DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

COMPOSITIONS CONTAINING A THROMBIN INHIBITOR

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

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF INVENTION
The present invention relates to the field of oral pharmaceuticals. The invention specifically relates to oral solid dosage forms and methods for the preparation of the same. The present invention further relates to the solid oral dosage forms of the drug Dabigatran etexilate and the methods of the preparation of the same.
BACKGROUND OF INVENTION
The active ingredient of the present invention is Dabigatran etexilate mesylate chemically known as “ß-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate” and has an empirical chemical formula C34H41N7O5 • CH4O3S with a structural formula as follows:

The product is a known direct thrombin inhibitor. This product has been primarily indicated for the treatment of deep venous thrombosis and pulmonary embolism and prevents their recurrence in previously treated patients. It is also used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
WO 98/37075 (US 6,087,380) discloses Dabigatran product as a compound with thrombin inhibiting effect. The invention relates to new disubstituted bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E. The invention also relates to their tautomers, their stereoisomers, their mixtures, and their salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, thus represent valuable intermediate products for the production of the other compounds of the general formula (I). Furthermore, the compounds of the above general formula (I), in which E stands for a RbNH-C(=NH)-group, have valuable pharmacological properties, in particular in inhibiting thrombin and prolonging thrombin time.
US 7,932,273 specifically discloses the Form II of Dabigatran etexilate mesylate with specific XRD data. The patent discloses ethyl3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in the crystalline modifications I, II, and the hemihydrate and the use thereof as a pharmaceutical composition.
The solubility of the active ingredient in water is only 1.8 mg/ml. Moreover, the active ingredient has a strong pH-dependent solubility that is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability, illness, or pre-medications (for example, PP inhibitors). There is therefore a need for oral pharmaceutical compositions of the active ingredient Dabigatran etexilate that provide a release that is independent from the pH value of the stomach and thus, provide bioavailability of the active ingredient.
US 2003/0181488 discloses a new administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof in combination with organic acid.
WO 2013/124340 discloses compositions comprising a mixture of at least two types of particles wherein a) the first type of particles comprise Dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid, use of said compositions in the reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and/or in the prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery and processes for the preparation of said compositions.
The use of organic acid to address this issue may cause incompatibilities in the patient. Moreover, the addition of the organic acid restricts the possible amount of active ingredient in an appropriate tablet or capsule. This problem is further exacerbated by the fact that, as a rule, organic acids have only a low buffer capacity so that relatively large amounts of acid have to be added to cause a possible effect on the pH value of the ambience in dissolution of an appropriate tablet.
US 2013/0052262 discloses an oral pharmaceutical composition containing a mixture of dabigatran etexilate or a pharmaceutically acceptable salt thereof as active ingredient in combination with an inorganic acidic excipient.
It can be comprehended from the background art that dabigatran has a strong pH dependent solubility and thus is effected significantly in patients in whom the stomach pH value is changed by physiological variability, illness, or pre-medications.
It is also understood from the prior art that organic and inorganic acids are used to address the solubility issue of dabigatran. However, it has been observed that organic acids may cause incompatibilities in patients or can limit the amount of drug used in the pharmaceutical preparation due to their intrinsic properties while these limitations are not observed in case of inorganic acids. However, it has been observed that Dabigatran is acid sensitive and hence, there is a need to overcome this incompatibility in the formulations containing the inorganic acid.
The present invention attempts to provide an alternative to the use of acids in the pharmaceutical preparation of Dabigatran etexilate for addressing the pH-dependent solubility of Dabigatran by eliminating the use of acids.
OBJECTIVE OF INVENTION
The objective of the present invention is to provide an oral solid dosage form for Dabigatran etexilate which is devoid of an acid.
Another objective of the present invention is to provide an alternative to the use of acids in the pharmaceutical preparation of dabigatran etexilate for addressing the pH-dependent solubility of Dabigatran by eliminating the use of an acid.
SUMMARY OF INVENTION
The present invention provides a solid oral dosage form of a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs which is devoid of an acid.
The present invention provides a solid oral dosage form of Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs devoid of an acid.
One embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a core, an isolating layer, and a drug containing coating layer.
Another embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a methacrylic acid copolymer core, an isolating layer and a drug layer; wherein
a) the core comprising methacrylate copolymer or its analogs,
b) the isolating layer comprising a coating composition comprising of a polymer,
c) the drug layer comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs.
Yet another embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a drug core, an isolating layer, and a coating layer.
Still another embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a drug core, an isolating layer, and a methacrylic acid copolymer coating layer; wherein
a) the drug core comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs,
b) the isolating layer comprising a coating composition comprising of a polymer,
c) the coating layer comprising of methacrylic acid copolymer or its analogs.
The present invention provides a solid oral dosage form of a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs which is devoid of an acid, wherein the solid oral dosage form comprises two different particles.
The present invention provides a solid oral dosage form of Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs devoid of an acid, wherein the solid oral dosage form comprises two different particles.
One embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form is a capsule comprising of two different pellets wherein,
a) First pellet comprising a methacrylic acid copolymer or its analogs,
b) Second pellet comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs.
Another embodiment of the present invention provides a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form is comprising two different pellets wherein,
a) First pellet comprising a methacrylic acid copolymer or its analogs which is coated with an isolating layer,
b) Second pellet comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form.
Yet another embodiment of the present invention provides that the pharmaceutically acceptable salt of Dabigatran etexilate is Dabigatran etexilate mesylate.
Yet another embodiment of the present invention provides that the polymorph of Dabigatran etexilate mesylate used in the present invention is Form I.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprising methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising methacrylic acid copolymer or its analogs thereof as particles, and
b) outer capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprising methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising methacrylic acid copolymer or its analogs thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising methacrylic acid copolymer or its analogs thereof as particles, and
b) outer capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising methacrylic acid copolymer or its analogs thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs, and
b) outer capsule comprising methacrylic acid copolymer or its analogs thereof as particles.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprising methacrylic acid copolymer or its analogs along with pharmaceutically acceptable excipients.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs thereof, and
b) outer capsule comprising methacrylic acid copolymer or its analogs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprises two different types of solid unit dosage forms filled into it; wherein one of the solid unit dosage form comprises methacrylic acid copolymer or its analogs thereof and the other solid dosage form comprising Dabigatran etexilate; wherein the two different types of solid unit dosage forms are an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form; wherein
a) inner capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs thereof as particles coated with pharmaceutically acceptable polymers, and
b) outer capsule comprising methacrylic acid copolymer or its analogs along with pharmaceutically acceptable excipients, coated with pharmaceutically acceptable polymers.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises a drug core, an isolating layer, and a coating layer containing a solubilizing agent; wherein
a) the drug core comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs,
b) the isolating layer,
c) the coating layer comprising a solubilizing agent.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises a drug core, an isolating layer, and a coating layer containing a solubilizing agent; wherein
a) the drug core comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs,
b) the isolating layer comprising of a polymer,
c) the coating layer comprising a solubilizing agent applied by fluid bed processor.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises an inner core comprising a solubilizing agent, an isolating layer, and a drug coating layer; wherein
a) the core comprising solubilizing agent,
b) the isolating layer,
c) the coating layer comprising Dabigatran etexilate and its pharmaceutically acceptable salts.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises an inner core comprising a solubilizing agent, an isolating layer, and a drug coating layer; wherein
a) the core comprising solubilizing agent, where in core coated with solubilizing agent using bottom spray granulator,
b) the isolating layer comprising of a polymer,
c) the coating layer comprising Dabigatran etexilate and its pharmaceutically acceptable salts applied by fluid bed processor.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises an inner core comprising a methacrylic acid copolymer and solubilizing agent, an isolating layer, and a drug coating layer; wherein
a) the core comprising a methacrylic acid copolymer or its analogs and solubilizing agent,
b) the isolating layer,
c) the coating layer comprising Dabigatran etexilate and its pharmaceutically acceptable salts.
Yet another embodiment of the present invention provides a method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises an inner core comprising a methacrylic acid copolymer and solubilizing agent, an isolating layer, and a drug coating layer; wherein
a) the core comprising a methacrylic acid copolymer or its analogs and solubilizing agent, where in core coated with solubilizing agent using bottom spray granulator,
b) the isolating layer comprising of a polymer,
c) the coating layer comprising Dabigatran etexilate and its pharmaceutically acceptable salts applied by fluid bed processor.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention avoids the use of an acid in the solid oral dosage form of Dabigatran.
In another embodiment, the present invention provides an alternative solution by using methacrylic acid copolymers in these solid oral pharmaceutical compositions. The methacrylic acid copolymer used in the present invention can be of different types without limiting to methacrylic acid - ethyl acrylate copolymer, methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, methacrylic acid copolymer Type C, and other ester derivatives of methacrylic acid.
In another embodiment, the present invention provides an alternative solution by using Solubilizing agent in these solid oral pharmaceutical compositions. The Solubilizing agent used in the present invention can be of different types without limiting to polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, fatty alcohols and fatty alcohol derivatives, and acids, particularly fatty acids and fatty acid derivatives and tocopherol derivatives. Useful fatty acids and alcohols include the C6-C22 fatty acids and C8-C22 alcohols, capric acid, caprylic acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, and their corresponding pharmaceutically acceptable salts. Examples of fatty acid and fatty alcohol derivatives include sodium dioctyl sulfosuccinate, sodium lauryl sulfate, amide esters (e.g., lauric acid diethanolamide, sodium lauryl sarcosinate, lauroyl carnitine, palmitoyl carnitine, and myristoyl carnitine), esters with hydroxy-acids (e.g., sodium stearoyl lactylate); sugar esters, e.g., lauryl lactate, glucose monocaprylate, diglucose monocaprylate, sucrose laurate, sorbitan monolaurate (Arlacel® 20), sorbitan monopalmitate (Span® 40), sorbitan monooleate (Span 80), lower alcohol fatty acid esters e.g., ethyl oleate (Crodamol® EO), isopropyl myristate (Crodamol IPM) and isopropyl palmitate (Crodamol IPP), esters with propylene glycol [e.g., propylene glycol monolaurate (Lauroglycol™ FCC), propylene glycol ricinoleate (Propymuls®), propylene glycol monooleate (Myverol® P-06), propylene glycol monocaprylate (Capryol® 90), propylene glycol dicaprylate/dicaprate (Captex® 200) and propylene glycol dioctanoate (Captex 800), esters with glycerol e.g., glyceryl monooleate, glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul GDO), glycerol monolinoleate (Maisine®), glyceryl mono/dioleate (Capmul GMO-K), glyceryl caprylate/caprate (Capmul MCM), caprylic acid mono/diglycerides (Imwitor® 988), mono- and di-acetylated monoglycerides (Myvacet® 9-45), triglycerides, e.g., corn oil, almond oil, soybean oil, coconut oil, castor oil, hydrogenated castor oil, hydrogenated coconut oil, Pureco 100, Hydrokote AP5, Captex 300, 350, Miglyol® 812, Miglyol 818 and Gelucire® 33/01), mixtures of propylene glycol esters and glycerol esters e.g., mixtures of oleic acid esters of propylene glycol and glycerol (Arlacel 186), and polyglycerized fatty acids such as polyglyceryl oleate (Plurol® Oleique), polyglyceryl-2 dioleate (Nikko DGDO), polyglyceryl-10 trioleate, polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nildcol Decaglyn 1-0), and polyglyceryl-10 mono dioleate (Caprol® PEG 860).
Dabigatran etexilate is acid sensitive. Hence, in another embodiment, the present invention provides separation of the acidic ingredients from the active ingredient by producing two different pellets.
Further, in another embodiment, the present invention discloses the isolation of both the pellets by coating the acidic ingredient containing pellet with an isolation layer. The isolation layer may comprise of inert polymers including but not limited to cellulose derivatives like hydroxypropyl methyl cellulose, hydroxylpropyl cellulose, carboxymethyl cellulose, preferably as sodium or calcium salt, hydroxyethyl cellulose, polyvinyl pyrrolidone, co-polymers comprising vinyl pyrrolidone and vinyl acetate units, poly(oxyethylene) alkyl ether, polyethylene glycol, co-block polymers of ethylene oxide, and propylene oxide, polyvinyl alcohol, polyvinyl alcohol derivatives, polyethylene glycol, and polyethylene glycol derivatives.
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, minitablets 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 and fluidized bed coating process. 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.
In an embodiment of the present invention said first type of particles has a particle size comprised between 50 and 1000 microns and said second type of particles have a particle size comprised between 100 and 1000 microns. The compositions of the present invention comprise from about 5% to about 100% by weight of the mixture of at least two types of particles. Ratio of the first and second types of particles is from about 1 :99 to about 99:1.
The solid oral dosage form described in various embodiments of the present invention can be further processed into compressed tablets, filled into capsules, used as powder, or as pellets as such.
It was surprisingly found that the composition of the present invention exhibits comparable or better dissolution of the drug, compared to the prior art compositions such as Pradaxa.
In one embodiment of the present invention the preferred pharmaceutically acceptable salt of the Dabigatran etexilate is the mesylate salt, i.e. the salt of the methanesulfonic acid and the preferred polymorph of the Dabigatran etexilate mesylate salt is Form I.
In another aspect the present invention further comprises at least one controlled-release polymer. The term "controlled release polymer", or its synonymous term "release-rate controlling polymer", refers to a polymer, on account of which a modified release, a retarded/delayed release, a prolonged release or a pulsatile release of the dabigatran active ingredient the pharmaceutical composition is accomplished, relative to a direct or immediate release (also sometimes called conventional release) defined by unaffected dissolution under a given condition. Suitable controlled release polymers include, without being limited thereto, polyvinylpyrrolidone, polymethacrylate, polyvinylacetate, dextranes, starch, cellulose ethers and esters like methyl cellulose, methylethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, or carboxymethylcellulose, polyethyleneoxide, carrageenan, agar, alginic acid, pectin or mixtures thereof, wherein where applicable controlled release types of a specified polymer, as opposed to immediate release types, are selected. It is preferably that the controlled release polymer is present in an amount that allows for the formation of a gel matrix or that allows a the active ingredient to be suitably released in a controlled manner, more preferably by gradual release. According to a further preferred embodiment, the controlled release polymer is Eudragit or ethyl cellulose.
In a preferred embodiment controlled release polymer is applied as an over-layer on the second layer comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof. Alternatively, controlled release polymer is comprised in the second layer of the present invention.
In a preferred embodiment the pharmaceutical composition according to the present invention further comprises an over-coat. The term "over-coat" used herein refers to a layer which completely covers an object and is applied by film coating. The over-coat can be selected from the group of ready to form dispersion such as OPADRY. The coating dispersion comprises hydrophilic film forming polymer (such as for example low viscosity HPMC, HPC, PVA (polyvinylalcohol) and the like), plastisizer (e.g. PEG), colorants and may optionally include other excipients such as anti-tacking agents.
In another aspect the present invention relates to a capsule comprising one or more units of the pharmaceutical composition of the present invention. Said capsules usually consist of the material selected from hydroxypropylmethylcellulose or gelatine. Further additives like carrageenan, potassium chloride, titanium dioxide and colorants may be present in the capsule shell.
The capsules may be packed into a primary packaging having decreased permeability for water vapor. Suitable packaging is selected from high density polyethylene containers, polypropylene containers, aluminum foil blisters and polychlorotriflouroethylene blisters.
In another aspect the present invention the pellets / particle according to the present invention are compressed into tablets.
In a preferred embodiment the composition according to the present invention further comprises pharmaceutically acceptable excipient selected from the group fillers, binders, lubricants, glidants and disintegrants.
The pharmaceutical compositions described herein can further contain fillers such as microcrystalline cellulose, powdered cellulose, compressible sugar, starch (e.g., corn starch or potato starch), pregelatinized starch, fructose, mannitol, dextranes, other sugars such as, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalciumphosphate, calcium lactate or mixtures thereof. The fillers may be present in the form of a single compound or in the form of a mixture of compounds or co-processed compounds.
The compositions described herein may also comprise binders, such as cellulose derivatives (e.g. hypromellose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose), polyvinylpyrrolidone, gelatin, lactose, sucrose, acacia, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, pregelatinized starch and sodium alginate. The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force. The binder may be present in the form of a single compound or in the form of a mixture of compounds.
The compositions described herein may also comprise lubricants. Various suitable lubricants include but are not limited to stearic acid, talc, hydrogenated vegetable oil (e.g. hydrogenated castor oil), sodium lauryl sulphate, glyceryl behenate, polyethylene glycol, magnesium stearate, calcium stearate and sodium stearyl fumarate.
The term "glidant" used herein is defined as an agent improving the flow of the powder and thus the filling of the compression chamber of the tablet press. Glidant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. In a preferred embodiment the glidant is selected from hydrated earth alkali silicates, preferably talc.
The compositions described herein may also comprise disintegrants. The term disintegrant as used herein is an agent accelerating the disintegration of the composition when in contact with a liquid. Preferred disintegrants are polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl glycolate and sodium bicarbonate.
The present invention also provides alternate processes for preparation of a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs devoid of an acid wherein the solid oral dosage form comprises of two different pellets in three different embodiments, each described as follows:
I. One embodiment provides the method comprising the following steps:
a) Preparing first pellets consisting of either methacrylic acid copolymer or its analogs by extrusion and spheronization,
b) Preparing the second pellet consisting of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs by extrusion and spheronization.
II. One embodiment provides the method comprising the following steps:
a) Preparing first pellets consisting of either methacrylic acid copolymer or its analogs by extrusion and spheronization,
b) Isolating the first pellet by coating with an isolating layer comprising of cellulosic derivatives by the fluidized bed process,
c) Preparing the second pellet consisting of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs by extrusion and spheronization.
III. One embodiment provides the method comprising the following steps:
a) Preparing first pellets consisting of either methacrylic acid copolymer or its analogs by extrusion and spheronization,
b) Isolating the first pellet by coating with an isolating layer comprising of cellulosic derivatives by the fluidized bed process,
c) Preparing the second pellet consisting of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs by spraying the drug onto an inert core by the fluidized bed process.
Another embodiment of the present invention provides a method of preparation of a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises a core, an isolating layer, and a drug layer; wherein
d) Preparing the core comprising either the drug or the methacrylate copolymer or its analogs is prepared by extrusion and spheronization,
e) Applying the isolating layer comprising a coating composition comprising of a polymer by the fluidized bed process,
a) Applying the coating layer comprising of either Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs or methacrylic acid copolymer or its analogs by the fluidized bed process.
The techniques and preparation methods followed in all of the above methods mentioned above are described in detail as follows:
A new modified method for preparing pellets is the Hot Melt Extrusion (HME) method where a thermal agent softens or gets melted during the process to obtain pellets.
The equipment used for the Extrusion includes extruders like the ram extruders, screw extruders and gravity fed extruders.The equipment used for the Spheronization includes spheronizers which consists of a wheel with a friction pattern machined on its top surfaceand spinning on a vertical axis within a parallel sided bowl.
The Fluidized Bed Process is performed preferably using the Wurster Process. The technology is characterized by the location of a spray nozzle at the bottom of a fluidized bed of solid particles. The particles are moved with a fluidizing air stream that is designed to induce a cyclic particle flow upward past the spray nozzle. The nozzle sprays atomized droplets of coating solution or suspension concurrently with particle flow. Passing particles move upward into an expansion chamber as droplets deposit on their surfaces. The expansion chamber reduces air velocity to allow particles to circulate back to the coating chamber. It also allows particles to further separate from one another temporarily and minimize the potential for particle agglomeration and accretion. The organic solvent or aqueous coating vehicle is evaporated as the particles move into and through the expansion chamber to leave non-volatile coat formulation ingredients on the particle surface as part of the developing film coat.
The solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs devoid of an acid described in the present invention may further include acceptable pharmaceutical ingredients like such as e.g. fillers, lubricants, flow control agents, release agents, and disintegrants which include but are not limited to micro crystalline cellulose, lactose, hydroxypropyl methyl cellulose, hydroxylpropyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, magnesium stearate, sodium stearylfumarate, stearic acid, dimethicone, Talc, Isopropanol, etc.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
EXAMPLES:
EXAMPLE 1:
S.No INGREDIENTS AMOUNT (mg)
Methacrylate copolymer coating
1. Sugar spheres 60.00
2. Methacrylate copolymer 177.14
3. Polyethylene glycol 17.72
4. Talc 4.00
5. Purified water Qs
Isolating layer
6. Hydroxypropyl methylcellulose E5 4.46
7. Dimethicone 0.08
8. Talc 1.36
9. Water Qs
Drug layering
10. Dabigatran Etexilate Mesilate 172.95
11. Hydroxypropyl cellulose 34.59
12. Talc 27.70
13. Isopropyl alcohol Qs
14. Empty Capsule Size 0
Capsule fill weight 500.00 mg

Manufacturing procedure
Methacrylate copolymer coating
Sugar spheres were coated using Methacrylate copolymer, Polyethylene glycol and talc in purified water in bottom spray granulator.
Seal coating
Methacrylate pellets were loaded in fluid bed processor and seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water.
Drug Layering
The seal coated pellets were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
Capsule filling:
Drug layered pellets were filled in size 0 HPMC capsules.
EXAMPLE 2:
S.No INGREDIENTS AMOUNT (mg)
Methacrylate copolymer coating
1. Sugar spheres 15.00
2. Methacrylate copolymer 210.00
3. Polyethylene glycol 21.00
4. Talc 6.30
5. Purified water Qs
Isolating layer
6. Hydroxypropyl methylcellulose E5 11.40
7. Dimethicone 0.08
8. Talc 3.48
9. Water Qs
Drug layering
10. Dabigatran Etexilate Mesilate 172.95
11. Hydroxypropyl cellulose 34.59
12. Talc 27.70
13. Isopropyl alcohol Qs
14. Empty Capsule Size 0el
Capsule fill weight 502.50 mg

Manufacturing procedure
Methacrylate copolymer coating
Sugar spheres were coated using Methacrylate copolymer, Polyethylene glycol and talc in purified water in bottom spray granulator.
Seal coating
Methacrylate pellets were loaded in fluid bed processor and seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water.
Drug Layering
The seal coated pellets were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
EXAMPLE 3:
S.No INGREDIENTS AMOUNT (mg)
1. Sugar spheres 35.00
2. Sodium lauryl sulphate 20.00
3. Purified water Qs
Isolating layer
4. Hydroxypropyl methylcellulose E5 1.35
5. Dimethicone 0.03
6. Talc 1.98
7. Water Qs
Drug layering
8. Dabigatran Etexilate Mesilate 172.95
9. Hydroxypropyl cellulose 34.59
10. Talc 27.70
11. Isopropyl alcohol Qs
12. Empty Capsule Size 0
Capsule fill weight 293.6 mg

Manufacturing procedure
Sugar spheres were coated using Sodium lauryl sulphate in purified water in bottom spray granulator.
Seal coating
Sodium lauryl sulphate pellets were loaded in fluid bed processor and seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water.
Drug Layering
The seal coated pellets were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
Capsule filling:
Drug layered pellets were filled in size 0 HPMC capsules.
EXAMPLE 4:
S.No INGREDIENTS AMOUNT (mg)
Substrate - 1
1. Sugar spheres 50.00
2. Dabigatran Etexilate Mesilate 172.95
3. Hydroxypropyl cellulose 34.59
4. Talc 27.70
5. Isopropyl alcohol Qs
Substrate - 2
6. Sugar spheres 60.00
7. Methacrylate copolymer 177.14
8. Polyethylene glycol 17.72
9. Talc 4.00
10. Purified water Qs
Isolating layer
11. Hydroxypropyl methylcellulose E5 4.46
12. Dimethicone 0.08
13. Talc 1.36
14. Water Qs
15. Empty Capsule Size 0el
Capsule fill weight 550.00 mg

Manufacturing procedure
Substrate – 1
Drug Layering
Sugar spheres were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
Substrate – 2
Methacrylate copolymer coating
Sugar spheres were coated using Methacrylate copolymer, Polyethylene glycol and talc in purified water in bottom spray granulator.
Seal coating
Methacrylate pellets were loaded in fluid bed processor and seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water.
Capsule filling:
Pellets of substrate – 1 & 2 were filled in size 0el HPMC capsules.
EXAMPLE 5:
S.No INGREDIENTS AMOUNT (mg)
Methacrylate copolymer coating
1. Sugar spheres 15.00
2. Methacrylate copolymer 177.00
3. Sodium lauryl sulphate 33.00
4. Polyethylene glycol 21.00
5. Talc 6.30
6. Purified water Qs
Isolating layer
7. Hydroxypropyl methylcellulose E5 11.40
8. Dimethicone 0.08
9. Talc 3.48
10. Water Qs
Drug layering
11. Dabigatran Etexilate Mesilate 172.95
12. Hydroxypropyl cellulose 34.59
13. Talc 27.70
14. Isopropyl alcohol Qs
15. Empty Capsule Size 0el
Capsule fill weight 502.50 mg

Manufacturing procedure
Methacrylate copolymer coating
Sugar spheres were coated using Methacrylate copolymer, sodium lauryl sulphate, Polyethylene glycol and talc in purified water in bottom spray granulator.
Seal coating
Methacrylate pellets were loaded in fluid bed processor and seal coated using Hydroxypropyl methylcellulose, Dimethicone and talc in purified water.
Drug Layering
The seal coated pellets were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
Capsule filling:
Drug layered pellets were filled in size 0el HPMC capsules.
EXAMPLE 6:
S.No INGREDIENTS AMOUNT (mg)
Inner capsule composition
1. Sugar spheres 15.00
2. Methacrylate copolymer 177.00
3. Polyethylene glycol 17.70
4. Talc 6.30
5. Purified water Qs
6. Empty Capsule Size 4
Outer capsule composition
7. Sugar spheres 15.00
8. Dabigatran Etexilate Mesilate 172.95
9. Hydroxypropyl cellulose 34.55
10. Talc 27.70
11. Isopropyl alcohol Qs
12. Empty Capsule Size 0
Outer capsule fill weight 250.20 mg
Inner capsule fill weight 216.00 mg

Manufacturing procedure
Inner Capsule
Sugar spheres were coated using Methacrylate copolymer, Polyethylene glycol and talc in purified water in bottom spray granulator.
Outer Capsule
Sugar spheres were loaded in fluid bed processor and coated with Dabigatran etexilate mesilate, hydroxypropyl cellulose and talc in IPA.
Capsule filling:
The size 4 capsule was kept in size 0 capsule followed by filled with the API pellets.
Dissolution profiles of the solid oral dosage forms of the present invention in comparison with Pradaxa® are given below :
The dissolution profile was performed in 900 ml of 0.01N HCl using USP-I rotating basket apparatus set at 100rpm.

Time (Min) Pradaxa®
(Australia reference)
(Lot: 406467) Example 1 Example 3 Example 4
% Drug release
10 18 27 61 21
15 76 86 84 30
20 95 96 88 35
30 99 103 91 43
45 99 106 91 55

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

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

,CLAIMS:We Claim:
1. A solid oral dosage form of a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs which is devoid of an acid.

2. The solid dosage form as claimed in claim 1 wherein the direct thrombin inhibitor is Dabigatran etexilate.

3. The solid dosage form as claimed in claim 2 wherein the composition comprises methacrylic acid copolymers which is selected from methacrylic acid - ethyl acrylate copolymer, methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, methacrylic acid copolymer Type C, and other ester derivatives of methacrylic acid.

4. The solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprises a core, an isolating layer, and a drug containing coating layer.

5. The solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a core, an isolating layer and a drug layer; wherein
a) the core comprising methacrylate copolymer or its analogs,
b) the isolating layer comprising a coating composition comprising of a polymer,
c) the drug layer comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs.

6. A solid oral dosage form of a direct thrombin inhibitor or its pharmaceutically acceptable salts or polymorphs which is devoid of an acid, wherein the solid oral dosage form comprises two different particles wherein,
a) First pellet comprising a methacrylic acid copolymer or its analogs,
b) Second pellet comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs.
7. A capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprising two different types of solid unit dosage forms filled into it; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form wherein
a) inner capsule comprising methacrylic acid copolymer or its analogs thereof as particles, and
b) outer capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs.

8. A capsule dosage form comprising a Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs; wherein the capsule comprising two different types of solid unit dosage forms filled into it; wherein the two different types of solid unit dosage forms are in an inner capsule and an outer capsule, i.e., capsule-in-capsule dosage form wherein
c) inner capsule comprising Dabigatran etexilate or its pharmaceutically acceptable salts or polymorphs, and
d) outer capsule comprising methacrylic acid copolymer or its analogs thereof as particles.

9. A method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising a drug core, an isolating layer, and a coating layer containing a solubilizing agent; wherein
a) the drug core comprising of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs,
d) the isolating layer,
e) the coating layer comprising a solubilizing agent.

10. A method of preparing a solid oral dosage form of Dabigatran etexilate and its pharmaceutically acceptable salts or polymorphs wherein the solid oral dosage form comprising an inner core comprising a solubilizing agent, an isolating layer, and a drug coating layer; wherein
a) the core comprising solubilizing agent,
b) the isolating layer,
c) the coating layer comprising Dabigatran etexilate and its pharmaceutically acceptable salts.