DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006

COMPLETE SPECIFICATION
(See Section 10 and rule 13)

TITLE OF THE INVENTION
Pharmaceutical composition comprising Dabigatran
APPLICANT:
(a) Name : ALKEM LABORATORIES LIMITED
(b) Nationality : India
(c) Address : ALKEM HOUSE,
SENAPATI BAPAT MARG, LOWER PAREL,
MUMBAI, MAHARASHTRA, INDIA, PIN CODE 400013
PREAMBLE TO THE DESCRIPTION

COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE OF THE INVENTION
Pharmaceutical composition comprising Dabigatran

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321073282 filed on October 27, 2023.

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising Dabigatran Etexilate or its pharmaceutically acceptable salts thereof. Further, the present invention also relates to a stable pharmaceutical composition of Dabigatran Etexilate or its pharmaceutically acceptable salts thereof, wherein the amount of nitrosamine impurity is below the FDA acceptable intake limit for shelf life of the pharmaceutical composition and method of manufacturing thereof.

BACKGROUND OF THE INVENTION
Dabigatran Etexilate Mesylate is a direct thrombin inhibitor having chemical name as ß-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino] iminomethyl] phenyl] amino] methyl]-1-methyl-1H-benzimidazol-5-yl] carbonyl]-N-2-pyridinyl-, ethyl ester, methanesulfonate. The empirical formula is C34H41N7O5 · CH4O3S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is shown below:

Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
Currently Dabigatran Etexilate Mesylate formulation marketed under tradename PRADAXA® and approved in pellets and capsule dosage forms. PRADAXA® Capsules are supplied in 75 mg, 110 mg, and 150 mg strengths for oral administration.
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.
US patent no. 6,087,380 discloses Dabigatran Etexilate Mesylate and its pharmaceutically acceptable salts.
US patent no. 10,464,938 discloses Ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino] methyl}-1-methyl-1H-benzimidazole-5-carbonyl) pyridin-2-ylamino] propionate methanesulfonate (Dabigatran Etexilate Mesylate) in the crystalline modifications I and II and as the hemihydrate and the use thereof as a pharmaceutical composition.
US patent no. 9,925,174 discloses a pharmaceutical composition for oral administration comprising: (a) a substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids with a water solubility of >1 g / 250 mL at 20° C.; and (b) an active substance layer containing one or more binders and optionally a separating agent, wherein said active substance is ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-- amino]-propionate mesylate; (c) an insulating layer separating said core material and active substance layer, wherein said insulating layer is comprised of a water-soluble polymer, optionally with addition of suitable plasticizers, separating agents and pigments; and (d) an optional coating layer enclosing the active substance layer, wherein the pharmaceutical composition provides a patient with the active substance having a bioavailability that is therapeutically effective at normal and elevated gastric pH.
US patent no. 10,251,840 discloses an improved method of manufacturing substantially spherical/ball-shaped tartaric acid starter pellets which are suitable for preparing active substance-containing medicament formulations, as well as the pellets as such that may be obtained in this way, and their use as starting material for the preparation of active substance-containing medicament formulations.
PCT patent application WO2009/118322 describes a process characterized by a series of partial steps. First, the core is produced from a pharmaceutically acceptable organic acid, preferably tartaric acid by powder layering. The cores are then converted into so-called isolated tartaric acid cores by spraying on an isolating suspension. A dabigatran etexilate suspension prepared subsequently is sprayed onto these coated cores in one or more process steps by means of a coating process. Dabigatran etexilate methanesulfonate, as polymorph I, is suspended together with talc and hydroxypropylcellulose in isopropanol (isopropyl alcohol, 2-propanol, 2-PrOH), the preparation of the suspension being carried out at a temperature not exceeding 30° C. Finally, the active substance pellets thus obtained are packed into suitable capsules.
The compositions described in the above patents/publications contain a tartaric acid core, which increases the dissolution rate of dabigatran by modifying the pH of the microenvironment when the pellet is dissolved. On the other hand, dabigatran is unstable in the presence of tartaric acid; therefore, an isolating layer between the tartaric acid and Active Pharmaceutical Ingredient (API) layer has to be applied.
Dabigatran contains amine functional group and the formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions.
The FDA has been investigating the presence of nitrosamine impurities in certain drug products since 2018. The FDA is concerned about exposure to nitrosamine impurities above acceptable levels over long periods of time, which may increase the risk of cancer. The FDA became concerned about seven nitrosamine impurities that theoretically could be present in drug product are N-nitrosodimethylamine (NDMA), Nnitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA).
On September 1, 2020, the U.S. Food and Drug Administration (FDA) issued Guidance for Industry: Control of Nitrosamine Impurities in Human Drugs to provide the agency’s current thinking on the issue of nitrosamine impurities in active pharmaceutical ingredients (APIs) and drug products. The Guidance describes what the FDA has learned from its investigation of nitrosamine impurities, the manufacturing conditions that have the potential to introduce these impurities, and the steps that manufacturers of APIs and drug products should take to prevent unacceptable levels of nitrosamine impurities. The Guidance also discusses risk assessment strategies to identify drugs that may be at risk for the presence of these impurities.
The March 2023 voluntary recall of Dabigatran Etexilate Capsules due to presence of N-Nitroso-dabigatran (NDAB) from the U.S. market is putting nitrosamine drug substance related impurities (NDSRI) in the spotlight once again.
Therefore, there is always a need in art to develop an alternate pharmaceutical composition of dabigatran which is stable and the amount of nitrosamines impurities does not exceed beyond the FDA acceptable intake limit for shelf life of the pharmaceutical composition. Surprisingly, inventors of the present invention reformulated stable composition of dabigatran which contains nitrosamine impurities within FDA acceptable intake limit by improved manufacturing process, by using stabilizer and by using microcrystalline cellulose having low nitrite content i.e. not more than 200 µg/kg.

SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising Dabigatran Etexilate or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises Dabigatran Etexilate or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients selected from the group consisting of diluents, lubricants, glidants, Antioxidants/stabilizers, binder, pH modifiers, enteric coating polymer, colorants and solvents.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or its pharmaceutically acceptable salts thereof comprising: a first portion/drug pellet; and a second portion/acid pellets.
In yet another aspect of the invention, the first portion of pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises microcrystalline cellulose and other pharmaceutically acceptable excipients.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises microcrystalline cellulose and other pharmaceutically acceptable excipients; wherein said composition is prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises: microcrystalline cellulose; ascorbic acid; and other pharmaceutically acceptable excipients; wherein said composition is prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the stable pharmaceutical composition comprising dabigatran, microcrystalline cellulose, one or more stabilizing agents, and one or more pharmaceutically acceptable excipients, wherein the stabilizing agent is ascorbic acid and wherein the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of dabigatran.
In one aspect of the invention, an oral stable pharmaceutical capsule composition comprising about 10 to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the present invention provides pharmaceutical composition comprising:
about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of diluent; about 0.1 % w/w to about 3 % w/w of binder; about 30 % w/w to about 50 % w/w of pH modifier; and optionally other pharmaceutically excipients, wherein the pharmaceutical composition is stable for at least 24 hours.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate mesylate which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 0.75 % w/w.
In yet another aspect, the present invention provides Dabigatran Etexilate mesylate, wherein one or more of Impurity – I (Ethyl 2-{[ ( 4- {N' -[ (hexyloxy) carbonyl]carbamimidoyl} phenyl)amino ]methyl}-1-methyl-1 H-benzimidazole-5-carboxylate), Impurity – II (Ethyl 3-{[(2-{[( 4-{N' -[(hexyloxy)carbonyl]carbamoyl}phenyl)amino ]methyl}-1-methyl-lH-benzimidazole-5-yl) carbonyl](2-pyridinyl)amino} propanoate), Impurity – III (3-{[(2-{[( 4-{N' -[(hexyloxy) Carbonyl]carbamimidoyl }phenyl)amino ]methyl }-1-methyl-1H-benzimidazole-5-yl)carbonyl(2-pyridinyl)amino} propanoic acid), Impurity – IV (Ethyl 3-{[(2-[( 4-carbamimidoyl-phenylamino )-methyl]-1-methyl-lH-benzoimidazole-5-carbonyl }-pyridin-2-yl-amino) propanoate), Impurity – a (N-[2-(4-Amidophenyl amino-methyl)-1-methyl-lH-benzodiol-5-yl carbonyl]-N-(2-pyridyl)-betaalanine ethyl ester), Impurity – b (3-( (2-( ( 4-Carbamoyl-phenylamino )-methyl)-1-methyl-1 H-benzoimidazole-5-carbonyl)-pyridin-2-yl-amino )-propionic acid ethyl ester), Impurity – c (N-[[2-[[[ 4-(Aminoiminomethyl)phenyl]amino ]methyl]-1-methyl-lH-benzimidazol-5-yl ]carbonyl ]-N-2-pyridinyl-B-alanine), Impurity – d (3-(2-(( 4-Carbamoylphenylamino) methyl)-1-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5- carboxamido) propanoic acid) and Impurity - e (N-[[2-[[[ 4-[[[(Hexylo ]amino ]methyl]-1-methyl-1 H-benzimidazol-5-xido-2-pyridinyl)- -Alanine Ethyl Ester),N-[[2-[[[4-[[[(Hexyloxy)carbonyl] amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-(1-oxido-2-pyridinyl)-ß-Alanine Ethyl Ester, Ethyl 3-(2-(((4-(N-((hexyloxy)carbonyl) carbamimidoyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, N-Nitroso- 4-(Methylamino)-3-nitrobenzoic acid, Ethyl 3-(nitroso(pyridin-2-yl)amino)propanoate, Ethyl 3-(3-amino-4-(methyl (nitroso)amino)-N-(pyridin-2-yl)benzamido)propanoate, N-(4-cyanophenyl)-N-nitrosoglycine, Ethyl 5-(3-(2-((4-cyanophenyl)(nitroso)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl) benzamido)pentanoate, Ethyl 3-(2-(((4-cyanophenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, Ethyl 3-(2-(((4-(ethoxy(imino)methyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, Ethyl 3-(2-(((4-carbamimidoylphenyl) (nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole -5-carboxamido) propanoate, Ethyl 2-(((4-carbamimidoylphenyl)(nitroso)amino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylate, Ethyl (E)-2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl) phenyl)(nitroso)amino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylate, 3-(2-(((4-(((Hexyloxy)carbonyl)carbamoyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid, Ethyl 3-(2-(((4-(((hexyloxy)carbonyl) carbamoyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, 3-(2-(((4-Carbamimidoylphenyl)(nitroso) amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid hydrochloride, (E)-3-(2-(((4-(N'-((Hexyloxy)carbonyl)carbamimidoyl) phenyl)(nitroso)amino) methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid, Methyl (E)-3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl) phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, Ethyl 3-(4-(methyl(nitroso)amino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate, Ethyl (E)-3-(2-(((4-(N'-(methoxycarbonyl) carbamimidoyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, Ethyl (E)-3-(2-(((4-(N'-(ethoxycarbonyl) carbamimidoyl)phenyl)(nitroso)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido)propanoate are present in an amount of less than 1.5 % w/w, preferably less than 0.75% w/w relative to the total amount of Dabigatran Etexilate mesylate.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate mesylate which is substantially free of nitrosamine impurity i.e. total nitrosamine impurity present in the composition in an amount of less than 1000 parts per billion (ppb), preferably less than 700 ppb. In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof which contains less than 700 ppb of N-Nitroso-dabigatran (NDAB) impurity after at least 1 months of storage at 25°C. and 60% relative humidity (RH). In yet another aspect, composition contains N-nitroso-dabigatran not more than 1.5 ppm after at least 3 months of storage at 25° C. and 60% RH.
Another aspect of the present invention provides pharmaceutical composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of diluent; about 0.1 % w/w to about 3 % w/w of binder; about 30 % w/w to about 50 % w/w of pH modifier; and optionally other pharmaceutically excipients, wherein, said pharmaceutical composition is in the form of capsule or tablet.
Another aspect of the present invention provides pharmaceutical composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of microcrystalline cellulose; about 0.01 % w/w to about 3 % w/w of binder selected from hydroxypropyl cellulose, povidone or mixture thereof; about 30 % w/w to about 50 % w/w of pH modifier selected from citric acid, malic acid, tartaric acid, adipic acid, or mixture thereof; and optionally other pharmaceutically excipients. In preferred embodiments, pH modifier contains about 30 % w/w to about 50 % w/w of combination of citric acid and tartaric acid.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol, wherein the said tartaric acid containing second portion is separate and distinct from the first portion.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, hydroxy propyl cellulose, and ascorbic acid; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, polyethylene and glycol, wherein the said tartaric acid containing second portion is separate and distinct from the first portion.
In yet another aspect, manufacturing method of the composition involves preparation of a first portion and a tartaric acid containing second portion separately followed filling into capsules.
In yet another aspect of the present invention provides pharmaceutical composition comprising: A) a first portion comprising: a) Core drug pellets comprising about 33 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 15 % w/w of microcrystalline cellulose; about 0.038 % w/w of Butylated hydroxytoluene; about 0.76 % w/w of Hydroxypropyl cellulose; b) Insulated Layering over Core drug pellets comprising coating with opadry white in an amount of about 2.3 % w/w; c) Moisture barrier layer coating over insulated drug pellets by using opadry white in an amount of about 1.9 % w/w; d) Citric acid layer coating on moisture barrier drug pellets using composition comprising: about 4.75 % w/w of citric acid monohydrate; about 0.095 % of povidone; about 3.80 % w/w of talc; and Ethanol 96% V/V in required quantity e) Lubrication of acid coated drug pellets by using about 0.20 % w/w of talc. B) a second portion comprising: about 38% w/w of tartaric acid; about 0.76 % w/w of Hypromellose phthalate; about 0.30 % w/w of talc; about 0.22 % w/w of Polyethylene glycol; and required quantity of Isopropyl alcohol and Methylene chloride; wherein the said second portion lubricated using about 0.2% w/w of talc C) Filling of first portion and second portion in capsule. In yet another aspect of the present invention provides pharmaceutical composition comprising: A) a first portion comprising a) Core drug pellets comprising about 33 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 15 % w/w of microcrystalline cellulose; about 0.038 % w/w of Butylated hydroxytoluene; about 0.76 % w/w of Hydroxypropyl cellulose; about 0.3 % w/w of ascorbic acid; b) Insulated Layering over Core drug pellets comprising coating with opadry white in an amount of about 2.3 % w/w; c) Moisture barrier layer coating over insulated drug pellets by using opadry white in an amount of about 1.9 % w/w; d) Citric acid layer coating on moisture barrier drug pellets using composition comprising: about 4.75 % w/w of citric acid monohydrate; about 0.095 % of povidone; about 3.80 % w/w of talc; and Ethanol 96% v/v in required quantity e) Lubrication of acid coated drug pellets by using about 0.20 % w/w of talc B) a second portion comprising: about 38% w/w of tartaric acid; about 0.76 % w/w of hypromellose phthalate; about 0.30 % w/w of talc; about 0.22 % w/w of Polyethylene glycol; and required quantity of isopropyl alcohol and methylene chloride; wherein the said second portion lubricated using about 0.2% w/w of talc C) Filling of first portion and second portion in capsule.
In yet another aspect, manufacturing method of the composition involves preparation of a first portion by steps: a) Dispensing of raw materials; b) Sifting of intra-granular material; c) Addition of binder solution; d) Granulation in rapid mixer granulator followed by extrusion and spheronization; e) Drying of the core of drug pellets by fluidized bed processor (FBP); f) Insulating layer coating to core of drug pellet followed by drying using FBP; g) Moisture barrier layer coating to insulated layer of coating followed by drying by FBP; h) Acid layer coating to moisture barrier layer coating followed by drying using FBP; i) Extragranular lubrication using lubricants followed by drying in FBP and then lubricating first portion.
In yet another aspect, manufacturing method of the composition involves preparation of a first portion by steps: a) Dispensing of raw materials; b) Sifting of intra-granular material; c) Addition of binder solution; d) Granulation in rapid mixer granulator followed by extrusion and spheronization; e) Drying of the core of drug pellets by Rotocone Vacuum Dryer (RCVD); f) Insulating layer coating to core of drug pellet followed by drying using RCVD; g) Moisture barrier layer coating to insulated layer of coating followed by drying by RCVD; h) Acid layer coating to moisture barrier layer coating followed by drying using RCVD; i) Extragranular lubrication using lubricants followed by drying in RCVD and then lubricating first portion.
In yet another aspect, manufacturing method of the composition involves preparation of a second portion containing tartaric acid by steps: a) Dispensing of raw materials; b) Coating of hypromellose phthalate coating on tartaric acid pellets followed by lubrication. In yet another aspect, addition of first portion and a tartaric acid containing second portion into capsules.
In yet another aspect, the composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related substances, content uniformity, blend uniformity, Hardness, thickness, Friability, Bulk density, tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."
The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.
The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.
The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. dabigatran etexilate and its salt, prodrugs, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.
The term “dabigatran or dabigatran etexilate” includes all pharmaceutically acceptable salts, prodrugs, esters, isomers, stereo isomers, crystalline and amorphous forms. Pharmaceutically acceptable salts of dabigatran include but not limited to tosylate, oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, mesylate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, palmitate, and gluconate salts; preferably mesylate salt of dabigatran etexilate. Dabigatran etexilate mesylate present in the composition in an amount of 25-500 mg, preferably 50-250 mg, more preferably 172.95 mg, 126.83 mg and 86.48 mg.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
As used herein, the term “substantially free of any impurity” means total impurity present in the composition in an amount of less than or equal to 0.75% w/w.
The terms “nitrosamine”, “N Nitroso dabigatran, and “NDAB” are used interchangeably and should be understood to refer to the following structure:

The terms “FDA acceptable intake limit” of nitrosamine impurity as used in the present invention is the upper limit set by FDA for daily intake of nitrosamine impurity below which there is no harmful side-effect likely to occur on long term treatment with the therapeutically active agent. Particularly, the NDAB impurity present in the composition in an amount of less than 700 parts per billion (ppb).
As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, diluents, lubricants, glidants, Antioxidants/stabilizers, binder, pH modifiers, enteric coating polymer, colorants, solvents and any other excipient known to the art for making solid oral pharmaceutical composition.
The term “core” as used herein, refers to an interior compartment of a unit dosage form.
The term “protective 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.
The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.
The term “excipient” means a pharmacologically inactive component such as a binder, solvent, diluent, disintegrant, carrier, lubricant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.
By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising dabigatran suitable for administration such as a hard or soft gelatin capsule, tablet, caplet, mini-tablets, pellets, granules, pills, suspension and the like. The pharmaceutical dosage form can be prepared by methods known in the art, such as dry granulation or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent. The material obtained by suitable methods known in the art can be filled into capsules or made into tablets.
The capsules of the present disclosure include, for example, hard or soft gelatin capsule. Hard gelatin capsules are two-piece gel encapsulations of solid material. The capsule shell consists of two halves, an outer half and an inner half, which when joined and sealed form a secure enclosure for the material contained therein. The active pharmaceutical ingredient, i.e., the dabigatran, may be comprised as a powder, or as one or more granules or pellets within the capsule. Soft gelatin capsules are single-piece gel encapsulations of solid material, and such solid material may be in the form of an aqueous gel.
Dabigatran etexilate or pharmaceutically acceptable salt thereof may be present in an amount of about 20 to about 50 % w/w, preferably about 30 to about 40 % w/w, more preferably about 35 % w/w of the composition.
The present invention provides a pharmaceutical composition comprising Dabigatran Etexilate or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises Dabigatran Etexilate or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients selected from the group consisting of diluents, lubricants, glidants, Antioxidants/stabilizers, binder, pH modifiers, enteric coating polymer, colorants and solvents.
Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, mannitol, sorbitol or other sugar alcohols, isomalt, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is microcrystalline cellulose. Different grades of microcrystalline cellulose were used as diluents such as Avicel® PH-101, Avicel® PH-102, Avicel® PH-105, Avicel® PH112, Avicel® PH112 LN, Avicel® PH-113, Avicel® PH-301, and Avicel® PH-302, etc. Diluent may be present in an amount of about 10 % w/w to about 20 % w/w, preferably about 15 % w/w of the composition. The pharmaceutical composition comprising microcrystalline cellulose has particle size distribution D90 in the range of about 160 µm to about 295 µm, loss on drying not more than 1.5 % w/w, bulk density about 0.28 to about 0.34 g/mL, and nitrite content not more than 200 µg/kg.
Disintegrants according to the present invention are selected from, but not limited to, croscarmellose sodium, crospovidone, carmellose calcium, sodium starch glycolate, polacrilin potassium, starches, substituted hydroxypropyl cellulose, powdered agar and like used either alone or in combinations thereof.
Lubricants/glidants according to the present invention are selected from, but not limited to, magnesium stearate, calcium stearate, aluminium stearate, sucrose stearate, sucrose fatty acid ester, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, polyethylene glycol, talc, and the like used either alone or in combinations thereof. Lubricant/glidant can be added in an amount of about 0.1 % w/w to about 10 % w/w of the composition.
Antioxidants/stabilizers are used to prevent oxidation, thereby preventing the deterioration of the preparation. Suitable Antioxidants/stabilizers for use in the present invention include but not limited to propyl gallate, butylated hydroxyanisole (BHA), ascorbic acid (vitamin C), butylated hydroxytoluene (BHT), and combinations thereof and the most preferably used antioxidant is butylated hydroxytoluene (BHT). Additionally, ascorbic acid (vitamin C) may be used in the present invention to lower nitrosamine formation. Addition of Ascorbic acid in the present invention in an amount of 1 mg to 5 mg has provided better control over the NDSRI impurity. Ascorbic acid is suppressing the impact of nitrite in the formulation and by which the control over the nitrosamine impurity in the finished product. Antioxidants/stabilizers may be present in an amount of about 0.01 % w/w to about 0.5 % w/w, preferably about 0.04 % w/w of the composition.
Binder according to the present invention are selected from, but not limited to microcrystalline cellulose, polyvinylpyrrolidone (PVP), eg, PVP K 30, PVP-K value 25, or PVP90F, polyethylene glycols (PEG), eg, PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, or combinations thereof. When present, a binder may be employed in an amount ranging from about 0.05 % to about 5%, by weight of the pharmaceutical composition.
pH modifiers according to the present invention are selected from, but not limited to organic acid or inorganic acid selected from fumaric acid, citric acid, tartaric acid, malic acid, succinic acid, adipic acid, maleic acid, lactic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid or combinations thereof; organic or inorganic base selected pyridine, alkanamines, methylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, imidazole, histidine, guanidine, and 1,2-diaminoethane or combinations thereof. pH modifier is used to coat the drug pellets as well as used as separate pellets. Preferably citric acid is present as second portion and acts as pH modifier. Preferably citric acid is used to coat the drug pellets and tartaric acid pellets used as separate pellets. pH modifiers may be present in an amount of about 1 % w/w to about 50 % w/w, wherein citric acid is present in an amount of 2 % w/w to about 8% w/w, preferably about 4.75 % w/w of the composition and tartaric acid is present in an amount of 30 %w/w to about 50% w/w, preferably about 38 % w/w of the composition.
Enteric coating polymers according to the present invention are selected from, but not limited to shellac poly (methacrylic acid-co-methyl methacrylate), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS)
‘‘Colorants’’ is a substance that is preferably added to the coating agent for coating of the pharmaceutical composition. Pharmaceutically acceptable colorants include but not limited to red iron oxide non-irradiated, iron oxide black, Ferrosoferric oxide, tartrazine, erythrosine, amaranth lake, opadry systems, titanium dioxide, and iron oxide yellow or any combination thereof.
A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a solution. Examples include but not limited to purified water, methylene chloride, alcoholic solvents methanol, ethanol, isopropyl alcohol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and nbutyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or its pharmaceutically acceptable salts thereof comprising: a first portion/drug pellet; and a second portion/acid pellets.
The oral pharmaceutical composition of the present invention comprises a mixture of at least two types of portions and optionally at least one pharmaceutically acceptable excipient, with a first portion comprising dabigatran etexilate and second type of particles comprising at least one pharmaceutically acceptable organic acid.
In a preferred embodiment of the present invention the first portion comprising dabigatran etexilate is free from organic acids.
In another preferred embodiment of the present invention the second portion comprising at least one pharmaceutically acceptable organic acid.
In yet another aspect of the invention, the first portion of pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises microcrystalline cellulose and other pharmaceutically acceptable excipients.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises microcrystalline cellulose and other pharmaceutically acceptable excipients; wherein said composition of is prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprises: microcrystalline cellulose; ascorbic acid; and other pharmaceutically acceptable excipients; wherein said composition is prepared by using Rotocone Vacuum Dryer (RCVD).
In yet another aspect of the invention, the stable pharmaceutical composition comprising dabigatran, microcrystalline cellulose, one or more stabilizing agents, and one or more pharmaceutically acceptable excipients, wherein the stabilizing agent is ascorbic acid and wherein the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of dabigatran.
In one aspect of the invention, an oral stable pharmaceutical capsule composition comprising about 10 to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the present invention provides pharmaceutical composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of diluent; about 0.1 % w/w to about 3 % w/w of binder; about 30 % w/w to about 50 % w/w of pH modifier; and optionally other pharmaceutically excipients, wherein the pharmaceutical composition is stable for at least 24 hours.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 0.75 % w/w.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof which is substantially free of nitrosamine impurity i.e. total nitrosamine impurity present in the composition in an amount of less than 1000 parts per billion (ppb), preferably less than 700 ppb.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof which contains less than 700 ppb of N-Nitroso-dabigatran (NDAB) impurity after at least 1 months of storage at 25° C. and 60% relative humidity (RH).
Another aspect of the present invention provides pharmaceutical composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of diluent; about 0.01 % w/w to about 3 % w/w of binder; about 30 % w/w to about 50 % w/w of pH modifier; and optionally other pharmaceutically excipients, wherein, said pharmaceutical composition is in the form of capsule or tablet.
Another aspect of the present invention provides pharmaceutical composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of microcrystalline cellulose; about 0.1 % w/w to about 3 % w/w of binder selected from Hydroxypropyl cellulose, povidone or mixture thereof; about 30 % w/w to about 50 % w/w of pH modifier selected from citric acid, malic acid, tartaric acid, adipic acid, or mixture thereof; and optionally other pharmaceutically excipients. In preferred embodiments, pH modifier contains about 30 % w/w to about 50 % w/w of combination of citric acid and tartaric acid.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising; a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol, wherein the said tartaric acid containing second portion is separate and distinct from the first portion.
In yet another aspect of the invention, the pharmaceutical composition comprising: a mixture of at least two distinct types of portions wherein a) the first type of portion comprise dabigatran etexilate in the form of the free base or in the form of a pharmaceutically acceptable salt thereof; and b) the second type of portion comprise at least one pharmaceutically acceptable organic acid, wherein the second type of particles is coated with a protective coating layer and is free from dabigatran etexilate.
In yet another aspect of the invention, the pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, hydroxy propyl cellulose, and ascorbic acid; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol, wherein the said tartaric acid containing second portion is separate and distinct from the first portion.
In yet another aspect of the invention, the pharmaceutical composition comprising: a mixture of at least two distinct types of portions wherein a) the first type of portion comprise dabigatran etexilate in the form of the free base or in the form of a pharmaceutically acceptable salt thereof; and b) the second type of portion comprise at least one pharmaceutically acceptable organic acid, wherein the second type of particles is coated with a protective coating layer and is free from dabigatran etexilate.
In yet another aspect, manufacturing method of the composition involves preparation of a first portion and a tartaric acid containing second portion separately followed filling into capsules.
In yet another aspect of the present invention provides pharmaceutical composition comprising A) a first portion comprising: a) Core drug pellets comprising about 33 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 15 % w/w of microcrystalline cellulose; about 0.038 % w/w of Butylated hydroxytoluene; about 0.76 % w/w of Hydroxypropyl cellulose; b) Insulated Layering over Core drug pellets comprising coating with opadry white in an amount of about 2.3 % w/w; c) Moisture barrier layer coating over insulated drug pellets by using opadry white in an amount of about 1.9 % w/w; d) Citric acid layer coating on moisture barrier drug pellets using composition comprising: about 4.75 % w/w of citric acid monohydrate; about 0.095 % of povidone; about 3.80 % w/w of talc; and Ethanol 96% V/V in required quantity e) Lubrication of acid coated drug pellets by using about 0.20 % w/w of talc B) a second portion comprising: about 38% w/w of tartaric acid; about 0.76 % w/w of Hypromellose phthalate; about 0.30 % w/w of talc; about 0.22 % w/w of Polyethylene glycol; and required quantity of Isopropyl alcohol and Methylene chloride; wherein the said acid pellets lubricated using about 0.2% w/w of talc C) Filling of first portion and second portion in capsule.
In yet another aspect, manufacturing method of the composition involves preparation of a first portion by steps: a) Dispensing of raw materials; b) Sifting of intra-granular material; c) Addition of binder solution; d) Granulation in rapid mixer granulator followed by extrusion and spheronization; e) Drying of the core of drug pellets by fluidized bed processor (FBP); f) Insulating layer coating to core of drug pellet followed by drying using FBP; g) Moisture barrier layer coating to insulated layer of coating followed by drying by FBP; h) Acid layer coating to moisture barrier layer coating followed by drying using FBP; i) Extragranular lubrication using lubricants followed by drying in FBP and then lubricating first portion.
In yet another aspect, manufacturing method of the composition involves preparation of a second portion containing tartaric acid by steps: a) Dispensing of raw materials; b) Coating of hypromellose phthalate coating on tartaric acid pellets followed by drying in FBP and lubrication.
In yet another aspect, addition of first portion and a tartaric acid containing second portion into capsules.
The composition of the invention can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc. Conventionally, the bottles used are composed of plastic, typically high-density polyethylene (HDPE).

EXAMPLES
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Example 1:
Ingredients 150 mg (mg/cap) 75 mg (mg/cap)
Part –I Drug Pellets a) Core drug pellets
Dabigatran etexilate mesylate 172.950 86.475
Microcrystalline cellulose (GR112) 80.000 40.000
Butylated hydroxytoluene 0.200 0.100
Hydroxypropyl cellulose 4.000 2.000
Isopropyl alcohol q.s. q.s.
Core Drug pellets Weight 257.15 128.575
b) Insulated Layering over core drug pellets
Opadry white YS-1-7040 12.000 6.000
Isopropyl alcohol q. s. q. s.
Methylene chloride q. s q. s
Weight of Insulated drug pellets 269.15 134.575
c) Moisture Barrier Layer over insulated drug pellets
Opadry 200 white 10.000 5.000
Purified water q. s. q. s.
Weight of Moisture Barrier drug Pellets 279.15 139.575
d) Citric Acid Layer over Moisture barrier drug pellets
Citric acid monohydrate 25.000 12.500
Povidone (k-value-25) 0.500 0.250
Talc 9.500 4.750
Ethanol 96% v/v q.s. q.s.
Talc 2.000 1.000
Weight of Acid Coated Drug Pellets 316.15 158.075
e) Lubrication of Acid Coated drug pellets
Talc 1.050 0.525
Weight of Lubricated Drug Pellets 317.2 158.600
Part –II Acid pellets: a) Seal coating over Tartaric acid pellets
Tartaric acid 200.000 100.00
Hypromellose phthalate (HP-50) 4.000 2.000
Talc 1.600 0.800
Polyethylene glycol 1.200 0.600
Isopropyl alcohol q.s. q.s.
Methylene chloride q. s q. s
Weight of seal coated Pellets 206.800 103.400
Lubrication of Seal coated Tartaric acid Pellets
Talc 1.000 0.500
Lubricated seal coated Pellets weight 207.800 103.900
Lubricated Drug Pellets + Lubricated Seal coated Tartaric acid Pellets 525.000 262.500
EHPMC CAP 1 No.
EHPMC CAP 1 No.

q. s: Quantity sufficient.
Manufacturing process for example 1:
A) Manufacturing of the composition involves preparation of a first portion by steps as below:
a) Raw materials were dispensed.
b) Dabigatran, Microcrystalline Cellulose (Avicel PH 112) and BHT were sifted.
c) HPC was added into the above step b.
d) Granulation was performed using rapid mixer granulator followed by extrusion and spheronization.
e) Core of drug pellets by fluidized bed processor (FBP) were dried.
f) Insulating layer was prepared using Opadry system in solvents isopropyl alcohol and methylene chloride; then insulating layer coating to core of drug pellet was done using opadry system followed by drying using FBP.
g) Moisture barrier layer coating to insulated layer of coating of aqueous opadry system was followed by drying by FBP.
h) Citric acid, povidone, ethanol under constant stirring for until clear solution was obtained and then citric acid layer coating to moisture barrier layer coating was followed by drying using FBP;
i) Extragranular lubrication using talc was followed by drying in FBP and then again lubricating first portion by using talc.
B) Manufacturing of the composition involves preparation of a tartaric acid coated pellets as below:
a) Preparation of seal coating dispersion of hypromellose phthalate using solvents isopropyl alcohol, methylene chloride, and polyethylene glycol 600.
b) Coating tartaric acid pellets using seal coating dispersion obtained in above step followed by drying in FBP and lubrication with talc.
C) Addition of first portion [A] and a tartaric acid containing second portion [B] into suitable capsule.
The composition obtained in example 1 was subjected for nitrosamine impurity testing and results as below:
Product Name Sample Result (N-Nitroso Dabigatran in ppb)
Dabigatran Etexilate Mesylate Capsules 150 mg Sample 1 (150 mg) 570.972 ppb
Sample 2 (150 mg) 507.083 ppb
Sample 3 (150 mg) 590.627 ppb
Dabigatran Etexilate Mesylate Capsules 75 mg Sample 1 (75 mg) 226.796 ppb
Sample 2 (75 mg) 1031.712 ppb
Sample 3 (75 mg) 1088.653 ppb
Based on the above results of N-Nitroso Dabigatran impurity some of the samples were out of specification, hence inventors of the present invention have checked nitrite contents of all excipients used in drug pellets which were found to be leading cause of formation of nitrosamine impurity in the finished product and method of manufacturing were modified in order to control the nitrosamine impurity. The reformulated examples 2-4 along with its results were compared with respect to example 1 and are mentioned as below:
Example 2:
Ingredients 150 mg (mg/cap) % w/w
Part-I Core drug pellets
a) Core Drug pellets
Dabigatran etexilate mesylate 172.95 32.94
Microcrystalline Cellulose (Avicel PH 112 LN) 80.00 15.24
Butylated hydroxytoluene (BHT) 0.20 0.038
Hydroxypropyl cellulose (HPC) 4.000 0.76
Isopropyl alcohol q.s. --
Drug pellets weight 257.150 48.98
b) Insulated Layering over Core drug pellets
OPADRY WHITE YS-1-7040 12.000 2.285
Isopropyl alcohol q.s. --
Methylene chloride q.s --
Weight of Insulated drug pellets 269.150 51.26
c) Moisture Barrier Layer Over Insulated Drug Pellets
OPADRY 200 WHITE (200F280000) 10.000 1.90
Purified water q.s. --
Weight of Moisture Barrier drug Pellets 279.150 53.17
Citric Acid Layer on Moisture barrier drug pellets
Citric acid monohydrate 25.000 4.76
Povidone (K-VALUE-25) 0.500 0.095
Talc 9.500 1.809
Ethanol 96% V/V q.s. --
Talc 2.000 0.38
Weight of Acid Coated Drug Pellets 316.150 60.22
Lubrication of Acid Coated Drug Pellets
Talc 1.050 0.20
Weight of Lubricated Drug Pellets 317.200 60.42
Part-II Acid Pellets
Tartaric acid 200.000 38.09
Hypromellose phthalate (hp-50) 4.000 0.76
Talc 1.600 0.30
Polyethylene glycol 600 1.200 0.22
Isopropyl alcohol q.s. --
Methylene chloride q. s --
Weight of seal coated Pellets 206.800 39.39
Lubrication of Seal coated Tartaric acid Pellets
Talc 1.000 0.19
Lubricated seal coated Pellets weight 207.80 39.58
Capsule Filling
Lubricated Drug Pellets + Lubricated Seal coated Tartaric acid Pellets 525.000 100
EHPMC CAP 1 No. --
q. s: Quantity sufficient.
Manufacturing process for example 2:
A) Manufacturing of the composition involves preparation of a first portion by steps as below:
a) Raw materials were dispensed
b) Dabigatran, Microcrystalline Cellulose (Avicel PH 112 LN) and BHT were sifted
c) HPC was added into the above step b
d) Granulation was performed using rapid mixer granulator followed by extrusion and spheronization
e) Core of drug pellets by fluidized bed processor (FBP) were dried
f) Insulating layer was prepared using Opadry system in solvents isopropyl alcohol and methylene chloride; then insulating layer coating to core of drug pellet was done using opadry system followed by drying using FBP
g) Moisture barrier layer coating to insulated layer of coating of aqueous opadry system was followed by drying by FBP
h) Citric acid, povidone, ethanol under constant stirring for until clear solution was obtained and then citric acid layer coating to moisture barrier layer coating was followed by drying using FBP;
i) Extragranular lubrication using talc was followed by drying in FBP and then again lubricating first portion by using talc.
B) Manufacturing of the composition involves preparation of a tartaric acid coated pellets as below:
a) Preparation of seal coating dispersion of hypromellose phthalate using solvents isopropyl alcohol, methylene chloride, and polyethylene glycol 600.
b) Coating tartaric acid pellets using seal coating dispersion obtained in above step followed by drying in FBP and lubrication with talc.
C) Addition of first portion [A] and a tartaric acid containing second portion [B] into suitable capsule.
Example 3
Ingredients 150 mg (mg/cap) % w/w
Part-I - Core Drug pellets
a) Core Drug pellets
Dabigatran etexilate mesylate 172.95 32.94
Microcrystalline Cellulose (Avicel PH 112 LN) 80.00 15.24
Butylated hydroxytoluene 0.20 0.038
Hydroxypropyl cellulose 4.000 0.76
Isopropyl alcohol q.s. --
Drug pellets weight 257.150 48.98
b) Insulated Layering over Core drug pellets
OPADRY WHITE YS-1-7040 12.000 2.285
Isopropyl alcohol q.s. --
Methylene chloride q.s --
Weight of Insulated drug pellets 269.150 51.26
c) Moisture Barrier Layer Over Insulated drug Pellets
OPADRY 200 WHITE (200F280000) 10.000 1.90
Purified water q.s. --
Weight of Moisture Barrier drug Pellets 279.150 53.17
Citric Acid Layer on Moisture barrier drug pellets
Citric acid monohydrate 25.000 4.76
Povidone (K-VALUE-25) 0.500 0.095
Talc 9.500 1.809
Ethanol 96% V/V q.s. --
Talc 2.000 0.38
Weight of Acid Coated Drug Pellets 316.150 60.22
Lubrication of Acid Coated Drug Pellets
Talc 1.050 0.20
Weight of Lubricated Drug Pellets 317.200 60.42
Part-II Acid Pellets
Tartaric acid 200.000 38.09
Hypromellose phthalate (HP-50) 4.000 0.76
Talc 1.600 0.30
Polyethylene glycol 600 1.200 0.22
Isopropyl alcohol q. s. --
Methylene chloride q. s --
Weight of seal coated Pellets 206.800 39.39
Lubrication of Seal coated Tartaric acid Pellets
Talc 1.000 0.19
Lubricated seal coated Pellets weight 207.80 39.58
Capsule Filling
Lubricated Drug Pellets + Lubricated Seal coated Tartaric acid Pellets 525.000 100
EHPMC CAP 1 No.

Manufacturing process for example 3 was similar to manufacturing process of example 2 except Rotocone Vacuum Dryer (RCVD) was used to dry core drug pellets.
Example 4
Ingredients 150 mg (mg/cap) % w/w
Part-I - Core Drug pellets
a) Core Drug pellets
Dabigatran Etexilate Mesylate 172.95 32.94
Microcrystalline Cellulose (Avicel PH 112 LN) 78.270 14.90
Butylated Hydroxytoluene 0.20 0.038
Hydroxypropyl Cellulose (Klucel LF) 4.000 0.76
Ascorbic Acid 1.730 0.32
Isopropyl Alcohol q.s. --
Drug pellets weight 257.150 48.98
b) Insulated Layering over Core drug pellets
Opadry White Ys-1-7040 12.000 2.285
Isopropyl Alcohol q.s. --
Methylene Chloride q.s --
Weight of Insulated drug pellets 269.150 51.26
c) Moisture Barrier Layer Over Insulated drug Pellets
OPADRY 200 WHITE (200F280000) 10.000 1.90
Purified water q.s. --
Weight of Moisture Barrier drug Pellets 279.150 53.17
Citric Acid Layer on Moisture barrier drug pellets
Citric acid monohydrate 25.000 4.76
Povidone (K-VALUE-25) 0.500 0.095
Talc 9.500 1.809
Ethanol 96% V/V q.s. --
Talc 2.000 0.38
Weight of Acid Coated Drug Pellets 316.150 60.22
Lubrication of Acid Coated Drug Pellets
Talc 1.050 0.20
Weight of Lubricated Drug Pellets 317.200 60.42
Part-II Acid Pellets
Tartaric Acid 200.000 38.09
Hypromellose Phthalate (HP-50) 4.000 0.76
Talc 1.600 0.30
Polyethylene Glycol 600 1.200 0.22
Isopropyl Alcohol q.s. --
Methylene Chloride q.s --
Weight of seal coated Pellets 206.800 39.39
Lubrication of Seal coated Tartaric acid Pellets
Talc 1.000 0.19
Lubricated seal coated Pellets weight 207.80 39.58
Capsule Filling
Lubricated Drug Pellets + Lubricated Seal coated Tartaric acid Pellets 525.000 100
EHPMC CAP 1 No.
Manufacturing process for example 4 was similar to manufacturing process of example 3 except ascorbic acid was additionally used in the core drug pellets.
Examples 2-4 were subjected for N Nitroso dabigatran analysis and results as below:
Example 2 Stage N Nitroso dabigatran (ppb)
Dried drug pellets 28.0
FBP dried Insulated coated 68.4
FBD dried Moisture barrier coated 96.5
FBD dried Citric acid coated 152.5
Filled capsule – FBD dried 189.2
Example 3 & 4- Stage N Nitroso dabigatran (ppb)
Example 3 Example 4
Dried drug pellets 24.0 21.8
RCVD dried Insulated coated 21.3 38.3
RCVD dried moisture barrier coated 47.1 50.7
RCVD dried citric acid coated 59.4 103.4
Filled capsule - RCVD dried 88.9 166.8

Stability Study: Stability study conducted on compositions in order to ensure the stable composition for longer period of time and to ensure control over nitrosamine impurity as depicted in below table:
## Tests Example 2 Example 3 Example 4
Initial Initial 3 Months Initial Initial
1 Water content (%) 1.6 0.6 0.4 1.5 1.5
2 Dissolution Time (Min) Mean (%) Mean (%) Mean (%) Time (Min) Mean Time (Min) Mean
5 0.0 - - 5 0.2 5 0.1
10 0.4 - - 10 1.9 10 2.9
15 21.2 - - 15 23.2 15 23.6
20 57.3 - - 20 54.9 20 67.3
30 97.6 Not less than 94 Not less than 99 30 94.9 30 96.8
45 102.4 - - 45 101.3 45 98.4
60 102.0 - - 60 101.2 60 98.1
3 Assay (%) 99.1 98.4 99.5 99.8 98.4
4 Butylated Hydroxy
Toluene content (%) 67.2 52.8 50.9 67.1 72.8
5 Impurity (%)
a Impurity - I 0.009 0.02 0.02 0.010 0.009
b Impurity - II 0.057 0.04 0.05 0.057 0.055
c Impurity - III 0.024 BLQ (0.015) BLQ (0.015) 0.023 0.021
d Impurity - IV 0.029 0.01 0.02 0.027 0.027
e Impurity - a 0.033 BLQ (0.014) BLQ (0.014) 0.026 0.032
f Impurity - b 0.001 0.01 0.01 ND ND
g Impurity - c ND ND ND ND ND
h Impurity - d ND ND ND ND ND
i Impurity - e ND ND ND ND ND
j Any unknown single impurity 0.034 0.03 0.03 0.038 0.037
k Total impurity 0.324 0.2 0.2 0.302 0.289
5 N-nitroso dabigatran (ppm) 0.12 0.18 0.18 - -
ND: Not detected, BLQ: Below Limit of Quantification
Based on above results obtained for examples 2-4, we can conclude that nitrosamine impurities can be controlled and maintained within FDA acceptable intake limit by improved manufacturing process, by using stabilizer and by using microcrystalline cellulose having low nitrite content i.e. not more than 200 µg/kg.
Although the inventions herein have 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.
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.

We claim:
1. A pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol.
2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of microcrystalline cellulose; about 0.01 % w/w to about 3 % w/w of binder selected from hydroxypropyl cellulose, povidone or mixture thereof; about 30 % w/w to about 50 % w/w of pH modifier contains combination of citric acid and tartaric acid; and optionally other pharmaceutically excipients.
3. The pharmaceutical composition as claimed in claim 1, wherein composition of Dabigatran Etexilate mesylate contains total nitrosamine impurity less than 700 ppb after at least 1 months of storage at 25° C. and 60% RH.
4. The pharmaceutical composition as claimed in claim 1, wherein the microcrystalline cellulose has particle size distribution D90 in the range of about 160 µm to about 295 µm.
5. The pharmaceutical composition as claimed in claim 1, wherein the microcrystalline cellulose has loss on drying not more than 1.5 % w/w, bulk density about 0.28 to about 0.34 g/mL, and nitrite content not more than 200 µg/kg.
6. A pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol; wherein composition contains not more than 1.5 ppm of N-nitroso-dabigatran after at least 3 months of storage at 25° C. and 60% RH.
7. A pharmaceutical composition for oral administration comprising: A) a first portion comprising: a) Core drug pellets comprising about 33 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 15 % w/w of microcrystalline cellulose; about 0.038 % w/w of butylated hydroxytoluene; about 0.76 % w/w of hydroxypropyl cellulose; b) Insulated Layering over Core drug pellets comprising coating with opadry white in an amount of about 2.3 % w/w; c) Moisture barrier layer coating over insulated drug pellets by using opadry white in an amount of about 1.9 % w/w; d) citric acid layer coating on moisture barrier drug pellets using composition comprising: about 4.75 % w/w of citric acid monohydrate; about 0.095 % of povidone; about 3.80 % w/w of talc; and Ethanol 96% v/v in required quantity e) Lubrication of acid coated drug pellets by using about 0.20 % w/w of talc. B) a second portion comprising: about 38% w/w of tartaric acid; about 0.76 % w/w of hypromellose phthalate; about 0.30 % w/w of talc; about 0.22 % w/w of polyethylene glycol; and required quantity of isopropyl alcohol and methylene chloride; wherein the said second portion lubricated using about 0.2% w/w of talc C) Filling of first portion and second portion in capsule.
8. The pharmaceutical composition as claimed in claim 7, wherein the said first portion of dabigatran and second portion of tartaric acid are separate and distinct from each other.
9. The pharmaceutical composition as claimed in claim 7, wherein the composition is stable for at least 24 months of storage at 25° C. and 60% RH.
10. The pharmaceutical composition as claimed in claim 7, wherein the first portion is prepared by wet granulation process.

Dated this 24h day of October 2024

Mr. Thirupathi Bendram
VP & Head - IPR
Alkem Laboratories Limited

,CLAIMS:We claim:
1. A pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol.
2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprising: about 10 % w/w to about 50 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 10 % w/w to about 20 % w/w of microcrystalline cellulose; about 0.01 % w/w to about 3 % w/w of binder selected from hydroxypropyl cellulose, povidone or mixture thereof; about 30 % w/w to about 50 % w/w of pH modifier contains combination of citric acid and tartaric acid; and optionally other pharmaceutically excipients.
3. The pharmaceutical composition as claimed in claim 1, wherein composition of Dabigatran Etexilate mesylate contains total nitrosamine impurity less than 700 ppb after at least 1 months of storage at 25° C. and 60% RH.
4. The pharmaceutical composition as claimed in claim 1, wherein the microcrystalline cellulose has particle size distribution D90 in the range of about 160 µm to about 295 µm.
5. The pharmaceutical composition as claimed in claim 1, wherein the microcrystalline cellulose has loss on drying not more than 1.5 % w/w, bulk density about 0.28 to about 0.34 g/mL, and nitrite content not more than 200 µg/kg.
6. A pharmaceutical composition of Dabigatran Etexilate or pharmaceutically acceptable salts thereof comprising: A) a first portion comprising a) Core of drug pellets comprising dabigatran etexilate mesylate, microcrystalline cellulose, butylated hydroxy toluene, and hydroxy propyl cellulose; b) Insulating layering of opadry over core of drug pellets; c) Moisture barrier layer over insulated drug pellets; d) Citric acid layer on moisture barrier drug pellets comprising citric acid, povidone, and talc B) a second portion comprising tartaric acid, hypromellose phthalate, talc, and polyethylene glycol; wherein composition contains not more than 1.5 ppm of N-nitroso-dabigatran after at least 3 months of storage at 25° C. and 60% RH.
7. A pharmaceutical composition for oral administration comprising: A) a first portion comprising: a) Core drug pellets comprising about 33 % w/w of Dabigatran Etexilate or pharmaceutically acceptable salts thereof; about 15 % w/w of microcrystalline cellulose; about 0.038 % w/w of butylated hydroxytoluene; about 0.76 % w/w of hydroxypropyl cellulose; b) Insulated Layering over Core drug pellets comprising coating with opadry white in an amount of about 2.3 % w/w; c) Moisture barrier layer coating over insulated drug pellets by using opadry white in an amount of about 1.9 % w/w; d) citric acid layer coating on moisture barrier drug pellets using composition comprising: about 4.75 % w/w of citric acid monohydrate; about 0.095 % of povidone; about 3.80 % w/w of talc; and Ethanol 96% v/v in required quantity e) Lubrication of acid coated drug pellets by using about 0.20 % w/w of talc. B) a second portion comprising: about 38% w/w of tartaric acid; about 0.76 % w/w of hypromellose phthalate; about 0.30 % w/w of talc; about 0.22 % w/w of polyethylene glycol; and required quantity of isopropyl alcohol and methylene chloride; wherein the said second portion lubricated using about 0.2% w/w of talc C) Filling of first portion and second portion in capsule.
8. The pharmaceutical composition as claimed in claim 7, wherein the said first portion of dabigatran and second portion of tartaric acid are separate and distinct from each other.
9. The pharmaceutical composition as claimed in claim 7, wherein the composition is stable for at least 24 months of storage at 25° C. and 60% RH.
10. The pharmaceutical composition as claimed in claim 7, wherein the first portion is prepared by wet granulation process.

Dated this 24h day of October 2024

Mr. Thirupathi Bendram
VP & Head - IPR
Alkem Laboratories Limited