A stable solid oral dosage form of dabigatran

Abstract

Described herein are stable solid oral capsule dosage form comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has controlled and reduced levels of N-nitroso dabigatran (NDAB). Also, disclosed are methods of manufacturing such stable solid capsule oral dosage forms of dabigatran etexilate and its pharmaceutically acceptable salt.

Description

[0001] A STABLE SOLID ORAL DOSAGE FORM OF DABIGATRAN

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of Indian Provisional Application No. 202321058899 filed on September 1, 2023; which is hereby incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a stable solid oral dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form is capable of reducing the nitrosamine genotoxic impurities. In particular, the invention relates to a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutical excipient with reduced nitrosamine impurities. The present invention also relates to a process for preparing said pharmaceutical composition to lower the risk of stroke and blood clots.

[0006] BACKGROUND OF THE INVENTION

[0007] The word nitrosamine first caught the attention of the pharmaceutical world and the drug regulatory agencies back in 2018 with the discovery of N-nitrosodimethyl amine (NDMA) in valsartan drug products.

[0008] This led to the detection of complex so-called nitrosamine drug-substance-related impurities (NDSRIs) which are formed due to the reaction between secondary or tertiary amine groups present in APIs or API impurities, which are prone to nitrosation and nitrites present as impurities, in excipients or packaging or residual solvents (albeit present in miniscule amounts).

[0009] The ICH M7 (Rl) guideline categorizes N-nitroso compounds in the “cohort of concern” of highly potent mutagenic carcinogens, which are associated with significantly high carcinogenic and mutagenic potential. This finding led to the implementation of stringent controls, in the form of guidance documents, by the different regulatory agencies across the globe on controlling the amount of nitrosamine impurity in drug products being approved by them since it poses a threat to the health and safety of patients.

[0010] N-Nitrosamines are a class of chemical compounds with the general structure shown in Figure 1. The essential feature of N-nitroso compounds is the N-N=O structure.

[0011]

[0012] Figure 1

[0013] Nitrosamines are metabolized in liver and their metabolic by-products have the potential to irreversibly change the DNA.

[0014] Investigations revealed sources of nitrosamine in drug products to be either the API, manufacturing processes of the API as well as the drug product, excipients as well as packaging or even printing ink and storage conditions. Investigations revealed tetrazole, which is an intermediate in synthesis of certain angiotensin receptor blockers, which utilizes nitrite in the presence of aqueous acid, to be the root cause behind NDMA contamination found in valsartan, losartan and irbesartan. High storage temperatures led to increased degradation of ranitidine and thus increased NDMA levels in ranitidine drug products. Residual dimethylamine in metformin API and residual nitrite and nitrate in excipients used in manufacture of metformin tablets were recognized as the source of NDMA contamination in metformin tablets. Thus, these lessons have pointed out that the root causes for nitrosamine contamination can arise from a myriad of sources. This leads to manufacturers getting entrapped in solving a complex maze of experiments in order to detect the true reason behind the nitrosamine generation.

[0015] Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. It reduces the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It is also useful in primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

[0016] Dabigatran is currently available as dabigatran etexilate mesylate under the brand name Pradaxa® from Boehringer Ingelheim as immediate release oral capsules of 75 mg, 110 mg and 150 mg strengths for twice daily administration. Dabigatran etexilate mesylate is stable in the solid state and not sensitive to light irradiation but it undergoes degradation by hydrolytic pathways in the presence of moisture. It is also acid sensitive. Due to these physicochemical and biopharmaceutical properties of dabigatran etexilate mesylate, some attempts have been made to provide compositions of Dabigatran etexilate mesylate that are stable and / or provide desirable in vitro release and bioavailability.

[0017] N-nitroso dabigatran (hereinafter referred to as NDAB), which has the chemical structure as shown in Figure 2, has the potential to increase the risk of cancer in patients, who consume such drug products for an extended treatment regime, when exposed to it for prolonged duration to levels higher than acceptable limits.

[0018] Figure 2

[0019] Multiple dabigatran products had uncontrolled and increased levels of NDAB and could not meet the level of NDAB prescribed by drug regulatory agencies.

[0020] US 9,925,174, discloses pharmaceutical compositions of dabigatran for oral administration in the form of pellets comprising (a) substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids such as tartaric acid; and (b) an active substance layer containing one or more binders along with an optional separating agent between the organic acid core and the active layer. But, US 9,925,174 does not disclose about levels of NDAB in the finished drug product or about efforts undertaken to control the NDAB level in such finished products.

[0021] There is thus a need to develop stable solid oral dosage forms of dabigatran etexilate or its pharmaceutically acceptable salt, with controlled and reduced levels of NDAB and associated manufacturing processes which leads to control of such genotoxic and carcinogenic NDAB impurity.

[0022] SUMMARY OF THE INVENTION

[0023] The present disclosure provides an improved and stable solid oral dosage form of dabigatran etexilate or its pharmaceutically acceptable salt wherein said dosage form contains less than 3 PPM of nitrite(NO2'). The invention in one embodiment relates to a stable solid oral dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein the said dosage form has nitrite (NCh') content of less than 3 PPM.

[0024] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2’) content of less than 3 PPM.

[0025] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2’) content of less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 40°C ± 2 °C and 75% ± 5%RH.

[0026] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO / ) content of less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 25°C ± 2 °C and 60 ± 5%RH.

[0027] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2‘) content of less than 2 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 40°C ± 2 °C and 75% ± 5%RH.

[0028] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2‘) content of less than 2 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 25°C ± 2 °C and 60 ± 5% RH.

[0029] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2‘) content of less than 1 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 40°C ± 2 °C and 75% ± 5%RH. Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2’) content of less than 1 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 25°C ± 2 °C and 60 ± 5%RH.

[0030] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 0.5 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 40°C ± 2 °C and 75% ± 5%RH.

[0031] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 0.5 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 6 months at 25°C ± 2 °C and 60 ± 5% RH.

[0032] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 3 months at 40°C ± 2 °C and 75% ± 5%RH.

[0033] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 3 months at 25°C ± 2 °C and 60 ± 5% RH.

[0034] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 2 months at 40°C ± 2 °C and 75% ± 5%RH.

[0035] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.

[0036] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.5 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 3 months at 40°C ± 2 °C and 75% ± 5%RH.

[0037] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.5 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 2 months at 40°C ± 2 °C and 75% ± 5%RH.

[0038] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, and / or less than 0.5 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.

[0039] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form, wherein said dosage form has less than 0.45 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.

[0040] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form, wherein said dosage form has less than 0.35 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.

[0041] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form, wherein said dosage form has less than 0.25 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.

[0042] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein capsule is hydroxy propyl methyl cellulose based capsule shell, wherein the capsule shell is devoid of carrageenan and / or potassium chloride.

[0043] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein capsule is gelatin based capsule / or polyethylene glycol based gelatin capsule.

[0044] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein the capsule shell is devoid of carrageenan and / or potassium chloride.

[0045] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has nitrite (NO2’) content of less than 0.5 PPM.

[0046] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said composition has nitrite (NO2’) content of less than 0.5 PPM.

[0047] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said capsule shell has nitrite (NO2‘) content of less than 0.5 PPM.

[0048] It is surprisingly found in present invention, the role of nitrite (NO2‘) content in generation or increase of N-Nitroso-dabigatran (ND AB) impurity. It is found that reducing the levels of nitrite (NCh') content from the capsule shell and the excipients in the dabigatran composition reduces the generation of N-Nitroso-dabigatran (ND AB) impurity.

[0049] DETAILED DESCRIPTION OF THE INVENTION

[0050] The various aspects and embodiments will now be fully described herein. These aspects and embodiments may, however, be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so the disclosure will be thorough and complete, and will fully convey the scope of the present subject matter to those skilled in the art. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0051] The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

[0052] In one embodiment, the present invention relates to pharmaceutical dosage form of dabigatran for oral administration in the form of pellets comprising (a) substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids such as tartaric acid; and (b) an active substance layer containing one or more binders and optionally a separating agent, that encloses said core material. The separating agent layer or insulating layer separates the acid core from the active substance containing layer, wherein said composition has nitrite (NCh') content of less than 3 PPM.

[0053] The composition of the present invention comprises a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, with first type of particles comprising dabigatran etexilate and second type of particles comprising at least one organic acid, wherein said composition has nitrite (NCh') content of less than 3 PPM.

[0054] The term "particle" as used herein is intended to mean any solid or semi-solid portion of a substance or a composition having defined physical boundaries. Examples of particles include, but are not limited to, powder, granules, pellets, beads, mini tablets or the like. The granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like. In an embodiment of the present invention, pellets may be prepared using extrusion spheronization. The inert carrier can be selected from, but not limited to, beads, pellets, spheres or similar particles that do not contain an active ingredient. Non-limiting examples of inert carrier include microcrystalline cellulose, sugar or silicon dioxide. In yet another embodiment, the particles of the present invention, in the powder form, may be incorporated in the compositions of the present invention. The term "dosage form" is as used herein is intended to mean a pharmaceutical composition which is suitable for administration to a patient. The compositions of the present invention can be in the form of capsules, tablets, mini tablets, dry suspension for reconstitution, powder or granule for solution or suspension, granules, tablet in capsules, pellets in capsule, granules in capsules, capsule in capsule and the like or any combinations thereof. Depending of the final dosage form the compositions of the present invention may comprise appropriate pharmaceutically acceptable excipients such as those mentioned above or some additional ones such as, but not limited to, sweeteners, flavors, colorants and the like or combinations thereof. Further it is contemplated within the scope of the invention that the dosage form can be encapsulated or coated. In one embodiment, the composition of the present invention is in the form of a capsule. Capsules include, for example, hard capsules of hydroxypropyl methylcellulose and the like. In a further embodiment, the compositions of the present invention may be manufactured using conventional techniques known in the art.

[0055] The term "stable solid oral dosage form" means solid oral dosage form which exhibits any one or all of the following conditions: (i) solid oral dosage form exhibits substantial chemical stability, when stored for 1 month or 2 month or 3 month or 6 months at 40°C ± 2 °C and 75% ± 5%RH; (ii) solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has less than 0.75 ppm of N- Nitroso-dabigatran (ND AB) impurity, when stored for 1 month or 2 month or 3 month or 6 month at 40°C ± 2 °C and 75% ± 5% RH (iii) solid oral dosage form exhibits substantial chemical stability, when stored for 1 month or 2 month or 3 month or 6 month or 9 month or 12 month or 18 month or 24 months at 25°C ± 2 °C and 60% ± 5% RH; (iv) solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said dosage form has less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 1 month or 2 month or 3 month or 6 month or 9 month or 12 month or 18 month or 24 month at 25°C ± 2 °C and 60% ± 5% RH.

[0056] The “stable solid oral capsule” means the capsule shell which has a pharmaceutical composition of dabigatran etexilate and / or its pharmaceutically acceptable salts along with one or more excipients enclosed within it; and which exhibits any one or all of the following conditions: (i) substantial chemical stability, when stored for 1 month or 2 month or 3 month or 6 months at 40°C ± 2 °C and 75% ± 5%RH; (ii) has less than 0.75 ppm of N-Nitroso- dabigatran (ND AB) impurity, when stored for 1 month or 2 month or 3 month or 6 month at 40°C ± 2 °C and 75% ± 5% RH (iii) exhibits substantial chemical stability, when stored for 1 month or 2 month or 3 month or 6 month or 9 month or 12 month or 18 month or 24 months at 25°C ± 2 °C and 60% ± 5% RH; (iv) has less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 1 month or 2 month or 3 month or 6 month or 9 month or 12 month or 18 month or 24 month at 25°C ± 2 °C and 60% ± 5% RH.

[0057] Capsule shell can have hydroxypropylmethyl cellulose as the base. Capsule shell is preferably free of carrageenan and / or potassium chloride.

[0058] The compositions of the present invention are stable, easy to prepare, and provide the desired in-vitro and in-vivo release of the active. The compositions of the present invention, comprise dabigatran etexilate. Dabigatran etexilate may be used in the compositions of the present invention as the free base (3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]methyl}-l -methyl-1 H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino- propionic acid ethyl ester) or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates thereof. The term dabigatran etexilate is employed in this specification to designate any of the above- mentioned forms except when the term is further qualified (i.e. dabigatran etexilate mesylate). Whenever it is necessary to designate the free base of dabigatran etexilate the term "dabigatran etexilate (free base)" is employed.

[0059] The term "pharmaceutically acceptable salt" refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

[0060] In one embodiment the amount of dabigatran etexilate (expressed as dabigatran etexilate mesylate) in the composition can vary from about 20 weight % to about 90 weight %, based on the total weight of the composition. In another embodiment the amount of dabigatran etexilate in the composition can vary from about 25 weight % to about 85 weight %, based on the total weight of the composition. In still another embodiment, the amount of dabigatran etexilate in the composition can vary from about 30 weight % to about 75 weight %, based on the total weight of the composition.

[0061] In one embodiment the compositions of the present invention may be in the form of unit dose forms comprising from 50 mg to 200 mg of dabigatran etexilate mesylate, preferably from 75 mg to 150 mg, more preferably 75 mg, 110 mg or 150 mg.

[0062] In one embodiment of the present invention dabigatran etexilate is used in the form of the mesylate salt, i.e. dabigatran etexilate mesylate. The pharmaceutically acceptable excipients that may be incorporated in the composition of the present invention include, but are not limited to, organic acid, binders, disintegrants, diluents, surfactants, glidants, lubricants, and the like or combinations thereof.

[0063] Organic acids that may be employed in the present composition include, but are not limited to, 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.

[0064] In one embodiment the organic acid is present in the composition of the present invention in an amount of about 2% by weight to about 95% by weight of the composition. In another embodiment the organic acid is present in the composition of the present invention in an amount of about 5% by weight to about 90% by weight of the composition. In a further embodiment the organic acid is present in the composition of the present invention in an amount of about 10% by weight to about 85% by weight of the composition.

[0065] The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, natural, modified or pregelatinized starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500), crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose and the like, combinations thereof and other such materials known to those of ordinary skill in the art.

[0066] The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. 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 or hyprolose), hydroxypropyl methylcellulose (or HPMC or hypromellose), hydroxyethylcellulose, hydroxyethyl methylcellulose, ethyl cellulose, cellulose gum, xanthan gum, sugars (such as sucrose, glucose, amilose, maltodextrin, dextrose and the like), starches such as corn or potato starch partially pregelatinized starches (such as Starch 1500), polyvinyl acetate (Kollicoat SR), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR), copovidone, cross-linked polyvinylpyrrolidone, acrylic acid polymer (Carbopol), poloxamer, polycarbophil, polyethylene oxide, polyethylene glycol, and the like, combinations thereof and other material known to those of ordinary skill in the art.

[0067] The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Examples of suitable diluents include, but are not limited to microcrystalline cellulose, co-processed microcrystalline celluloses (such as Avicel CI-611, 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 known to those of ordinary skill in the art. The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds 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 materials known to those of ordinary skill in the art.

[0068] The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anticaking effect. Such compounds include, but not limited to, colloidal silica, silica gel, precipitated silica, calcium silicate, magnesium silicate, Com starch, talc and their combinations thereof.

[0069] The term "surfactant" as used herein is intended to mean substances used to reduce the surface tension of the aqueous solutions comprising them. Examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, mixtures thereof and other such materials known to those of ordinary skill in the art.

[0070] Further the oral pharmaceutical compositions of the present invention comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein optionally at least one type of particles are coated with a protective coating layer or seal coating layer or barrier coating layer. In one embodiment, the first type of particles is coated with a protective coating layer or seal coating layer or barrier coating layer. In another embodiment, the second type of particles is coated with a protective coating layer or seal coating layer or barrier coating layer. In yet another embodiment, the first and the second type of particles are coated with a protective coating layer or seal coating layer or barrier coating layer. The term "protective coating layer" or “seal coating layer” or “barrier coating layer” as used herein is intended to mean a layer of a polymeric or a non-polymeric material disposed on the surface of a particle core in order to avoid direct contact of the particle core with its environment. In one embodiment, protective coating layer is formed of a polymeric or a non- polymeric pharmaceutically acceptable agent or any combination thereof.

[0071] The polymeric pharmaceutically acceptable agents used for the protective coating layer include, but are not limited to, cellulose derivatives, vinyl derivatives, polymers and copolymers, gums, acrylic or methacrylic acid polymers, copolymers, esters or derivatives thereof, and the like or combinations thereof. 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, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, and the like or combinations thereof. Vinyl derivatives, polymers and copolymers thereof that may be employed include, but are not limited to copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol (Kollicoat IR), polyvinylpyrrolidone or combinations thereof. Gums that may be employed include, but are not limited to, gum arabic, alginates, guar gum, locust bean gum, carrageenan, pectin, xanthan gum, gellan gum, acacia, arabic gum, maltodextrin, galactomannan, karaya, and the like, or combinations. Acrylic or methacrylic acid polymers, copolymers, esters or derivatives thereof, that may be employed include, but are not limited to, a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with / without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate methymethacrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof.

[0072] The non-polymeric pharmaceutically acceptable agents used for the protective coating layer include, but are not limited to C8-C22 fatty acids, C8-C22 fatty alcohols, fats, in particular mono-, di- or triesters of glycerol and C8-C22 fatty acids, waxes, and the like, or combinations thereof. Fatty acids that may be employed include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Long chain monohydric alcohols that may be employed include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof. Waxes that may be employed include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate and the like, or mixtures thereof.

[0073] In a further embodiment, in addition to polymeric or non-polymeric pharmaceutically acceptable agent or any combination thereof, the protective coating layer or seal coating layer may optionally further comprise one or more pharmaceutically acceptable excipients such as, but not limited to, plasticizer, anti-tacking agent, pigment, and the like, or combinations thereof. A plasticizer that may be employed includes, but is not limited to, triethyl citrate, acetyl triethyl citrate, propylene glycol, polyethylene glycol, acetyl tributyl citrate, acetylated monoglycerides, glycerin, triacetin, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl sebacate or a combination thereof. An anti-tacking agent that may be employed includes, but is not limited to, talc, or glyceryl monostearate. A pigment such as, but not limited to, titanium dioxide, iron oxide, or a mixture thereof may be employed.

[0074] The protective coating layer or seal coating layer may be optionally applied onto at least one type of particles of the present invention. For example, the protective coating layer or seal coating layer is applied onto the first type of particles which comprise dabigatran etexilate in the form of free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof. In a preferred embodiment of the present invention the protective coating layer or seal coating layer is coated onto the second type of particles which comprise at least one pharmaceutically acceptable organic acid. In a particular embodiment said coating layer comprises hydroxypropyl methyl cellulose and talc. In another embodiment said coating layer comprises hydroxypropyl cellulose and talc. In another embodiment, both particles are coated with the said protective coating layer or seal coating layer. The protective coating layer or seal coating layer may be optionally applied onto at least a type of particles of the present invention in any suitable equipment where coating can be achieved, such as, but not limited to, coating pan, conventional film coating apparatus or a fluidized bed apparatus, or the like. Furthermore, in one embodiment, the protective coating layer can be applied from an aqueous or organic solution or dispersion. In another embodiment, the particles being coated with the protective coating layer may be coated to a weight gain of about 2% to about 50% by weight. In one embodiment, in order to reduce any damage to the protective coating layer during transfer into capsules, the particles coated with the protective coating layer may be further seal coated with conventional pharmaceutically acceptable film forming agents which may optionally be combined with plasticizers or pigments. Suitable film forming agents include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic and methacrylic acid polymers, copolymers or esters, and the like or combinations thereof. Plasticizers or pigments as discussed above may optionally be used with the film forming agents.

[0075] In another embodiment, the compositions of the present invention comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient. In a further embodiment, the first type of particles comprising dabigatran etexilate may optionally further comprise at least one pharmaceutically acceptable excipient. In another embodiment, the second type of particles comprising at least one organic acid, may optionally further comprise at least one pharmaceutically acceptable excipient. In yet another embodiment, at least two types of particles that are present in the pharmaceutical composition optionally further comprise at least one pharmaceutically acceptable excipient.

[0076] In another aspect the present invention provides a process for the preparation of a composition comprising the two types of particles described above comprising the step of mixing said first type of particles and said second type of particles with a at least one pharmaceutically acceptable excipient. In a particular embodiment of the present invention said first type of particles are prepared by granulation.

[0077] In one embodiment the process of preparing the compositions of the present invention comprises the steps of:

[0078] (i) protective layer is applied to this organic acid containing core material.

[0079] This can be done by conventional methods, e.g. by applying an aqueous dispersion of the water- soluble, pharmaceutically acceptable polymer, optionally with the addition of plasticizers, separating agents and / or pigments, in a fluidized bed, in coating pans or in conventional film coating apparatus. (ii) the active substance is applied from a dispersion containing binder and optionally separating agent. The volatile dispersant is removed during or after the process by drying. Suitable binders in the dispersion may be for example hydroxypropylcellulose, hydroxypropylmethyl cellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copoly mers of N-vinylpyrrolidone and vinyl acetate or combinations of these polymers. Preferably, hydroxypropylcellulose or copolymers of N vinylpyrrolidone and vinyl acetate are used. Suitable separating agents include e.g. talc or silicic acid; preferably, talc is used. The dispersants may be for example ethanol, 2- propanol, acetone or mixtures of these solvents with one another or with water, preferably 2- propanol. The application of active substance to the core material may be carried out by established methods known in pharmaceutical technology, e.g. in coating pans, conventional film coating apparatus or by the fluidized bed method. Then a further screening process may be carried out.

[0080] (iii) To reduce any increased abrasion during transfer into capsules or to increase the shelf life the system may finally be coated with a coating of a pharmaceutically conventional film forming agent, plasticizer and optionally pigment. This may be done by conventional methods as mentioned earlier in the description of the application of the insulating layer.

[0081] (iv) When core material with an average diameter of 0.4 - 2.0 mm is used, the process described above produces pellets containing active substance, which can then be packed into hard capsules, for example. To do this, a number of these units corresponding to the required dosage are packed into hard capsules in a standard capsule filling machine. Suitable hard capsules include, for example, hard gelatin capsules or PEG based gelatin capsules or hard capsules of hydroxy propyl methylcellulose (HPMC); HPMC capsules are preferred. The active substance content of the pharmaceutical composition is 5 to 60 % w / w, preferably 20 to 50 % w / w; the content of the pharmaceutically acceptable organic acid is usually between 10 and 90 % w / w, preferably between 20 and 80 % w / w.

[0082] In another embodiment, the capsule shells are devoid of carrageenan.

[0083] In another embodiment, the capsule shells are devoid of potassium chloride.

[0084] In another embodiment the process of preparing the compositions of the present invention comprises the steps of:

[0085] (i) blending dabigatran etexilate and at least one pharmaceutically acceptable excipient such as diluent;

[0086] (ii) granulating the blend of step (i) with a binder solution to form granules of the active agent; (iii) coating the organic acid pellets with a protective coating layer;

[0087] (iv) blending the granules of step (ii) with the coated pellets of step (iii) to form a mixture of at least two types of particles;

[0088] (v) optionally blending the mixture of at least two types of particles of step (iv) with at least one pharmaceutically acceptable excipient;

[0089] (vi) filling the lubricated mixture of step (viii) into suitable hard capsules.

[0090] In another embodiment the process of preparing the compositions of the present invention comprises the steps of:

[0091] (i) coating dabigatran etexilate and at least one pharmaceutically acceptable excipient over the inert core;

[0092] (ii) coating organic acid pellets with a protective coating layer;

[0093] (iii) blending the pellets of step (i) and (ii);

[0094] (iv) filling the mixture of step (iii) into suitable hard capsules.

[0095] In another embodiment, the present invention relates to pharmaceutical composition of dabigatran for oral administration in the form of pellets comprising (a) substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids such as tartaric acid in weight percentage ranging from 35-45%; and (b) an active substance layer containing one or more binders and optionally a separating agent, that encloses said core material. The separating agent layer or insulating layer which separates the acid core from the active substance containing layer, is present in amounts ranging between 0.75-2 weight percentages of the final filled weight of the finished product. The insulating layer can be selected from cellulosic polymers such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose; gum Arabic, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations of these polymers. This layer can further comprise saccharide polymers such as maltodextrin in 2-4 weight percentages along with the insulating layer polymer and other suitable excipients. The drug layer is layered over the barrier layer. The drug layer can also comprise other pharmaceutically suitable excipients. Such pellets were then filled in capsule shells.

[0096] Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, wherein said dosage form has less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored for 2 months at accelerated conditions at 40°C ± 2 °C and 75% ± 5%RH. Another embodiment relates to a stable solid oral capsule dosage form containing pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein said solid oral capsule dosage form has nitrite (NCh') content of less than 3 PPM, wherein said dosage form has less than 0.75 ppm of N-Nitroso-dabigatran (ND AB) impurity, when stored for 2 months at 25°C ± 2 °C and 60% ± 5%RH.

[0097] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (Nt ') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose.

[0098] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (Nt ') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of carrageenan.

[0099] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (NCb') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of potassium chloride.

[0100] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (NCb') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of both carrageenan and potassium chloride.

[0101] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite (NCh' ) content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.

[0102] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate or its pharmaceutically acceptable salt, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite (NCh') content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.

[0103] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (NCb') content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0. 5 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of carrageenan.

[0104] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (Nt ') content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of potassium chloride.

[0105] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite (NCb') content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm; wherein the capsule comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of both carrageenan and potassium chloride.

[0106] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of carrageenan and has nitrite (NCh') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.

[0107] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate or its pharmaceutically acceptable salt, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of carrageenan and has nitrite (NCh') content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.

[0108] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of potassium chloride and has nitrite (NCh') content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months. Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of potassium chloride and has nitrite (NCh') content less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity for 3 months.

[0109] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of both carrageenan and potassium chloride and has nitrite (NCh') content less than 3 ppm and N- nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity for 3 months.

[0110] Another embodiment of the invention comprises a stable solid oral capsule comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of both carrageenan and potassium chloride and has nitrite (NCh') content less than 3 ppm and N- nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity for 3 months.

[0111] In yet another embodiment, the invention relates to use of a HPMC based capsule shell, to formulate a stable capsule dosage form of dabigatran etexilate mesylate with one or more pharmaceutically acceptable excipient, with a nitrite content nitrite (NCh') content less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity and when stored at 25°C ± 2°C and 60% ± 5% relative humidity.

[0112] In yet another embodiment, the invention relates to use of a HPMC based capsule shell, to formulate a stable capsule dosage form of dabigatran etexilate mesylate with one or more pharmaceutically acceptable excipient, with a nitrite content nitrite (NCh') content less than 1 ppm and N-nitroso-dabigatran (ND AB) content less than 0.5 ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity and when stored at 25°C ± 2°C and 60% ± 5% relative humidity.

[0113] EXAMPLES

[0114] Manufacturing Process The inert core of organic acid was coated with polymer or Acacia or film former either alone or in combination with suitable excipients.

[0115] An additional separation protective layer can be given to the above granulated organic acid or insulated organic acid with suitable protective layer of polymer or film former alone or in combination with suitable excipients to give additional protection from inert organic acid.

[0116] Dabigatran Etexilate Mesylate drug granules / pellets / particles were prepared using inert core with suitable binder or suspension or dispersion consisting of suitable excipients for drug deposition with the process of mixing with suitable excipients or drug loading with binder / dispersion or granulation with binder or blending or compaction or extrusion or fluid bed microencapsulation process.

[0117] Drug particles can be further separated with barrier or seal coating to give additional protection to drug with suitable polymers or film-formers with suitable excipients to give desirable insulation.

[0118] The above insulated organic acid and / or granulated drug and / or seal coated drug were lubricated with suitable lubricant like talc in suitable blender at suitable time to ensure uniform mixing of lubricant with uniform layer on insulated organic acid or granulated particle or seal coated drug.

[0119] Different permutation combinations of drug layer or portions with organic acid layer were filled into capsule shells.

[0120] It was also surprisingly discovered that stable oral capsule compositions of dabigatran etexilate and / or its pharmaceutically acceptable salts when enclosed within hydroxypropyl methylcellulose capsule shells which were devoid of carrageenan and / or potassium chloride and which had low levels of nitrite, displayed the lowest NDAB levels in comparison with capsule compositions of dabigatran etexilate and / or its pharmaceutically acceptable salts which are enclosed within hydroxypropyl methylcellulose capsule shells containing carrageenan and / or potassium chloride.

[0121] Solid oral capsule dosage forms of dabigatran etexilate mesylate were manufactured with formula as depicted in Table-1. Such formulations were then filled in capsule shells of hydroxypropyl methylcellulose, which were devoid of carrageenan and potassium chloride and the solid oral capsules were tested for their nitrite content and NDAB content. Such formulations were also filled in hydroxypropyl methylcellulose capsule shells containing carrageenan and potassium chloride and the solid oral capsules were tested for their nitrite content and NDAB content. The comparative nitrite and NDAB contents of such capsule dosage forms are depicted in Table-2. Table-1: Example-1 Disclose Oral Capsule Formulations of Dabigatran Etexilate Mesylate.

[0122] Table-2: Effect of capsule shell composition on N-Nitroso-dabigatran (ND AB) levels in drug product. The capsule dosage forms of Example- 1 encapsulated in capsule shell comprising hydroxypropyl methylcellulose but devoid of carrageenan and potassium chloride were further tested for stability and its results are shown in Table-3.

[0123] Table-3: N-Nitroso-dabigatran (ND AB) levels in PPM of Example-1.

[0124] Another solid oral capsule dosage forms of dabigatran etexilate mesylate were also manufactured with formula as depicted in Table-4. Such formulations were then filled in capsule shells comprising hydroxypropyl methylcellulose, which were devoid of carrageenan and potassium chloride. The ND AB levels of such finished dosage forms are depicted in Table- 5.

[0125] Table-4: Example-2 Disclose Oral Capsule Formulation of Dabigatran Etexilate Mesylate.

[0126] Table-5: N-Nitroso-dabigatran (ND AB) levels in PPM of Example-2.

[0127] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. A stable solid oral capsule dosage form comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule has nitrite content less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm.

2. A stable solid oral capsule dosage form according to claim 1, wherein the solid oral capsule has nitrite content less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months.

3. A stable solid oral capsule dosage form according to claim 1 , wherein the capsule has nitrite content less than 1 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months.

4. A stable solid oral capsule dosage form according to claim 1, wherein the capsule has N- nitroso-dabigatran (ND AB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months.

5. A stable solid oral capsule dosage form according to claim 1, wherein the capsule comprises a capsule shell of hydroxyl propyl methyl cellulose.

6. A stable solid oral capsule dosage form according to claim 1, wherein the capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of carrageenan.

7. A stable solid oral capsule dosage form according to claim 1, wherein the capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is devoid of potassium chloride.

8. A stable solid oral capsule dosage form according to claim 1, wherein the capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite content less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm.

9. A stable solid oral capsule dosage form according to claim 1, wherein the capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite content less than 1 ppm and N-nitroso-dabigatran (ND AB) content less than 0.5 ppm.

10. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate a stable solid oral capsule dosage form of dabigatran etexilate and at least one pharmaceutically acceptable excipient wherein the stable solid oral capsule has nitrite content (NCU) less than 3 ppm and N-nitroso-dabigatran (ND AB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity and when stored at 25°C ± 2 °C and 60% ± 5% relative humidity.

11. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate a stable solid oral capsule dosage form of dabigatran etexilate as claimed in claim 10 wherein the stable solid oral capsule has nitrite (NCU) content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity and when stored at 25°C ± 2 °C and 60% ± 5% relative humidity.

12. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate a stable solid oral capsule dosage form of dabigatran etexilate as claimed in claim 10 wherein the capsule shell is devoid of carrageenan.

13. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate a stable solid oral capsule dosage form of dabigatran etexilate as claimed in claim 10, wherein the capsule shell is devoid of potassium chloride.

14. A stable solid oral capsule dosage form comprising dabigatran etexilate and at least one pharmaceutically acceptable excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite content less than 3 ppm and N- nitroso-dabigatran (NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months, wherein the capsule shell is devoid of carrageenan and potassium chloride.

15. A stable solid oral capsule dosage form according to claim 14, wherein the solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite content less than 1 ppm and N-nitroso-dabigatran (ND AB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months, wherein the capsule shell is devoid of carrageenan and potassium chloride.

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