-spheronization, compression and pelletization.

The term "inert core" as mentioned throughout the present invention refers to pellets, beads, granules, minitablets substantially made up of inactive excipients such as lactose sugar and microcrystalline cellulose. Preferably having dimensions more than 0.5 mm and less than 2.0 mm.

In an embodiment, an oral pharmaceutical composition comprising plurality of units comprising first component of dabigatran etexilate or salts thereof and a second component of at least one organic acid.

In another embodiment, there is provided an oral pharmaceutical composition, wherein the release of organic acid begins from second component before the release of dabigatran etexilate or salts thereof starts from first component.

In another embodiment, there is provided an oral pharmaceutical composition in the form of a capsule.

In another embodiment, the unit comprises cores of dabigatran etexilate or salts thereof and a binder as a first component. Such cores are coated with a film forming polymer that acts as separating/insulating layer. A layer comprising at least one organic acid is coated surrounding the separating/insulating layer, which layer acts as second component. The second component layer of organic acid may be further coated with a film forming polymer.

In another embodiment, the unit comprises inert cores coated with a layer comprising dabigatran etexilate or salts thereof as a first component. Such drug coated cores are coated with a film forming polymer that acts as separating/insulating layer. A layer comprising at least one organic acid is coated surrounding the separating/insulating layer, which layer acts as second component. The second component layer of organic acid may be further coated with a film forming polymer.

In another embodiment, a composition comprising plurality of separate units of dabigatran etexilate or salts thereof and plurality of units of at least one organic acid, wherein units of organic acid begins to release its content before the units of dabigatran or salts thereof start releasing its content.

In another embodiment, the amount of dabigatran or salts thereof to the amount of organic acid is selected such that corresponding ratio of dabigatran or salts thereof to organic acid is in the range of from about 1:0.1 to 1:20, preferably from about 1:1 to 1: 5.

In another embodiment, there is provided a composition comprising dabigatran etexilate or salts thereof which exhibits release of more than about 80% of dabigatran etexilate or salts thereof in about 30 minutes, when measured in 900 ml of 0.01N HCl at 37ºC using USP Type I dissolution apparatus at 100 rpm.

In another embodiment, there is provided a process for the preparation of a composition, which process comprises of following steps:
(a) dispersing or dissolving dabigatran etexilate or salts thereof with a solution or dispersion of at least one binder in alcoholic or non-alcoholic vehicle;
(b) coating the dispersion or solution of step (a) over inert cores;
(c) coating a layer of film forming polymer over the drug coated cores of step (b);
(d) dispersing or dissolving one or more binders and an organic acid in an alcoholic or non-alcoholic vehicle;
(e) coating the dispersion or solution of step (d) over coated cores of step (c);
(f) coating a layer of film forming polymer over coated cores of step (e); and
(g) filling the units of step (e) in capsule.

In another embodiment, there is provided a process for the preparation of a composition, which process comprises of following steps:
(a) dissolving hypromellose and talc in ethanol and spray coating on sugar spheres to form seal coated sugar spheres;
(b) dissolving dabigatran etexilate mesylate, hydroxypropyl cellulose and talc in ethanol;
(c) coating the solution of step (b) over seal coated sugar spheres of step (a);
(d) dissolving hypromellose, dimethicone and talc in ethanol and spray coating on drug coated sugar spheres of step (c);
(e) dissolving tartaric acid, hypromellose and talc in ethanol and spray coating on coated sugar spheres of step (d);
(f) dissolving hypromellose and talc in ethanol and spray coating on sugar spheres of step (e); and
(g) filling the units of step (f) in capsule.

The prepared units may release their content immediately, wherein organic acid component begins to release its content before dabigatran or salts thereof release starts from first component of dabigatran or salts thereof. Such units are filled in a capsule to prepare an immediate release unit dosage form.

The composition of the present invention can be prepared by methods known to the person skilled in the art. Preferably, the composition comprises plurality of pellets of dabigatran or salts thereof and pellets of organic acid, prepared by pelletization technique.

The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, diluent, binder, disintegrant, glidant, lubricant, stabilizing agent, and flavoring agents.

The present invention further provides a method of reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation by administering the composition of dabigatran or salts thereof as substantially described throughout the specification.

The present invention further provides a method of substantially minimizing the intersubject variability and improving the quality of life, especially in the patients in whom the stomach pH value is changed by physiological variability, illness, or premedications (for example, PP inhibitors), which method comprises administering a composition of dabigatran or salts thereof as substantially described throughout the specification.

Diluents increase the bulk of a pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

The present invention is illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

Example 1: Dabigatran etexilate mesylate capsule
Table 1
S.No Ingredients % w/w


1 Sugar spheres 1-50
Seal Coat
2 Hypromellose (E6 LV) 0.1-5
3 Talc 0.1-5
4 Ethanol (absolute) qs
Drug layering
5 Dabigatran Etexilate Mesylate 20-80
6 Klucel LF (HPC) 1-20
7 Talc 1-20
8 Isopropyl alcohol qs
Seal Coat
9 Hypromellose (E6 LV) 0.1-5
10 Talc 0.1-5
11 Dimethicone 0.08
12 Ethanol (absolute) qs
Tartaric acid coat
13 Tartaric acid 20-80
14 Hypromellose (E6 LV) 0.5-10
15 Talc 0.5-10
16 Ethanol (absolute) qs
Seal Coat (optional)
17 Hypromellose (E6 LV) 0.5-10
18 Talc 0.5-10
19 Dimethicone 0.01-1
20 Ethanol (absolute) qs
Total 100.00
21 HPMC based Capsule Shell Size 00

Process: Hypromellose and talc were dissolved in ethanol and spray coated on sugar spheres to form first seal coating on sugar spheres. Dabigatran etexilate mesylate, hydroxypropyl cellulose and talc were dissolved in isopropyl alcohol and spray coated on these seal coated pellets. Hypromellose, talc and dimethicone were dissolved in ethanol and spray coated on drug coated pellets to form a second seal coating. Tartaric acid, hypromellose and talc were dissolved in ethanol and spray coated on second seal coat of sugar spheres. Optionally, hypromellose, talc and dimethicone were dissolved in ethanol and spray coated on these sugar spheres to form third seal coating.

Example 2: Dabigatran etexilate mesylate capsule
Table 2
S.No Ingredients % w/w


Intragranular
1 Dabigatran Etexilate Mesylate 20-80
2 Lactose monohydrate 10-50
3 Crospovidone 1-10
Top spray granulation
4 Hypromellose (E6 LV) 0.1-5
5 Talc 0.1-5
6 Dimethicone 0.01-1
7 Ethanol (absolute) qs
Tartaric acid coat
8 Tartaric acid 20-80
9 Hypromellose (E6 LV) 0.1-5
10 Talc 0.1-5
11 Ethanol (absolute) qs
Seal Coat (optional)
12 Hypromellose (E6 LV) 0.1-5
13 Talc 0.1-5
14 Dimethicone 0.01-1
15 Ethanol (absolute) qs
Total 100.00
HPMC based Capsule Shell Size 00

Process: Dabigatran etexilate mesylate, lactose and crospovidone were granulated with solution of hydroxypropyl cellulose, dimethicone and talc in ethanol to form drug cores. Hypromellose, talc and dimethicone were dissolved in ethanol and spray coated on drug cores to form a coating. Tartaric acid, hypromellose and talc were dissolved in ethanol and spray coated on coated drug cores. Hypromellose, talc and dimethicone were dissolved in ethanol and spray coated on these coated drug cores.