DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PHARMACEUTICAL FORMULATIONS OF DABIGATRAN
INTRODUCTION TO THE INVENTION
The present invention relates to pharmaceutical formulations of Dabigatran etexilate or its salts thereof, and processes for preparing the same. The invention also relates to stable pharmaceutical formulations of Dabigatran etexilate or its salts thereof and processes for preparing the same. Further the invention relates to pharmaceutical formulations of dabigatran etexilate or its salts for oral administration and its use in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Dabigatran (PRADAXA in Australia, Europe and USA, PRADAX in Canada, PRAZAXA in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is used for various clinical indications, and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant ("blood thinner"), since it does not require frequent blood tests for international normalized ratio monitoring, while offering similar results in terms of efficacy.
The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is 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:

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. Dabigatran is not absorbed orally; however, the etexilate pro-drug is orally bioavailable. Dabigatran etexilate is manufactured as a mesylate salt, which itself possesses no anticoagulant activity. To improve lipophilic nature of dabigatran, its etexilate ester has been prepared, and to increase its solubility, mesylate salt has been prepared.
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. Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.
In the USA, Dabigatran is available in the form of 75 mg and 150 mg
PRADAXA immediate release HPMC (hydroxy propyl methyl cellulose) capsules in the bottle and blister packages. Once a bottle of dabigatran is opened, the medication has to be used within four months. This unusually short period exists because the drug can be affected by humidity. The bottle cap contains a desiccant to reduce the humidity and prevent degradation of the drug. Blister packs do not have same four-month expiration because a capsule is not exposed to humidity until its own blister is opened.
The PRADAXA 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.
PRADAXA is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, with or without food. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twice daily.
Dabigatran etexilate mesylate is a BCS Class II drug substance (low solubility / high permeability), with pH dependent solubility (higher at pH < 3). Aqueous solubility is better at lower pH (pH less than 3) but the drug substance is virtually insoluble at neutral or basic pH. However the drug substance is also acid sensitive i.e. prone for degradation in acidic environment. Dabigatran etexilate mesylate is stable in the solid state when protected from moisture. In solution, sensitivity to oxidation and sensitivity to hydrolysis is observed, especially in acidic and basic aqueous media. The compound is not sensitive to photolysis.
Absorption of dabigatran etexilate is incomplete; the absolute bioavailability of dabigatran after oral administration of dabigatran etexilate is approximately 3-7%. The low bioavailability is most likely caused by the narrow range of suitable pH for sufficient dissolution of mesylate salt of dabigatran etexilate (drug substance) in addition to being a P-gp substrate. Absorption is most likely one of the major factors influencing the inter–
and intra-subject variability in bioavailability of dabigatran.
Two different polymorphic forms have been reported for Dabigatran etexilate mesylate. They are anhydrous Form I and form II. Anhydrous form II is thermodynamically more stable than anhydrous form I.
PCT patent application publication WO 98/37075A1 discloses Dabigatran etexilate or its salts and method for prophylaxis or treatment of venous and arterial thrombotic disease by administering Dabigatran etexilate or its salts.
U.S. patent application publication 2003/0181488s discloses the mesylate salt of Dabigatran etexilate, compositions comprising mesylate salt and processes for preparing the same.
U.S. patent application publications 2012/0277269, & US20110269799 disclose method of reducing error while administering 150 mg dose of Dabigatran etexilate or salt and method of preventing the stroke by administering of 150 mg b.i.d of Dabigatran etexilate or its salts. U.S. patent application publications 2005/0038077 discloses tablet formulations of Dabigatran etexilate or its salts and an organic acid.
U.S. patent application publication 2006/183779 discloses the administration forms for oral applications of Dabigatran etexilate or its salts. U.S. patent application publications 2011/123635, 2012/0276206A1, 2011/129538 disclose processes for preparing the dosage forms of Dabigatran etexilate or its salts.
Many dabigatran formulations are also disclosed in different PCT & US patent application publications such as US 2012/301541, WO 2012/001156, WO 2011/110478, WO 2011/107427
As discussed above, the drug substance Dabigatran etexilate or its salts exhibit pH dependent solubility i.e. higher solubility at pH less than 3, at the same time the drug substance is susceptible to hydrolysis at acidic environment. Therefore there is a need to develop a stable and bioequivalent compositions of dabigatran etexilate mesylate as formulating compositions of dabigatran poses challenges to the formulation scientist.
This and other needs are addressed by the present invention.

SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical formulations of Dabigatran etexilate or its salts, and processes for preparing the same. The invention also relates to stable pharmaceutical formulations of Dabigatran etexilate or its salts and processes for preparing the same. Further the invention relates to pharmaceutical formulations of dabigatran etexilate or its salts for oral administration and their use in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In one of the embodiment, the invention includes a pharmaceutical formulation comprising
a) non-spherical cores optionally having an intermediate coating
b) layer of Dabigatran etexilate or its salts on the top of the non-spherical cores or intermediate coated non-spherical cores and
c) optionally top layer enclosing active substance layer.
In an embodiment, the non-spherical cores relate to cylindrical or rod shaped cores.
In an embodiment, the non-spherical cores include pharmaceutically acceptable acids.
In an embodiment, the pharmaceutically acceptable acid substances include organic acids.
In another embodiment, the pharmaceutically acceptable acid substances include inorganic acids.
In an embodiment, the invention relates to a pharmaceutical formulation comprising
a) a core comprising dabigatran etexilate or its salts optionally with intermediate layer.
b) an acid layer enclosing the core or intermediate coated core.
c) optionally top layer enclosing the acid layer.
In an embodiment, the acid layer includes pharmaceutically acceptable acids.
In an embodiment, the pharmaceutically acceptable acids include organic acids.
In another embodiment, the pharmaceutically acceptable acids include inorganic acids.
In an embodiment, the active is dabigatran etexilate mesylate salt.
In another embodiment, the cores comprising dabigatran etexilate or its salts are in the form of granules or pellets or minitablets.
Another emodiment of the invention includes pharmaceutical formulations of dabigatran etexilate or its salts, wherein formulation comprises encapsulation of
a) pellets or granules or powder or minitablets of pharmaceutically acceptable acids and
b) pellets or granules or powder or minitablets of dabigatran etexilate or salts thereof, together in a capsule.
Yet another aspect of the invention relates to multilayer tablet formulations of dabigatran etexilate or salts thereof, wherein first layer comprise a pharmaceutically acceptable acids and second layer comprise of dabigatran etexilate or salts and optionally third layer between first and second layer.
Further the invention relates to pharmaceutical formulations comprising dabigatran etexilate or its salts, wherein formulations prepared by granulating a mixture of dabigatran etexilate or salts thereof and pharmaceutically acceptable acids followed by encapsulation of the granules.
In one of the embodiment, the invention relates to stable pharmaceutical formulations comprising dabigatran etexilate or its salts thereof.
In an embodiment, the invention relates to stable pharmaceutical formulations comprising dabigatran etexilate or its salts thereof and pharmaceutically acceptable acids.
In another embodiment, the invention relates to processes for preparing the pharmaceutical formulations comprising dabigatran etexilate or its salts thereof and atleast one pharmaceutically acceptable excipient.
In another aspect the invention relates to method of using the pharmaceutical formulations comprising Dabigatran etexilate or its salts thereof for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical formulations of Dabigatran etexilate or its salts, and processes for preparing the same. The invention also relates to stable pharmaceutical formulations of Dabigatran etexilate or its salts thereof and processes for preparing the same. Further the invention relates to pharmaceutical formulations of dabigatran etexilate or its salts for oral administration and its use in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Dabigatran etexilate is a prodrug that is rapidly absorbed following oral administration and converted by non-specific plasma and hepatic esterases into the active moiety, dabigatran. Conversion to dabigatran involves the hydrolysis of two functional groups: an ethyl ester and the etexilate group. There are two intermediate metabolites, depending upon which of these groups is hydrolysed first. Dabigatran etexilate and the two intermediate metabolites are only transiently detectable in plasma. Dabigatran is further metabolised to four pharmacologically active acyl glucuronides.
Dabigatran etexilate is a weakly basic substance that is soluble in acidic media (> 5% in 0.1 M HCl) but practically insoluble in neutral and basic media (0.0003% at pH 7.4).
The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate capsules is approximately 6.5%.
Dabigatran compounds as per the present invention include dabigatran or dabigatran etexilate or its pharmaceutically acceptable salts, amides, esters, prodrugs, racemates, isomers etc. The pharmaceutically acceptable salts can be with inorganic or organic acids. Examples of suitable inorganic acids include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid; suitable organic acid include for example fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methane sulfonic acid.
In an embodiment, the salt is methane sulfonate salt of dabigatran etexilate i.e. dabigatran etexilate mesylate.
According to the present invention dabigatran may be used in the form of free base (dabigatran) or its ester (dabigatran etexilate) or a pharmaceutically acceptable salt (dabigatran etexilate mesylate).
In the context of the present invention, the terms “cores” or “beads” or “spheres” or “granules” or “pellet” or “inert particles” or “particles” or “nucleus” are used synonymously.
In the context of the present invention the term “compositions” or “formulations” or “dosage forms” or “dosage units” are used synonymously.
Further, according to the present invention the pharmaceutical formulations for oral administration include but are not limited to solid oral dosage forms such as capsules, tablets, pills, powders or granules or sachets etc.
In the context of the present invention, the pharmaceutically acceptable acid include organic acid or inorganic acid or inorganic acidic substances.
According to the invention, the organic acid include but not limited to tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid and one of the hydrates or acid salts thereof.
The inorganic acids include but are not limited to hydrochloric acid, sulfuric acid and phosphoric acid. The inorganic acidic substances include but are not limited to hydrogen and dihydrogenphosphates, hydrogen sulfates of alkali or ammonium salts, especially sodium, potassium, and ammonium salts; magnesium sulfate, magnesium chloride, ferrous chloride, ferric chloride, ammonium chloride, ammonium sulfate, calcium chloride, and calcium sulfate. The salts mentioned include their solvates, especially hydrates, such as for example magnesium chloride hexahydrate, calcium chloride mono or dihydrate, calcium sulfate dihydrate, magnesium sulfate monohydrate, and ferric chloride hexahydrate.
Further in the context of the present invention, the terms “layer” or “coating” or “deposit” is used synonymously.
The present invention relates to plurality of coated particles of dabigatran etexilate or its salts.
In one of the embodiment, the invention includes a pharmaceutical formulation comprising
a) non-spherical cores optionally having an intermediate coating
b) layer of Dabigatran etexilate or its salts on the top of the non-spherical cores or intermediate coated non-spherical cores, and
c) optionally top layer enclosing active substance layer.
In an embodiment, the non-spherical cores relate to cylindrical or rod shaped cores.
In an embodiment, the non-spherical cores include pharmaceutically acceptable acids.
In an embodiment, the pharmaceutically acceptable acid substances include organic acids.
In another embodiment the pharmaceutically acceptable acid substances include inorganic acids.
The present invention also relates to pharmaceutical formulations comprising dabigatran etexilate or its salts and atleast one pharmaceutical acceptable excipient, wherein the formulation comprises:
a) non-spherical cores optionally with pharmaceutically acceptable excipient.
b) optionally intermediate coating
c) active substance layer onto a) or b) comprising dabigatran etexilate or its salts and atleast one pharmaceutically acceptable excipient.
d) optionally outermost top coating onto active substance layer.
For the purpose of the present invention, the term “non-spherical” refers to a three dimensional closed surface such that atleast one point on the surface is not equidistant from the center. The cores used in the present invention may be regular or irregular shapes.
Different non-spherical shapes include but not limited to cylindrical or rod shape, dumbbell, needle, rectangle, square, pentagon, hexagon, octagon, triangle, diamond, elliptical, oval and combinations thereof.
In an embodiment, the shape of the non-spherical cores are cylindrical or rod shape.
The invention also relates to process for preparing the non-spherical cores.
In an embodiment, the invention relates to extrusion process for preparing the non-spherical cores.
Extrusion is a process used to create objects of a fixed, cross-sectional profile. A material is pushed or drawn through a die of the desired cross-section. The two main advantages of this process over other manufacturing processes are its ability to create very complex cross-sections and work materials that are brittle, because the material only encounters compressive and shear stresses. It also forms finished parts with an excellent surface finish.
Extrusion may be continuous (theoretically producing indefinitely long material) or semi-continuous (producing many pieces). The extrusion process can be done with the material hot or cold.
The non spherical cores in the context of present invention include but are not limited to:
-water-soluble cores such as sucrose spheres, lactose, organic acids such as fumaric acid, tartaric acid, citric acid, malic acid, succinic acid, ascorbic acid, glutamic acid, aspartic acid or mixtures of any of these acids as well as pharmacologically acceptable acid substances such as acid salts, sodium or potassium hydrogen sulphate, monosodium or monopotassium salts of polybasic acids (tartaric acid or citric acid, and mixtures thereof) and betaine hydrochloride and the like and mixtures thereof.
-water-insoluble cores such as microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like and mixtures thereof.
In one of the embodiment, the invention includes use of an organic acid or mixtures of organic acids as the non-spherical cores for the preparation of coated particles.
In an embodiment, the non-spherical cores include organic acids such as tartaric acid or fumaric acid or succinic acid.
In another embodiment, the present invention relates to sugar spheres or cellulose spheres or silicilic acid as the cores.
In an embodiment, the invention relates to sugar spheres or cellulose spheres wetted by inorganic acids.
In the context of the present invention, the inorganic acids include but are not limited to hydrochloric acid, phosphoric acid, sulfuric acid and the like.
In an embodiment the invention relates to pharmaceutical formulations of dabigatran etexilate or its salts and inorganic acid.

An aspect of the invention relates to processes of preparing the pharmaceutical formulations of dabigatran etexilate or its salts and inorganic acid, wherein process comprise
a) sugar spheres or cellulose spheres as cores optionally with seal coating.
b) inorganic acid layering onto the cores of step a); optionally with seal coating.
c) active substance layering onto acid coated cores of step b).
d) encapsulation of coated particles of step c)
An aspect of the invention also relates to use of inorganic acidic substances as the cores.
In an embodiment, the invention includes processes for preparing the pharmaceutical formulations of dabigatran etexilate or its salts and inorganic acidic substances, wherein process comprises
a) inorganic acidic substances as cores optionally with intermediate coating.
b) active substance layering comprising dabigatran etexilate or its salts thereof and atleast one pharmaceutically acceptable excipient.
c) optionally outermost top layer.
In an embodiment, the invention relates to a pharmaceutical formulations comprising
a) a core comprising dabigatran etexilate or its salts optionally with intermediate layer.
b) an acid layer enclosing the core or intermediate coated core.
c) optionally top layer enclosing the acid layer.
In an embodiment, the acid layer include pharmaceutically acceptable acids.
In an embodiment, the pharmaceutically acceptable acids include organic acids.
In another embodiment, the pharmaceutically acceptable acids include inorganic acids.
In an embodiment, the active is dabigatran etexilate mesylate salt.
In another embodiment, the cores comprising dabigatran etexilate or its salts are in the form of granules or pellets or minitablets.
In another embodiment, the invention relates to pharmaceutical formulations comprising cores of dabigatran etexilate or its salts, thus invention includes
a) cores comprising dabigatran etexilate or its salts and atleast one pharmaceutically acceptable excipient.
b) optionally an intermediate layer enclosing the core of step a)
c) acid layer enclosing a) or b).
d) optionally top layer enclosing the organic acid layer of step c)
In an embodiment, the cores comprising dabigatran etexilate mesylate can be spherical or non-spherical in shape.
In another embodiment, the dabigatran etexilate or its salts as cores are in the form of granules or pellets or minitablets.
In a embodiment, the invention the acid used in the above compositions can be organic or inorganic acid.
In yet another embodiment, the invention relates to processes for preparing the cores comprising dabigatran etexilate or its salt.
Various processes for preparing the cores comprising dabigatran etexilate or its salts include layering, powder layering, wet granulation, dry granulation, direct compression etc.
Further embodiments of the invention relates to processes for preparing the pharmaceutical formulation comprising dabigatran etexilate or its salts as cores, wherein process comprises
a) preparing the cores comprising dabigatran etexilate or its salts and atleast one excipient.
b) optionally giving intermediate layering comprising atleast one binder.
c) acid layering, optionally with top coating.
d) encapsulation.
Further in an embodiment, pharmaceutical compositions of dabigatran etexilate or its salts are prepared as follows:
a) non –spherical cores are layered or sprayed over with an intermediate layer, optionally with other pharmaceutically acceptable excipients, by techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like.
b) the coated cores are layered with dabigatran etexilate or its salts, optionally with other pharmaceutically acceptable excipients.
c) the cores formed in step b) are optionally coated with top layer
d) the cores of step c) are dried, and are filled into capsules or compressed into tablets, optionally with other pharmaceutically acceptable excipients.
In another embodiment, of the present invention, cores can be layered or coated with dabigatran etexilate or its salt by:
a) layering dabigatran etexilate or its salt as a powder, along with solvent system optionally comprising a binder; or
b) layering dabigatran etexilate or its salts as a suspension or solution with or without a binder in equipment such as a fluid bed processor.
In an embodiment, the dabigatran etexilate or its salt include dabigatran etexilate mesylate.
In one of the embodiment, the invention includes active substance layer without binder.

As described earlier, and without being bound by any particular theory of operation, direct contact between dabigatran etexilate or its salts and acid is believed to generate high levels of impurities as the drug is sensitive to acidic environment, hence an intermediate layer between the organic acid core and active substance layer is advantageous to prevent direct contact of acid and active substance.
In the context of the present invention, the terms “intermediate coating” or “insulating” or “seal coating” or “sub coating” or “isolation” are used synonymously.
Various materials that may be used in an intermediate coating include but are not limited to: to: hydrophilic or water soluble polymers of various grades such as celluloses such as methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose or hypromellose (hydroxypropyl methyl cellulose provided by DOW chemical under the trade name METHOCEL™, various grades being METHOCEL K 4M, METHOCEL K 15M, METHOCEL K 100M, METHOCEL K100M CR, METHOCEL K100LV), hydroxy propyl cellulose, homopolymers or copolymers of N-vinylpyrrolidone, vinyl and acrylic polymers; polyacrylic acid and the like; cross-linked sodium carboxymethyl cellulose and cross-linked hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; gums such as agarose, gum arabic, gum ghatti, gum karaya, gum tragacanth; hydrophilic colloids such as alginates; other substances such as arbinoglactan, pectin, amylopectin, N-vinyl lactams, polysaccharides; and the like. hydrophobic substances such as celluloses like ethyl cellulose, low substituted hydroxylpropyl cellulose (“L-HPC”), cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate; polyalkyl methacrylates; polyalkyl acrylates; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil; and the like.
The intermediate layer (or seal coating) may be coated over the cores by techniques such as powder coating, spray coating, dip coating, fluidized bed coating and the like.
In an embodiment, a core is coated with an intermediate coating and then layered with active substance coating. In an aspect of this embodiment, more than one intermediate coating between the core and the active substance layer are also contemplated within the scope of the present invention.
Another aspect of the invention includes pharmaceutical formulations of dabigatran etexilate or its salts, wherein formulation comprises encapsulation of
a) Pellets or granules or powder or minitablets of pharmaceutically acceptable acids and
b) Pellets or granules or powder or minitablets of dabigatran etexilate or salts thereof, together in a capsule.
In an embodiment, the invention includes pharmaceutical formulations of dabigatran etexilate or its salts wherein formulation includes encapsulation of pellets of pharmaceutically acceptable acid optionally seal coated and free drug powder, together in the hard capsules.
In another embodiment, the invention relates to pharmaceutical formulation of dabigatran etexilate or its salts wherein formulation includes encapsulation of minitablets of dabigatran etexilate or its salts and powder or pellets of pharmaceutically acceptable acid, together in the hard capsules.
In an embodiment, the pharmaceutically acceptable acid is organic acid and dabigatran salt is dabigatran etexilate mesylate.
In another embodiment, the pharmaceutically acceptable acid is inorganic acid or its salt and dabigatran salt is dabigatran etexilate mesylate.
Yet another aspect of the invention relates to multilayer tablet formulations of dabigatran etexilate or salts thereof, wherein first layer comprises a pharmaceutically acceptable acids and second layer comprise of dabigatran etexilate or salts and optionally third layer between first and second layer.
Further the invention relates to pharmaceutical formulations comprising dabigatran etexilate or its salts, wherein formulations prepared by granulating a mixture of dabigatran etexilate or salts thereof and pharmaceutically acceptable acids followed by encapsulation of the granules.
In one of the embodiment, the invention relates to stable pharmaceutical formulations comprising dabigatran etexilate or its salts thereof.
In an embodiment, the invention relates to stable pharmaceutical formulations comprising dabigatran etexilate or its salts thereof and pharmaceutically acceptable acids.
In another embodiment, the invention relates to processes for preparing the pharmaceutical formulations comprising dabigatran etexilate or its salts thereof and atleast one pharmaceutically acceptable excipient.
Being an insoluble compound, it is expected that particle size reduction would improve the solubility of dabigatran etexilate. As the decrease in particle size increases the surface area and thus increases the solubility. The present compositions involve a reduced particle size of dabigatran etexilate mesylate to improve the dissolution profile.
The solubility of dabigatran etexilate mesylate in water is strongly pH dependent with rather high solubility in acidic media (>50 mg/mL in 0.1 N HCl) and very poor solubility in neutral and basic media (0.003 mg/mL at pH 7.4). The solubility in water is 1.8 mg/mL (0.18%). In its neutral form it is very lipophilic (log P = 3.8, determined in different mixtures of aqueous solution and n-octanol).
Particle size reduction increases the surface area of the solid phase that is in contact with a liquid medium. These particle size distributions according to the present invention provide an enhanced rate of dissolution of the dabigatran etexilate or salt and provide reproducible bioavailability.
There are instances where the rate of dissolution of a poorly soluble drug is a rate-limiting factor in its absorption by the body. It is recognized that such drugs may be more readily bioavailable if administered in a finely divided state. Because of the poor water solubility of dabigatran etexilate mesylate, the rate of dissolution of drug from a dosage form is a controlling factor in determining the rate and extent of drug absorption. The rate of dissolution depends on factors including particle size (or particle surface area, which can be related to particle size).
The percent of particles with different dimensions that exist in a powder is called the particle size distribution. It is represented in certain ways. Particle size is the maximum dimension of a particle, normally expressed in units of µm. Particle size distributions can be expressed in terms of, D10, D50, D90 and D[4,3]. The D10, D50 and D90 represent the 10th, median or the 50th percentile, and the 90th percentile of the particle size distribution, respectively, as measured by volume. That is, the D10, D50, D90 is a value of the distribution such that 10%, 50%, 90% by volume of the particles have a size of this value or less, or is the percentage of particles smaller than that size. D50 is also known as median diameter of particle. It is one of the important parameters representing characteristics of particle of powder. For a sample, if D50= 5 µm, it means that 50% of the particles are smaller than 5 µm. Similarly, if D10= 5 µm, 10% by volume of the particles are less than or equal to 5 µm, and if D90=5 µm, 90% of the particles are less than or equal to 5 µm. D[4,3] means the volume moment mean of the particle or the volume weighted particle size.
In one of the embodiments, the invention includes dabigatran etexilate mesylate, having mean particle size of 0.1 to 100 microns.
Further the invention include other pharmaceutically acceptable excipients, which are not limited to diluents, binders, disintegrants, glidants/ antistickening agents, wetting agents or surfactants, lubricants, solvents, film forming polymers etc
Diluents:
Various useful fillers or diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle products), Pharmatose™ (available from DMV) and others. Different grades of starches included but not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (Commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (Commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
Disintegrants:
Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxy methylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (FMC-Asahi Chemical Industry Co., Ltd.), crospovidone, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, Xl-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcellulose. Examples of low-substituted hydroxypropylcellulose include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starch.
Binders:
Various useful binders include but are not limited to hydroxypropylcellulose (Klucel™-LF), hydroxypropyl methylcellulose (Methocel™), polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30), powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starch.
Glidants/ antisticking/anti tacking agents:
Various glidants or antisticking agents, which include but not limited to talc, silica derivatives, colloidal silicon dioxide and the like or mixtures thereof.
Lubricants:
Various lubricants that can be used include but are not limited to magnesium stearate, sucrose esters of fatty acid, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate, zinc stearate, castor oils.
Surfactants/Wetting agents:
Various useful surfactants include but are not limited to sodium lauryl sulfate, polysorbate 80, poloxamer 188, poloxamer 407, sodium carboxy methylcellulose hydrogenated oil, polyoxyethylene glycol, and polyoxypropylene glycol, polyglycolized glycerides grades such as GELUCIRE 40/14, GELUCIRE 42/12, GELUCIRE 50/13 and so on.
Solvents:
Various solvents used in the preparation of starter cores, drug layering or coated particles or further aesthetic or any functional coatings, granulation of durg layered particles or coated particles with or without other excipients include but not limited to water, lower alcohols like methanol, ethanol, acidified ethanol, acetone, polyols, polyethers, oils, esters, alkyl ketones, ethyl alcohol or ethanol, methylene chloride, isopropanol or isopropyl alcohol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran.
The coatings mentioned according to this invention can contain conventional excipients such as plasticizers, wetting agents, colourants etc.
Plasticizers:
Various plasticizers include but not limited to monoacetin, triacetin, diacetin, diethyl adipate, dibutyl adipate, dioctyl adipate dimethyl phathalate, diethyl plthalate, dibutyl phthalate, dioctyl maleate, epoxidized soyabean oil, Tri n-butyl citrate, Tributyl phosphate, Tricresyl phosphate, mineral oils, fatty acids and esters thereof with polyethylene glycol, glycerine or sugars, fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars and vegetable oils, or a non ionic surfactant such as glyceryl monostearate.
Colourants:
Various useful colourants include but are not limited to Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, and ferric oxide
Film forming polymers:
Various film forming polymers included but not limited to hydrophilic or water soluble polymers of various grades such as celluloses such as methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methyl cellulose provided by DOW chemical under the trade name METHOCEL™, various grades are, METHOCEL K 4M, METHOCEL K 15M, METHOCEL K 100M, METHOCEL K100M CR, METHOCEL K100LV) cross-linked sodium carboxymethyl cellulose and cross-linked hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone; gums such as agarose, gum arabic, gum ghatti, gum karaya, gum tragacanth; hydrophilic colloids such as alginates; other substances such as arbinoglactan, pectin, amylopectin, N-vinyl lactams, polysaccharides and the like.
Water-insoluble polymers or combinations but not limited to: oils such as hydrogenated castor oil; waxes such as beeswax, carnauba wax, and microcrystalline wax; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol, and myristyl alcohol; fatty acid esters such as glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, and glyceryl behenate; celluloses such as ethyl cellulose, low substituted hydroxyl propyl cellulose (L-HPC), cellulose acetates, and their derivatives, cellulose acetate phthalate, hydroxyl propyl methylcellulose phthalate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-cellulose arylates, and mono-, di- and tri-cellulose alkenylates; polymers, polymethacrylic acid based polymers and copolymers sold using the trademark EUDRAGIT (Eudragit RL and RS, NE-30D); zein; aliphatic polyesters; copolymers of the above polymers; or mixtures of any two or more in various ratios and proportions as required are within the scope of this invention without limitation. Of course, any other substance or excipient, which demonstrates such characteristics and is useful to modulate the release, is also acceptable in the practice of this invention.
Various antifoaming agents or defoamers include but not limited polyethylene glycol, glycerine, mineral oil defoamers, silicone defoamers, non-silicone defoamers (such as polyethers, polyacrylates), dimethylpolysiloxanes or dimethicone (silicone oils), arylalkyl modified polysiloxanes, and polyether siloxane copolymer containing fumed silica. The anti-foaming agent may be present in the composition of the invention in an amount of 0.1-0.3 wt.%, based on the total weight of the coating composition
The membrane is applied to the particles by methods known per se. This can be affected in a rapidly rotating vessel or via the fluidized-bed process by spraying lacquer solution over the particles (drug layered starter cores.
In another aspect the invention relates to method of using the pharmaceutical formulations comprising Dabigatran etexilate or its salts thereof for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
The dosage forms can be subjected to an in vitro dissolution evaluation according to Test 711 “Dissolution” in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, to determine the release of drug from the dosage forms, and drug content can conveniently be determined in dissolution solutions using techniques such as high performance liquid chromatography. The pharmaceutical dosage forms of the present invention are intended for oral administration to a patient in need thereof.
The present invention includes the use of certain packaging materials to store active substance or pharmaceutical formulations. In an embodiment, the invention includes use of packaging materials such as containers and lids of HDPE, low-density polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene. The described packaging materials are only representative, as many other materials will be suitable. Optionally, dried silica pouches or molecular sieves are placed in or along with the packing materials. The silica pouches can be dried previously at 100°C for about 3 hours, or longer.
Certain specific aspects and embodiments of the invention are described in further detail by the examples below, which examples are provided solely for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES:
Example 1: Pharmaceutical formulation of dabigatran etexilate mesylate comprising non-spherical organic acid core.
Ingredients mg/capsule
Core
Tartaric acid* 177
Microcrystalline cellulose 35
Acacia 9
Purified Water q.s.
Sub coat
Hydroxypropylcellulose 11
Talc 10.9
Dimethicone or dimethylpolysiloxane 0.1
Isopropyl alcohol q.s.
Purified Water q.s.
Drug layer
Dabigatran etexilate mesylate 173
Hypromellose or hydroxy propyl methyl cellulose (HPMC) 17
Talc 17
Isopropyl alcohol q.s.
Encapsulation
Drug layered pellets 450.00
Hydroxy propyl methyl cellulose (HPMC) Capsule shell, size 0 1 No.

*Tartaric acid cores are in cylindrical shape.
Manufacturing process:
1. Granulate tartaric acid powder and microcrystalline cellulose by using acacia water binder solution followed by extrusion spheronization and drying to form cylindrical tartaric acid cores.
2. Sub coat layer – Disperse hydroxypropylcellulose in Isopropyl alcohol to this add water to form clear solution, then add dimethylpolysiloxane to prevent foaming and finally disperse talc. Coat this dispersion onto the cores of step 1.
3. Drug layer - In isopropyl alcohol add hypromellose with stirring, then add dabigatran etexilate mesylate and finally disperse talc. Coat this dispersion onto the sub coated cores of step 1.
4. Encapsulation –Encapsulate the drug coated cores in HPMC capsules.

Example 2: Pharmaceutical formulations comprising dabigatran etexilate mesylate in the form of cores.
Ingredient mg/capsule
Dabigatran etexilate mesylate 173
Microcrystalline cellulose 35
Hydroxy propyl methyl cellulose (HPMC) 9
Isopropyl alcohol q.s
Sub coat
Hydroxy propyl cellulose 11
Talc 10.9
Dimethicone or dimethylpolysiloxane 0.1
Isopropyl alcohol q.s
Purified water q.s
Acid layering
Tartaric acid 177
Hydroxy propyl methyl cellulose 17
talc 17
Isopropyl alcohol q.s
Encapsulation
Acid layered pellets 450
HPMC capsule shell, size 0 1 No.

Manufacturing process:
1. Granulate dabigatran etexilate mesylate, microcrystalline cellulose by using HPMC and isopropyl alcohol binder solution to form cores
2. Sub coat layer – Disperse hydroxypropylcellulose in Isopropyl alcohol to this add water to form clear solution, then add dimethylpolysiloxane to prevent foaming and finally disperse talc. Coat this dispersion onto the cores of step 1.
3. Acid layer - In isopropyl alcohol add hypromellose with stirring, then to this add tartaric acid and finally disperse talc. Coat this dispersion onto the sub coated cores of step 2.
4. Encapsulation –Encapsulate the acid coated cores of step 3 in HPMC capsules.

Example 3: Pharmaceutical formulations comprising minitablets of tartaric acid as cores.
Ingredients mg/tab mg/cap
Core
Tartaric acid 7.375 177
Microcrystalline cellulose 1.04 24.96
Magnesium stearate 0.085 2.04
Sub coat
Hydroxypropylcellulose 0.42 10.08
Talc 0.42 10.08
Dimethicone or dimethylpolysiloxane 0.01 0.24
Isopropyl alcohol q.s.
Purified Water q.s.
Drug layer
Dabigatran etexilate mesylate 7.21 173.0
Hypromellose 0.72 17.28
Talc 0.72 17.28
Isopropyl alcohol q.s.
Encapsulation
Drug layered minitablets 24 Nos.
HPMC Capsule shell, size 0 1 No.

Manufacturing process:
1. Organic acid core–Tartaric acid powder, microcrystalline cellulose and magnesium stearate were mixed together and compressed using multi-tip punches to get minitablets.
2. Sub coat layer - Hydroxypropylcellulose was dispersed in Isopropyl alcohol to this water was added to form clear solution, then dimethylpolysiloxane added to prevent foaming and finally talc is dispersed. This dispersion was coated onto minitablets of step 1.
3. Drug layer - In a sufficient amount of isopropyl alcohol hypromellose was added under stirring, then dabigatran etexilate mesylate was added and finally talc was dispersed. This dispersion was coated onto sub coated cores of step 2.
4. Encapsulation – The drug layered minitablets of step 3 were filled in HPMC capsules.

Example 4: Pharmaceutical formulations comprising granulation of dabigatran etexilate mesylate and organic acid.
Ingredients mg/cap
Dabigatran etexilate mesylate 173.00
Fumaric acid 177.00
Mannitol 56.00
Croscarmellose sodium 20.00
Magnesium stearate 4
Isopropyl alcohol * q.s
Purified water * q.s
Encapsulation
Powder/Granules/pellets 430.0
HPMC Capsule shell, size 0 1 No.
* Only for granulation process of step 2.
Manufacturing process:
1. Mix dabigatran etexilate mesylate, fumaric acid, mannitol, croscarmellose sodium and magnesium stearate and filled in hard capsule or
2. Granulate dabigatran etexilate mesylate, fumaric acid, mannitol, croscarmellose sodium using isopropyl alcohol and water, followed by drying, milling to form granules or pelletized by extrusion-spheronization process and blend with magnesium stearate and fill in hard capsules.

Example 5: Pharmaceutical formulations comprising inorganic acids core pellets.
Ingredients mg/tab
Acid Core
Microcrystalline cellulose 180
Phosphoric acid 3
Hypromellose 17
Purified Water q.s.
Sub coat
Hypromellose or hydroxy propyl methyl cellulose 10
Talc 9.9
Dimethicone or dimethyl polysiloxane 0.1
Isopropyl alcohol q.s.
Purified Water q.s.
Drug layer
Dabigatran etexilate mesylate 173
Hypromellose 17
Talc 17
Isopropyl alcohol q.s.
Encapsulation
Drug layered pellets 427.0
HPMC Capsule shell, size 0 1 No.

Manufacturing process:
1. Binder solution – Prepare binder by dissolving hypromellose in purified water to form clear solution and finally phosphoric acid added to it.
2. Acid core –Granulate microcrystalline cellulose using step 1 binder solution followed by extrusion spheronization and drying to form non-spherical acid core
3. Sub coat layer – Disperse hypromellose in Isopropyl alcohol and add water to form clear solution then add dimethyl polysiloxane to prevent foaming and finally disperse talc. Coat this dispersion onto non-spherical acid core of step 2.
4. Drug layer - In isopropyl alcohol add hypromellose with stirring, then add dabigatran etexilate and finally disperse talc. Coat this dispersion onto sub coated cores of step 3.
5. Encapsulation –Encapsulate the drug layered cores in HPMC capsules.

Example 6: Pharmaceutical formulations comprising encapsulation of dabigatran etexilate mesylate pellets and organic acid pellets.
Ingredients mg/cap
Drug pellets
Sugar sphere 45.00
Dabigatran etexilate mesylate 173
Hydroxypropylcellulose 19
Talc 13
Isopropyl alcohol q.s.
Acid Pellets
Tartaric acid 177
Hydroxy propyl methyl cellulose 12
Talc 10.9
Dimethicone or dimethyl polysiloxane 0.1
Ethanol q.s.
Encapsulation
Drug pellets + Tartaric Acid pellets 450.0
HPMC Capsule shell, size 0 1 No.

Manufacturing process:
1. Drug pellets: Disperse hydroxypropylcellulose in a sufficient amount of isopropyl alcohol, then add dabigatran etexilate mesylate and finally disperse talc. Coat this dispersion onto sugar spheres to form drug pellets.
2. Tartaric acid pellets- Disperse hydroxy propyl methylcellulose in ethanol and to this add dimethyl polysiloxane to prevent foaming and finally disperse talc. Coat this dispersion onto tartaric acid to form tartaric acid pellets.
3. Encapsulation – Encapsulate drug pellets and tartaric acid pellets in HPMC capsules.
,CLAIMS:WE CLAIM:
1. A pharmaceutical formulation comprising a non-spherical core layered with dabigatran etixilate or a pharmaceutically acceptable salt thereof, wherein the non-spherical core is optionally coated with an intermediate coating.
2. A pharmaceutical formulation according to claim 1, wherein the non-spherical core comprises a pharmaceutically acceptable organic or inorganic acids or combinations thereof.
3. A pharmaceutical formulation according to claim 1, wherein, the non-spherical core is in form of a minitablet.
4. A pharmaceutical formulation according to claim 1, wherein the shape of non-spherical core is selected from a group of cylindrical or rod shaped, dumbbell, needle, rectangle, square, pentagon, hexagon, octagon, triangle, diamond, elliptical, oval, and combinations thereof.
5. A pharmaceutical formulation comprising a core layered with dabigatran etixilate or a pharmaceutically acceptable salt thereof, wherein the core comprises an inorganic acid.
6. A pharmaceutical formulation comprising a core layered with a pharmaceutically acceptable acid, wherein the core comprises dabigatran etixilate or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical formulation according to claim 6, wherein the pharmaceutically acceptable acid is selected from the group of organic acid, inorganic acid, and combinations thereof.
8. A pharmaceutical formulation according to claim 6, wherein the core is in the form of a granule or a pellets or a minitablet.
9. A stable pharmaceutical formulation comprising dabigatran etixilate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acid, wherein dabigatran etixilate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acid are granulated together.
10. A pharmaceutical capsule dosage form comprising pellets or granules or powder or minitablets of a pharmaceutically acceptable acid, and pellets or granules or powder or minitablets of dabigatran etixilate or a pharmaceutically acceptable salt thereof.