CLIAMS:We Claim:

1. An immediate release oral pharmaceutical composition comprising one or more units of dabigatran etexilate or salts thereof and one or more units of organic acid.

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

3. The immediate release oral pharmaceutical composition of claim 1, wherein the one or more units of dabigatran etexilate or salts thereof may be present in the form of granules, beads, extrudates or minitablets.

4. The immediate release oral pharmaceutical composition of claim 1, wherein the dimension of units of dabigatran etexilate or salts thereof and units of organic acid is more than 0.5 mm and less than 2.0 mm.

5. The immediate release oral pharmaceutical composition of claim 1, wherein the amount of one or more units comprising dabigatran or salts thereof to the amount of one or more units comprising organic acid is selected such that corresponding ratio of dabigatran or salts thereof and organic acid is in the range of about 1:0.1 to about 1:10.

6. The immediate release oral pharmaceutical composition of claim 1, wherein the composition 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.

7. The immediate release oral pharmaceutical composition of claim 1, wherein the composition 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 40°C and 25% relative humidity for 3 months.

8. The immediate release oral pharmaceutical composition of claim 2, prepared by a process comprising steps of:
(a) mixing dabigatran or salts thereof with at least one pharmaceutically acceptable excipients;
(b) granulating the dry blend with binder solution or dispersion to form wet mass;
(c) optionally drying and milling wet mass of step (b) to form granules;
(d) optionally extrusion of wet mass of step (b) to form extrudates;
(e) lubricating the granules or extrudates of step (c) or (d) with lubricating agent;
(f) dispersing or dissolving one or more binders and organic acid in a alcoholic or non-alcoholic vehicle.
(g) spraying the dispersion or solution of step (f) over sugar spheres to form units of organic acid; and
(h) filling the lubricated granules or extrudates of step (e) and units of step (f) in a capsule.
,TagSPECI:4. Description

The present invention relates to oral pharmaceutical compositions of dabigatran etexilate or salts thereof. In particular, present invention relates to compositions comprising of one or more units of dabigatran etexilate or salts thereof and one or more units of organic acid. The present invention further provides a process of preparing compositions of dabigatran etexilate or salts thereof and use thereof for treatment of 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).

In light of the above-mentioned prior arts and available marketed formulation of dabigatran etexilate (Pradaxa®) it can be understood that so far tartaric acid and dabigatran are present in the same units (pellets) separated by an insulating/separating layer. As suggested in prior art, insulating/separating layer was used for providing a physical barrier to protect certain active agents, including dabigatran, from undesirable interactions with the acid in the core. But the coating fractures in the insulating/separating layer may lead to undesirable interactions.

Therefore, inventors of the present invention envisioned separate units for the organic acid and dabigatran or salts thereof and tried to formulate a dosage form with minimal chances of such undesirable interactions.

Moreover, the administration of exact number of such pellets, as described in prior art and marketed formulation (Pradaxa®), depends on the dose strength of the capsule. As the organic acid and drug are present in same units (pellets), the ratio of organic acid to drug remains constant for higher strengths also. This has implications in interpatient variability in some cases such as achorhydria, where patient is unable to secrete acid.

Thus, there exists an enduring need to develop an improved simple pharmaceutical composition of dabigatran etexilate which will provide an alternative to existing formulations that could give control over organic acid quantity and overcome the associated problems.

The inventors of the present invention have surprisingly found that it is possible to devise composition comprising one or more units of dabigatran etexilate or salts thereof and one or more units of organic acid. In the present invention, separate units of drug and organic acid are employed as an arrangement for increasing the ratio of organic acid to drug at higher dose strengths which will lead to less interpatient variability.

In one general aspect, there is provided an immediate release oral pharmaceutical composition comprising one or more of units of dabigatran etexilate or salts thereof and one or more of units of organic acid.

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

In another general aspect, the amount of units comprising dabigatran or salts thereof to the amount of units comprising organic acid is selected such that corresponding ratio of dabigatran or salts thereof to organic acid is in the range of about 1:0.1 to about 1:10.

In another general aspect, the amount of dabigatran or salt thereof in the compositions may present in the range from about 0.1 % to about 95% w/w, and preferably from about 5% to about 85% w/w of the composition.

In another general aspect, there is provided an immediate release oral pharmaceutical composition comprising one or more units of dabigatran etexilate or salts thereof and one or more pellets of organic acid which 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.

In another general aspect, there is provided a process for the preparation of an immediate release capsule, which process comprises steps of:
(a) mixing dabigatran or salts thereof with at least one pharmaceutically acceptable excipients;
(b) granulating the dry blend with binder solution or dispersion to form granules;
(c) optionally, coating the granules with film forming polymer coating;
(d) lubricating the granules of step (b) or (c) with lubricating agent;
(e) dispersing or dissolving one or more binders and organic acid in a alcoholic or non-alcoholic vehicle.
(f) spraying the dispersion or solution of step (e) over sugar spheres to form units of organic acid.
(g) filling the lubricated granules of step (d) and units of step (f) in capsule.

In another general aspect, there is provided a process for the preparation of an immediate release capsule, which process comprises steps of:
(a) mixing dabigatran or salts thereof with microcryastalline cellulose or lactose to form dry blend;
(b) granulating the dry blend of step (a) with hydroxypropyl cellulose in isopropyl alcohol to form granules;
(c) optionally, mixing microcryastalline cellulose or lactose extragranularly;
(d) lubricating the granules of step (b) or (c) with magnesium stearate;
(e) dissolving or dispersing hydroxypropyl methyl cellulose, dimethicone, talc, acacia and tartaric acid in ethanol or water;
(f) spraying the solution or dispersion of step (e) over sugar spheres to form units of tartaric acid;
(g) filling the lubricated granules of step (d) and units of (f) in capsule.

In another general aspect, there is provided a process for preparation of an immediate release capsule, which process comprises steps of:
(a) mixing dabigatran or salts thereof with at least one pharmaceutically acceptable excipients;
(b) granulating the dry blend of step (a) with binder solution or dispersion to form wet mass;
(c) extruding the wet mass to form extrudates, optionally spheronizing the extrudates;
(d) lubricating the extrudates or spheroids with lubricating agent;
(e) dispersing or dissolving one or more binders and organic acid in a alcoholic or non-alcoholic vehicle.
(f) spraying the dispersion or solution of step (e) over sugar spheres to form units of organic acid.
(g) filling the lubricated extrudates of step (d) and units of step (f) in capsule.

In another general aspect, there is provided an immediate release composition of dabigatran etexilate or salts thereof, characterized in that the composition 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.

In another general aspect, there is provided a composition comprising one or more units of dabigatran etexilate or salts thereof and one or more units of organic acid that reduces the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

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 hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. Preferred salt is dabigatran etexilate mesylate.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.

The term "units" as mentioned throughout the present invention refers to granules, extrudates, minitablets, beads or spheroids. The units may be prepared by methods known to person skilled in the art such as granulation, spheronization or extrusion.

The immediate release composition of the present invention can be prepared by methods known to the person skilled in the art. Preferably, the composition comprises one or more units of dabigatran or salts thereof in the form of granules, beads, spheroids, extrudates or minitablets. The composition can be prepared by various methods known to the person skilled in the art, such as wet granulation or extrusion and spheronization.

In one embodiment, the composition of the present invention is an immediate release oral pharmaceutical composition comprising one or more of units of dabigatran etexilate or salts thereof and one or more of units of organic acid.

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

In another embodiment, the units of dabigatran or salts thereof and units of organic acid are having the dimension of more than 0.5 mm, preferably, more than 0.5 mm and less than 2.0 mm.

In another embodiment, the amount of one or more units comprising dabigatran or salts thereof to the amount of one or more units comprising organic acid is selected such that corresponding ratio of dabigatran or salts thereof to organic acid is in the range of about 1:0.1 to about 1:10.

In another embodiment, the amount of dabigatran or salt thereof in the compositions may present in the range from about 0.1 % to about 95% w/w, and preferably from about 5% to about 85% w/w of the composition.

In another embodiment, an immediate release oral pharmaceutical composition of the present invention 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 40ºC and 25% relative humidity for 3 months.

There is provided an immediate release oral pharmaceutical composition of dabigatran etexilate or salts thereof which 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.

In another embodiment, the immediate release composition in the form of a capsule prepared by a process, which process comprises steps of:
(a) mixing dabigatran or salts thereof with microcryastalline cellulose or lactose to form dry blend;
(b) granulating the dry blend of step (a) with hydroxypropyl cellulose in isopropyl alcohol to form granules;
(c) optionally, mixing microcryastalline cellulose or lactose extragranularly;
(d) lubricating the granules of step (b) or (c) with magnesium stearate;
(e) dissolving or dispersing hydroxypropyl methyl cellulose, dimethicone, talc, acacia and tartaric acid in ethanol or water;
(f) spraying the solution or dispersion of step (e) over sugar spheres to form units of tartaric acid;
(g) filling the lubricated granules of step (d) and units of (f) in capsule.

In another embodiment, the immediate release composition in the form of a capsule prepared by a process, which process comprises steps of:
(a) mixing dabigatran or salts thereof with at least one pharmaceutically acceptable excipients;
(b) granulating the dry blend of step (a) with binder solution or dispersion to form wet mass;
(c) extruding the wet mass to form extrudates, optionally spheronizing the extrudates;
(d) lubricating the extrudates or spheroids with lubricating agent;
(e) dispersing or dissolving one or more binders and organic acid in a alcoholic or non-alcoholic vehicle.
(f) spraying the dispersion or solution of step (e) over sugar spheres to form units of organic acid.
(g) filling the lubricated extrudates of step (d) and units of step (f) in capsule.

Diluents increase the bulk of a solid 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 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 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 immediate release 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 immediate release composition of dabigatran or salts thereof as substantially described throughout the specification.

The present invention is further 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: Preparation of units of tartaric acid
Table 1
S. No Ingredients Category % w/w
1. Tartaric acid Acidic substance 10-90
2. Acacia Binder 0.1-10
3. HPMC E6 Binder 0.1-10
4. Dimethicone Anti-foaming 0.05-5
5. Talc Anti-tacking agent 1-20
6. Ethanol Solvent q.s
7. Purified water Solvent q.s
8. Sugar spheres (#40/50 mesh) Substrate/ Carrier 1-20
Total 100

Process: HPMC and dimethicone were dissolved in ethanol and talc was added to form dispersion. Acacia and tartaric acid were dissolved in water, with continuous stirring and added to the dispersion of HPMC. The dispersion was sprayed over sugar spheres to form units (pellets) of tartaric acid.

Example 2: Dabigatran etexilate mesylate capsule
Table 2
S. No Ingredients Category % w/w
1. Dabigatran Etexilate Mesylate Anticoagulant 10-40
2. Lactose anhydrous Filler 5-50
3. Microcrystalline cellulose Filler 5-50
4. Hydroxy propyl cellulose Binder 1-30
5. Isopropyl alcohol Granulating aid q.s
6. Lactose anhydrous Filler 5-50
7. Microcrystalline cellulose Filler 5-50
8. Talc Glidant 0.1-10
9. Tiny units containing tartaric acid Acidic substance 10-40
Total 100

Process: Dabigatran etexilate mesylate was mixed with lactose anhydrous or microcrystalline cellulose and granulated with HPC in IPA as a binder. The granules were dried in fluid bed dryer and mixed with extragranular excipients. The granules of dabigatran etexilate mesylate and units of tartaric acid prepared in example 1 were filled in proper quantity into suitable sized capsules depending on dosage strength.

Example 3: Dabigatran etexilate mesylate capsule
Table 3
S. No Ingredients Category % w/w
10. Dabigatran Etexilate Mesylate Anticoagulant 10-40
11. Lactose anhydrous Filler 5-50
12. Microcrystalline cellulose Filler 5-50
13. Hydroxy propyl cellulose Binder 1-30
14. Isopropyl alcohol Granulating aid q.s
15. Lactose anhydrous Filler 5-50
16. Microcrystalline cellulose Filler 5-50
17. Talc Glidant 0.1-10
18. Tiny units containing tartaric acid Acidic substance 10-40
Total 100

Process: Dabigatran etexilate mesylate was mixed with lactose anhydrous or microcrystalline cellulose and granulated with HPC in IPA as a binder to form wet mass. The wet mass was extrudate from extruder to form extrudates which were spheronized using a spheronizer. The extrudates of dabigatran etexilate mesylate and units of tartaric acid prepared in example 1 were filled in proper quantity into suitable sized capsules depending on dosage strength.