CONTROLLED RELEASE PHARMACEUTICAL FORMULATIONS OF DIRECT THROMBIN INHIBITORS
Field of the Invention
The present invention relates to controlled release pharmaceutical formulations of direct
thrombin inhibitors and processes for preparing such compositions. Particularly the
present invention relates to oral controlled release pharmaceutical compositions
comprising dabigatran etexilate or pharmaceutically acceptable salts thereof.
Background of the Invention
Atrial fibrillation is the most common cardiac arrhythmia which is characterized by
abnormal heart rhythm. It is considered to be a common cause of irregular heart beat
and can cause stroke and other systemic embolic events, eventually leading to death. It
has been seen that the incidence of atrial fibrillation increases with age and nearly 6% of
individuals over the age of 65 are affected while the prevalence is about 8% in
individuals over the age of 80. The lack of organized cardiac contractions in atrial
fibrillation generally results in some stagnant blood in the left atrium or left atrial
appendage. This lack of movement of blood leads to thrombus formation or blood
clotting. Patients with atrial fibrillation are therefore at greater risk of developing clots
which increases the risk of stroke and other systemic embolic events. Since the
consequence of stroke or systemic embolism is devastating, a primary aim of therapy for
atrial fibrillation is to reduce the risk of arterial thrombus formation and
thromboembolism. Anticoagulants such as warfarin are mainly used in case of atrial
fibrillation along with other medications such as beta blockers and calcium channel
blockers or some noninvasive rhythm control methods. Though anticoagulation therapy
with warfarin has been shown to significantly reduce the incidence of stroke or systemic
embolism, its use is found to be cumbersome due to multiple diet and drug interactions,
chances of hemorrhage which are difficult to manage, requirement of frequent laboratory
monitoring etc. Use of a newer safe and effective anticoagulant is therefore necessary.
Direct thrombin inhibitors, is another class of anticoagulants that act by directly inhibiting
the enzyme thrombin and are expected to replace heparin (and derivatives) and warfarin
in various clinical scenarios. Thrombin, a serine protease protein formed by proteolytic
cleavage of prothrombin, converts soluble fibrinogen into insoluble strands of fibrin and
further catalyzes many other coagulation-related reactions. Direct thrombin inhibitors
inhibit thrombin including fibrin-bound thrombin, thereby delimiting thrombus growth,
provide predictable anticoagulant responses because they are not bound to plasma
proteins and have no drug-drug interactions. Depending on their interaction with the
thrombin molecule, there are bivalent as well as univalent types of direct thrombin
inhibitors, with some being in clinical use, while others undergoing clinical development.
Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. It reduces the risk
of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It is also
useful in primary prevention of venous thromboembolic events in adult patients who have
undergone elective total hip replacement surgery or total knee replacement surgery.
Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet
aggregation. Dabigatran was first disclosed in WO98/37075, which claimed compounds
with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the
name 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl] aminomethyl]
benzimidazol-5-ylcarboxylic acid-N-(2-pyridyl)-N-(2 ethoxycarbonylethyl)amides.
Dabigatran is currently available as dabigatran etexilate mesylate (DEM) in Europe and
United States under the brand name Pradaxa® from Boehringer Ingelheim as immediate
release oral capsules containing pellets of 75 g, 0 g and 150 g and 75 g and
150 mg strengths respectively to be administered twice daily. DEM is a salt form of the
prodrug dabigatran etexilate which after oral administration is rapidly absorbed and
converted to dabigatran by esterase-catalyzed hydrolysis in the liver. U.S Patent
Application 2006/01 83779A1 describes the marketed formulation of DEM in the form of
pellets that comprise tartaric acid cores coated with active layer coating with a separating
agent layer separating the acid core from the active substance containing layer.
DEM is a yellow-white to yellow non-hygroscopic powder that exists in two anhydrous
polymorphic forms, Form I and II. The aqueous solubility of DEM is strongly pH
dependent with rather high solubility in acidic media and very poor solubility in neutral
and basic media while solubility in water is 1.8mg/ml_. Therefore, dabigatran etexilate is
absorbed better in an acidic milieu in the gastrointestinal tract. However, at higher pH in
intestine where solubility is low, absorption tends to be poor and erratic. DEM is BCS
Class II drug, indicating poor aqueous solubility but good membrane permeability. DEM
is stable in the solid state and not sensitive to light irradiation but it predominantly
undergoes degradation by hydrolytic pathways in the presence of moisture. It is also
acid sensitive. The elimination half life is 12-17 hours with single dosing and decreases
to about 8 hours upon multiple dosing. Dabigatran etexilate is a substrate of the efflux
transporter P-glycoprotein. After oral administration of dabigatran etexilate in healthy
volunteers, Cmax occurs at 1 hour post-administration in the fasted state.
Coadministration with a high-fat meal delays the time to Cmax by approximately 2 hours
but has no effect on the bioavailability of dabigatran.
The absolute bioavailability of dabigatran following oral administration of dabigatran
etexilate is approximately about 3-7%. However, the oral bioavailability of dabigatran
etexilate from the marketed formulation increases by 75% when the pellets are taken
without the capsule shell as compared to the intact capsule formulation. Without being
bound to any theory, the low bioavailability of DEM is primarily because the active agent
is unavailable for absorption as the dosage form passes down the gastrointestinal tract,
resulting in precipitation of the drug therein in the intestinal region where its solubility is
low than in acidic milieu. Moreover, dabigatran etexilate also undergoes P-glycoprotein
mediated efflux, which further limits systemic absorption of the active and its
bioavailability.
Additionally, pharmaceutically active agents which exhibit low bioavailability
unfortunately create a need for frequent dosing of a large amount of pharmaceuticals in
order to provide and maintain therapeutic levels. However, the need for multiple dosings
in a day, present patient compliance problems and also cause fluctuations in serum
concentrations of the active agents and toxicity. Furthermore direct thrombin inhibitors
such as dabigatran etexilate have low therapeutic index and therefore fluctuations in
serum concentrations of these agents due to multiple dosings can reduce the safety and
efficacy of these agents and increase side effects such as increased risk of bleeding.
Need thus exists for controlled release dosage form of direct thrombin inhibitors such
dabigatran etexilate or pharmaceutically acceptable salts thereof that would enable
better patient compliance and offer advantages over conventional immediate release
formulations. Controlled release formulations would also lessen or prevent potentially
undesirable effects by reducing peak blood levels (Cmax) and' increase drug efficacy
(Cmin) by maintaining desired therapeutic plasma concentrations for longer period. Need
also exists to address the low bioavailability issue of direct thrombin inhibitors and
develop dosage forms thereof with desired, high or improved and reproducible
bioavailability. Particularly, need exists for controlled release formulations of direct
thrombin inhibitors with improved solubility, absorption and bioavailability. Further, direct
thrombin inhibitor such as dabigatran etexilate mesylate is sensitive to acid and moisture
and therefore need also exists to develop controlled release formulations thereof that are
stable over the shelf life.
Attempts have not been made by researchers to provide controlled release compositions
of direct thrombin inhibitors. Attempts have also not been made by researchers to
provide controlled release formulations of direct thrombin inhibitors with improved
solubility, absorption and bioavailability.
The present inventors after rigorous experimentation provide controlled release
formulations of direct thrombin inhibitors that not only release the active agent
continuously in a predetermined manner and lessen the frequency of dosing but also
reduce peak-trough fluctuations thereby maintaining desired therapeutic concentrations
for longer duration of time and minimizing side effects otherwise associated immediate
release tablets. The present inventors further provide controlled release formulations of
direct thrombin inhibitors with improved solubility and bioavailability of the active agent.
Furthermore since direct thrombin inhibitor such as dabigatran etexilate mesylate is a
substrate of efflux pump P-glycoproteins and has pH dependent solubility with high
solubility in acidic media and very poor solubility in neutral and basic media, the present
inventors provide controlled release formulations of direct thrombin inhibitor in the form
of gastroretentive dosage form. Such a dosage form continuously delivers the active at a
predetermined rate in the upper regions of the gastrointestinal tract in an acid milieu
where solubility of dabigatran etexilate mesylate is better resulting in improved
absorption of the active agent and improved bioavailability. Such a dosage form also
minimizes exposure of the drug to efflux pump P-glycoproteins thereby further improving
bioavailability and efficacy. Such a dosage form may comprise solubilized active agent to
further improve the bioavailability of the active agents.
The present inventors thus provide controlled release formulations comprising at least
one direct thrombin inhibitor such as dabigatran etexilate mesylate, at least one release
controlling agent and at least one pharmaceutically acceptable excipient. The
formulations of the present invention are stable, easy or convenient to prepare, and
provide the desired in vitro release and bioavailability.
Summary of the Invention
The present invention relates to controlled release pharmaceutical formulations of direct
thrombin inhibitors. Particularly the present invention relates to oral controlled release
pharmaceutical compositions comprising dabigatran etexilate or pharmaceutically
acceptable salts thereof.
Detailed Description of the Invention
The present invention provides oral controlled release pharmaceutical compositions
comprising at least one direct thrombin inhibitor, at least one release controlling agent
and at least one pharmaceutically acceptable excipient.
The term "composition" or "formulation" or "dosage form" has been employed
interchangeably for the purpose of the present invention and mean that it is a
pharmaceutical composition which is suitable for administration to a patient or subject.
The subject can be an animal, preferably a mammal, more preferably a human. For the
purpose of the present invention terms "controlled release" or "sustained release" or
"extended release" or "prolonged release" have been used interchangeably and mean
broadly that the direct thrombin inhibitor is released at a predetermined rate that is
slower than the immediate release formulation.
The term "direct thrombin inhibitor/s" as employed herein refers to any compound that
acts by directly inhibiting the enzyme thrombin, both free and fibrin-bound thrombin as
well as thrombin-induced platelet aggregation; including, but not limited to, dabigatran,
argatroban, inogatran, melagatran, ximelagatran, hirudin, bivalirudin, lepirudin, desirudin
and the like, in the form of free acid or free base or pharmaceutically acceptable
prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of
prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, optical
isomers, precursors, derivatives, analogs, amorphous form, diastereomers,
diastereomeric mixtures, tautomers or racemic mixtures thereof. In one embodiment, the
direct thrombin inhibitors employed in the compositions of the present invention include,
but are not limited to, univalent inhibitors such as, but not limited to , dabigatran,
argatroban, melagatran, ximelagatran, and the like; or bivalent inhibitors such as, but not
limited to hirudin, bivalirudin, lepirudin, desirudin and the like; and various combinations
thereof in the form of free acid or free base or pharmaceutically acceptable prodrugs,
pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active
metabolites, polymorphs, solvates, hydrates, enantiomers, optical isomers, tautomers or
racemic mixtures thereof.
Pharmaceutically effective amount of direct thrombin inhibitor is employed in the
composition of the present invention. The term "effective amount" refers to an amount
effective to achieve desired preventive, therapeutic and/or beneficial effect, such as but
not limited to reducing the risk of stroke and systemic embolism in patients with nonvalvular
atrial fibrillation or preventing venous thromboembolic events in adult patients
who have undergone elective total hip replacement surgery or total knee replacement
surgery, and the like. In one embodiment the amount of direct thrombin inhibitor in the
composition can vary from about 0.01 weight % to about 90 weight %, based on the total
weight of the composition. In another embodiment the amount of direct thrombin inhibitor
in the composition can vary from about 0.02 weight % to about 85 weight %, based on
the total weight of the composition. In still another embodiment, the amount of direct
thrombin inhibitor in the composition can vary from about 0.05 weight % to about 80
weight %, based on the total weight of the composition. In one embodiment the
compositions of the present invention may be administered at a dose of about 0.01 mg to
about 400 mg of direct thrombin reductase inhibitor. In another embodiment the
compositions of the present invention may be administered at a dose of about 0.1 mg to
about 350 mg of direct thrombin inhibitor. In still another embodiment the compositions of
the present invention may be administered at a dose of about 0.2 mg to about 300 mg of
direct thrombin inhibitor. In one embodiment, the direct thrombin inhibitor employed for
the present invention is dabigatran in the form of free acid or free base or
pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts,
pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, solvates,
hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof. In a
further embodiment, the direct thrombin inhibitor employed in the present invention is
dabigatran etexilate mesylate.
The controlled release compositions of the present invention comprise along with at least
one direct thrombin inhibitor, at least one release controlling agent. The term "release
controlling agent" as used herein means any excipient that can retard the release of
active agent and includes, but is not limited to, polymeric release controlling agent, nonpolymeric
release controlling agent or combinations thereof.
Suitable polymeric release controlling agent may be employed in the compositions of the
present invention. In one embodiment, the polymeric release controlling agent that may
be employed in the compositions of the present invention may be pH independent or pH
dependent or any combination thereof. In another embodiment, the polymeric release
controlling agent employed in the compositions of the present invention may be swelling
or non-swelling. In a further embodiment, polymeric release controlling agents that may
be employed in the compositions of the present invention include, but are not limited to,
cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-
poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or
copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers,
acrylic acid derivatives or the like or any combinations thereof.
Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose,
hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl
cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl
cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose,
hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose,
carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose,
carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate,
cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose
acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose
phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate
maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate
phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or
combinations thereof.
Saccharides or polysaccharides include, but are not limited to, guar gum, xanthan gum,
gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and
copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion
(Kollicoat® SR 30D , copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol,
mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol
phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal
phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and
derivatives thereof include, but are not limited to, polyethylene oxide and the like or any
combinations thereof.
Acrylic acid derivatives include, but are not limited to, methacrylic acids, poiymethacrylic
acids, polyacrylates, especially polymethacrylates like a) copolymer formed from
monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and
acrylic acid esters b) copolymer formed from monomers selected from butyl
methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer
formed from monomers selected from ethyl acrylate, methyl methacrylate and
trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and
methacrylates with/without quarternary ammonium group in combination with sodium
carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark
Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic
butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl
methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate
methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic
acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate
copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium
carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer
based polymeric release controlling agent includes, but is not limited to,
vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer,
styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride
copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid
anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl
acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In
one embodiment, polymers with low viscosity are employed in the compositions of the
present invention as release controlling agent such as, but not limited to, Methocel K4M,
and the like or combinations.
The term "non-polymeric release controlling agent" as used herein refers to any excipient
that can retard the release of an active agent and that does not comprise of repeating
units of monomers. Suitable non-polymeric release controlling agents employed in the
present invention include, but are not limited to, fatty acids, long chain alcohols, fats and
oils, waxes, phospholipids, eicosonoids, terpenes, steroids, resins and the like or
combinations thereof. Non-polymeric release controlling agents employed may be pH
dependent or pH independent in nature.
Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat
or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon
atoms and are characterized by a terminal carboxyl group. Fatty acids that may be
employed in the present invention include, but are not limited to, hydrogenated palm
kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil,
hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil,
hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof.
Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic
acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one
embodiment the fatty acids employed include, but are not limited to, hydrogenated palm
oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and
mixtures thereof. Suitable long chain monohydric alcohols include, but are not limited to,
cetyl alcohol, stearyl alcohol or mixtures thereof.
Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are
often mixtures of such esters, and may also contain hydrocarbons. Waxes are lowmelting
organic mixtures or compounds having a high molecular weight and are solid at
room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols.
Waxes that may be employed in the present invention include, but are not limited to,
natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e.,
paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic
waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax,
Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax,
sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax,
carbowax, and the like, or mixtures thereof. Mixtures of these waxes with the fatty acids
may also be used. Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl
esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10
to about 22 carbon atoms and glycerol, wherein one or more of the hydroxy! groups of
glycerol is substituted by a fatty acid. Glycerides that may be employed in the present
invention include, but are not limited to, glyceryl monostearate, glyceryl distearate,
glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate,
glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate,
glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl
dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl
trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate,
glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl
macrogolglycerides, stearoyl macrogolglycerides, and the like, or mixtures thereof.
Resins employed in the compositions of the present invention include, but are not limited
to, shellac and the like or any combinations thereof.
In one embodiment the non-polymeric release controlling agent employed includes, but
is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean
oil), Castorwax® (Hydrogenated castor oil, Croduret® (Hydrogenated castor oil),
Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil),
Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated
cottonseed oil), Softisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean
oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl
Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl
Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof.
The amount of release controlling agent used in the controlled release formulations of
the present invention may vary depending upon the degree of controlled or sustained
release desired. In an embodiment, release controlling agent is present in the
composition in an amount from about 1% to about 95% by weight of the dosage form. In
another embodiment, release controlling agent is present in the formulation in an amount
from about 2% to about 90% by weight of the dosage form. In a further embodiment,
release controlling agent is present in the formulation in an amount from about 5% to
about 85% by weight of the dosage form.
In one embodiment, the direct thrombin inhibitor in the form of, but not limited to, powder,
granules, pellets, beads, minitablets or the like is treated with at least one release
controlling agent. In a further embodiment the active agent may be in micronized form.
The active ingredient may be treated by any of the techniques known in the art such as,
but not limited to, melt granulation, hot melt extrusion, fluid bed coating, wet granulation,
spray drying, extrusion-spheronization, dry granulation or roll compaction. Lipids or
waxes can also be employed in the form of an aqueous dispersion stabilized by
surfactants and suitable stabilizers. In one embodiment, the direct thrombin inhibitor is.
incorporated in the controlled release formulations of the present invention in the
/solubilized form. In another embodiment, the direct thrombin inhibitor or solubilized direct
thrombin inhibitor is blended or physically mixed with release controlling agent. In one
embodiment, the direct thrombin inhibitor or solubilized direct thrombin inhibitor when
coated with a release controlling agent, coating may be carried out in the range from
about 1% to about 80% weight gain, preferably from about 2% to about 60% weight gain,
more preferably from about 5 to about 50% weight gain. In a further embodiment treated
direct thrombin inhibitor or solubilized direct thrombin inhibitor is incorporated in the
dosage forms of the present invention.
Controlled release of direct thrombin inhibitor may be accomplished by any means
known in the pharmaceutical art, such as, but not limited to, matrix controlled-release
systems, coated controlled release systems, coated-matrix controlled release systems,
osmotic controlled-release systems, multiparticulate controlled-release systems, nongastroretentive
controlled release systems and the like.
In one embodiment the controlled release formulation of the present invention is in the
form of a gastroretentive dosage form. For the purpose of the present invention the term
"gastroretentive" or "gastric retention" or "gastroretention" or "retained in upper
gastrointestinal tract" when used with respect to the dosage form of the present
invention, means that the dosage form or at least a portion thereof remains in the upper
gastrointestinal tract including stomach, for about 30 minutes or more. In another
embodiment, the gastroretentive dosage form of the present invention remains in the
upper gastrointestinal tract including stomach, for about 30 minutes to about 12 hours.
In another embodiment controlled release formulation of the present invention is in the
form of a gastroretentive dosage form for improved bioavailability. In a further
embodiment, gastroretentive dosage forms that are retained in the upper gastrointestinal
tract for a prolonged period of time after oral administration and release the active
ingredient continuously at a predetermined rate or in a sustained manner are employed
for delivering direct thrombin inhibitors that exhibit low oral bioavailability. Design of such
gastroretentive dosage forms is a challenge for a formulator because of the complexities
of physiological effects that have implications on drug release and absorption in vivo.
The controlled release gastroretentive dosage forms of the present invention release the
active at a predetermined rate and provide improved bioavailability when compared to
conventional immediate release dosage forms.
The controlled release formulations of the present invention in addition to at least one
direct thrombin inhibitor and at least one release controlling agent as discussed above,
comprise at least one swelling agent. The controlled release formulations of the present
invention in the form of a gastroretentive dosage form comprise in addition to at least
one direct thrombin inhibitor and at least one release controlling agent as discussed
above, at least one swelling agent. The swelling agents employed herein swell
voluminously in the presence of gastric contents to increase the size of dosage form
such that it precludes its passage through the pyloric sphincter thereby retaining the
compositions of the present invention in the upper gastrointestinal tract. The controlled
release gastroretentive formulations of the present invention comprise at least one direct
thrombin inhibitor, at least one release controlling agent, at least one swelling agent and
at least one pharmaceutically acceptable excipient.
The swelling agent used in the present invention includes, but is not limited to, one or
more swellable biocompatible hydrophilic polymers. In one embodiment, the swelling
agents are employed in the dry state or in a form that has substantial capacity for water
uptake. Hydrophilic polymers used as swelling agents that are useful in preparation of
the dosage forms of the present invention are polymers that are nontoxic and swell in a
dimensionally unrestricted manner upon imbibing gastric fluid.
Suitable swelling agents employed in the dosage forms of the present invention include,
but are not limited to, polyalkylene oxides; cellulosic polymers such as, but not limited to,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium
carboxy methylcellulose, methyl cellulose; acrylic acid and methacrylic acid polymers,
and esters thereof, polyethylene oxide, maleic anhydride polymers; polymaleic acid;
poly(acrylamides); carbopol, poly(olefinic aicohol)s; poly(N-vinyl lactams); polyols;
polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates;
polyimines; starch and starch-based polymers; polyurethane hydrogels; chitosan;
polysaccharide gums such as xanthan gum; alginates; zein; shellac-based polymers;
polyacrylic acid, maltodextrin, pre-gelatinized starch and polyvinyl alcohol, or mixtures
thereof. In one embodiment, swelling agents of different viscosity grades can be
incorporated in the compositions of the present invention to achieve gastroretention. In
another embodiment, swelling agents of high viscosity can be incorporated in the
compositions of the present invention to achieve gastroretention such as, but not limited
to, Methocel K100M, Polyox WSR303, and the like or combinations thereof. In one
embodiment, the swelling agent employed may function as a release controlling agent. In
another embodiment, the swelling agent employed may be a swelling release controlling
agent.
The amount of swelling agent employed in the controlled release gastroretentive dosage
forms of the present invention is from about 2% to about 98 % by weight of the final
dosage form. In one embodiment, the weight percent of the swelling agent in the final
dosage form is about 5% to about 95%. In another embodiment, the weight percent of
the swelling agent in the final dosage form is about 10% to about 90%. The amount and
type of swelling agents employed in the gastroretentive dosage forms of the present
invention ensures that there is sufficient swelling for retention of the dosage form. In one
embodiment, the controlled release dosage form is a multilayered gastroretentive tablet
with drug layer comprising at least one direct thrombin inhibitor and at least one release
controlling agent; and at least one gastroretentive layer/s comprising at least one
swelling agent wherein the swelling agents ensure that there is sufficient swelling for
retention of the dosage form despite erosion of the drug layer. These swelling agents
ensure that within 2 hours at least two dimensions of the dosage form namely length and
width is more than 8 mm, preferably more than 10 mm.
In addition to the above discussed excipients, the controlled release compositions of the
present invention comprise at least one pharmaceutically acceptable excipients, such as,
but not limited to, solubility enhancing agents, p-glycoprotein inhibitors, swelling
enhancers, permeation enhancers, pH modifiers, binders, lubricants, diluents,
disintegrants, glidants, stabilizers, preservatives, colorants and the like or combinations
thereof.
In one embodiment the increase in instantaneous solubility of direct thrombin inhibitor is
achieved by using at least one solubility enhancing agent. In another embodiment, the
controlled release formulations of the present invention comprise solubilized direct
thrombin inhibitor which comprises at least one direct thrombin inhibitor, at least one
solubility enhancing agent and optionally at least one pharmaceutically acceptable
excipient, such as, but not limited to diluents and the like. In one embodiment, the
controlled release formulation of the present invention comprises at least one direct
thrombin inhibitor, at least one release controlling agent, at least one solubility enhancing
agent, and at least one pharmaceutically acceptable excipient. In a further embodiment,
the controlled release gastroretentive dosage form of the present invention comprises at
least one direct thrombin inhibitor, at least one release controlling agent, at least one
swelling agent, at least one solubility-enhancing agent, and at least one pharmaceutically
acceptable excipient.
The solubility enhancing agent or solubilizer that may be employed in the compositions
of the present invention may include one or more surfactant, complexing agent,
hydrotropic agent, ion pairing agent and the like or combinations thereof. The solubility
enhancing agent as employed in the present invention includes, but is not limited to,
hydrophilic surfactants, lipophilic surfactants and the like or mixtures thereof. The
surfactants employed in the present invention may also include, but are not limited to,
ionic surfactants comprising cationic or anionic surfactants, zwitterionic or amphiphilic
surfactants or nonionic surfactants or the like or any combinations thereof. The ionic
surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty
acid derivatives of amino acids, oligopeptides, or polypeptides; glyceride derivatives of
amino acids; lecithins or hydrogenated lecithins; lysolecithins or hydrogenated
lysolecithins; phospholipids or derivatives thereof; lysophospholipids or derivatives
thereof; carnitine fatty acid ester salts; salts of alkylsulfates; sodium lauryl sulphate, fatty
acid salts; sodium docusate; acyl lactylates; mono- or di-acetylated tartaric acid esters of
mono- or di-glycerides; succinylated mono- or di-glycerides; citric acid esters of mono- or
di-glycerides; or mixtures thereof. The amphiphilic surfactants include, but are not limited
to, d-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) and d-atocopherol
acid salts such as succinate, acetate, etc. The non-ionic surfactants include,
but are not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty
acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan
fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol
derivatives; polyoxyethylated sterols or sterol derivatives; polyethylene glycol alkyl
ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- or di-glycerides; oilsoluble
vitamins/vitamin derivatives; PEG fatty acid esters; polyglycerized fatty acid;
polyoxyethylene-polyoxypropylene block copolymers; transesterification products of a
polyol with at least one member of the group consisting of glycerides, vegetable oils,
hydrogenated vegetable oils, fatty acids and sterols wherein the commonly used oils are
castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil,
peanut oil, palm kernel oil, almond oil and the commonly used polyols include glycerol,
propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol; or
mixtures thereof.
The solubility enhancing agent that may be employed include, but are not limited to,
PEG-20-glyceryl stearate (Capmul® by Abitec), PEG-40 hydrogenated castor oil
(Cremophor RH 40® by BASF), PEG-35 castor oil, PEG 6 corn oil (Labrafil® by
Gattefosse), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse), stearoyl
macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate
(Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene
glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac®
by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate
(Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec), PEG- 20
sorbitan monolaurate (Tween 20® by ICI), PEG - 4 lauryl ether (Brij 30® by ICI), sucrose
distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by
Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Poloxamer or Lutrol®
series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium
lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate, L- hydroxypropyl
cellulose,- hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate,
sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains , polyethylene
glycol (Carbowax® by DOW), d-a-tocopheryl polyethylene glycol 1000 succinate
(Vitamin E TPGS® by Eastman), or mixtures thereof.
The complexing agent that may be employed include, but are not limited to, cyclodextrin
class of molecules, such as cyclodextrins containing from six to twelve glucose units,
especially, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their
derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof. The
complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as
well as gentistic acid. In this complexation process, a hydrophilic polymer may be
additionally added to further enhance the solubility along with the complexing agent.
In the composition of the present invention, the direct thrombin inhibitor and one or more
solubility enhancing agents may be employed in different ratios. The selected ratio
depends upon the desired improvement in solubility and the type of solubility enhancing
agents employed. It is contemplated within the scope of the invention that the ratio of
direct thrombin inhibitor to solubility enhancing agents may range from about 50:1 to
about 1:50. In one embodiment, the ratio of direct thrombin inhibitor to solubility
enhancing agent is from about 20:1 to about 1:20. In another embodiment, the ratio of
direct thrombin inhibitor to solubility enhancing agent is from about 10:1 to about 1:10.
In one embodiment in the composition, the direct thrombin inhibitor may be present in
the form of physical blend, solid dispersion, solid solution or complex with the solubility
enhancing agent. Different processes may be employed to prepare the composition of
the direct thrombin inhibitor with the solubility enhancing agents. It is contemplated within
the scope of the invention that the processes for preparing solubilized direct thrombin
inhibitor may include, but not limited to, solubilization using melt granulation, solvent
treatment, wet granulation, physical mixing or spray drying of the dissolved direct
thrombin inhibitor in a solvent with a solubility enhancing agent, melt extrusion, jet
milling, shock cooling and the like or combinations thereof. In the case of melt
granulation, the solubility enhancing agent is melted. The direct thrombin inhibitor is
then added and mixed with the molten mass, and allowed to solidify to form granules
which are then separated from each other. In another embodiment the solubility
enhancing agents are melted. The direct thrombin inhibitor is then added and mixed with
the molten mass. This blend is further mixed with diluents capable of converting this
semisolid mass into dry powder. Non limiting examples of such drying agents include
celluloses such as microcrystalline cellulose, silicon dioxide, silicates, magnesium
aluminium silicate etc. In another illustrative embodiment of this system, the direct
thrombin inhibitor is granulated using a molten solubility enhancing agent. In some
cases, the direct thrombin inhibitor and the solubility enhancing agent both may be
melted together and congealed to room temperature. In using a solvent treatment
method, either the solubility enhancing agents or the direct thrombin inhibitor, or both,
are dissolved in a solvent which is then evaporated or spray dried. The resultant mass is
a blend of direct thrombin inhibitor and solubility enhancing agent, such that the solubility
of the direct thrombin inhibitor is increased. The solvent employed in this system may be
aqueous or non-aqueous. In the case of physical mixing, the direct thrombin inhibitor and
the solubility enhancing agent are preferably intimately dry-mixed using a low shear
granulator, a V-blender, or a high shear granulator. In the complexation method, complex
of direct thrombin inhibitor can be prepared using different techniques such as ball
milling, solvent evaporation method which includes, but is not limited to, spray drying and
lyophilization process, slurry method, and paste method. It is contemplated within the
scope of the invention that a combination of aforementioned processes can be
employed. For example, a combination of hot melt process, physical mixing, and solvent
treatment method may be employed. In this case, the direct thrombin inhibitor may be
initially granulated with one or more molten solubility enhancing agents, which can be
further treated with the same or different solubility enhancing agents in a solvent or with
simple physical mixing or vice versa. It is also contemplated within the scope of the
invention that any process known in the art suitable for making pharmaceutical
compositions in general may be employed for the purpose of this invention.
In one embodiment suitable permeation enhancers that may be employed in the
compositions of the present invention include, but are not limited to, surfactants, such as,
but not limited to, ionic, non ionic, hydrophilic, amphiphilic, lipophilic surfactants; bile
salts; polysaccharides; synthetic polymers; cyclodextrins; chelators and the like or any
combinations thereof. Suitable ionic surfactants, include, but are not limited to,
cetylpyridinium chloride, alkylammonium salts, sodium lauryl sulfate, sodium laureate,
fusidic acid salts, fatty acid derivatives of amino acids, oligopeptides, polypeptides,
glyceride derivatives of amino acids, lecithins or hydrogenated lecithins, lysolecithins or
hydrogenated lysolecithins, phospholipids or derivatives thereof, lysophospholipids or
derivatives thereof, carnitine fatty acid ester salts, salts of alkylsulfates, fatty acid salts,
sodium docusate, acyl lactylates, mono- or di-acetylated tartaric acid esters of mono- or
di-glycerides, succinylated mono- or di-glycerides, citric acid esters of mono- or diglycerides,
and the like or mixtures thereof. Suitable nonionic surfactants, include, but
are not limited to, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty
acid monoesters, polyethylene glycol fatty acid diesters, hydrophilic trans-esterification
products of alcohols or polyols with at least one member of the group consisting of
natural and/or hydrogenated oils such as castor oil or hydrogenated castor oil, or an
edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil;
polysorbate-80, diethylene glycol octadecyl ether, and the like or mixtures thereof.
Suitable bile salts include, but are not limited to, bile salts not limited to sodium
glycodeoxycholate, sodium glycocholate, sodium taurodeoxycholate, sodium
taurocholate and the like or mixtures thereof. Suitable polysaccharides include, but are
not limited to, chitosan and the like or mixtures thereof. Suitable synthetic polymers
include, but are not limited to carbopol, carbomer; fatty acids not limited to oleic acid,
caprylic acid; thiolated polymers of polyacrylates not limited to thiolated sodium carboxy
methyl cellulose and the like or mixtures thereof. Suitable chelators, include but are not
limited to ethylenediaminetetraacetic acid, sodium citrate and the like or mixtures thereof.
In another embodiment the controlled release of the present invention with improved
bioavailability optionally comprise P-glycoprotein inhibitors. The P-glycoprotein inhibitors
that may be included in the compositions of the present invention include, but are not
limited to, curcumin; phenyl cinnamate; coumarin; beta-amyrin cinnamate; apiole;
bergamotin; caffeine; morin; nariturin; piperine; qurcetin; slavironin; silybin; theobromin;
vanillin; vanillyl-N-nonlymine; surfactants such as, but not limited to, tocopherol
polyethylene glycol succinic acid esters (TPGS) not limited to those that are
commercially under the trade name Vitamin E TPGS; reaction products of a natural or
hydrogenated castor oil and ethylene oxide not limited to those that are available
commercially under the trade name Cremophor ® EL, Cremophor ® RH40;
polyoxyethylene-sorbitan-fatty acid esters not limited to those available commercially
under the trade name Tween®; polyoxyethylene-polyoxypropylene co-polymers and
block co-polymers or, poloxamers not limited to those available commercially under the
trade name Pluronic®; transesterified, polyoxyethylated caprylic-capric acid glycerides
not limited to those available commercially under the trade name Labrasol® , and the like
or combinations thereof.
In a further embodiment the controlled release of the present invention with improved
bioavailability comprise swelling enhancers. Swelling enhancers help the swelling agents
to swell rapidly to a large extent resulting in a dramatic increase in the size of the tablet.
At lower concentrations, these excipients are used as superdisintegrants; however at
concentration above 5 % w/w these agents function as swelling enhancers and help
increase the size of the dosage form. According to the present invention, swelling
enhancers that may be incorporated include, but are not limited to, low-substituted
hydroxypropyl cellulose, microcrystal!ine cellulose, cross-linked sodium or calcium
carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked
polyacrylic acid, cross-linked amberlite resin, alginates, colloidal magnesium-aluminum
silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinised
starch, sodium starch glycolate and sodium carboxymethyl starch. In one embodiment
matrix osmogents, such as but not limited to, dextrose, mannitol, sodium chloride and
the like or combinations thereof are employed as swelling enhancers.
The amount of swelling enhancers used in the dosage forms of the present invention is
about 5 to about 90 weight percent. In one embodiment, the amount of the swelling
enhancer is about 0 to about 70 weight percent. In another embodiment, the amount of
the swelling enhancer is about 15 to about 50 weight percent. In one embodiment, the
dosage forms according to the present invention include at least one swelling agent and
a swelling enhancer. When a combination of swelling agent and swelling enhancer is
employed for gastric-retention, it allows a rapid and dramatic increase in the size of the
tablets. Such a combination may be employed which allows rapid swelling and
maintenance of integrity by polymeric network formed upon swelling of the polymer(s).
Gas generating agents aid in the formation of highly porous, preferably honeycombed
structure and enhance the buoyancy of the formulation. The gas generating agent
employed in the present invention is selected from, but not limited to, alkali and alkalineearth
metal carbonates and bicarbonates such as sodium bicarbonate, sodium glycine
carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium
metabisulfite, sodium carbonate, potassium carbonate and the like. In one embodiment,
the gas generating agent is sodium bicarbonate. The pharmaceutical composition can
further optionally comprise an acid source. The acid source may be, but is not limited to,
citric acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid,
fumaric acid, phthalic acid, aspartic acid, glutamic acid, malic acid or tartaric acid. In a
dry granulation process, the gas generating agent may be incorporated into the dosage
form by blending it into the expanding composition before or after first compaction. In a
wet granulation process, it may be provided as an extragranular constituent after wet
granulation.
Examples of suitable binders include, but are not limited to, starch, pregelatinized starch,
polyvinyl prrolidone, copovidone, cellulose derivatives, such as hydroxypropylmethyl
cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose and their
salts. Examples of suitable diluents include, but are not limited to, starch, dicalcium
phosphate, microcrystalline cellulose, lactose monohydrate, dextrate hydrated and the
like. Examples of suitable lubricants include, but are not limited to, magnesium stearate,
calcium stearate, stearic acid, talc, and sodium stearyl fumarate. Compositions of the
present invention may optionally also include a glidant such as, but not limited to,
colloidal silica, silica gel, precipitated silica, or combinations thereof. Suitable
disintegrants may optionally be employed in the compositions of the present invention
include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or
combinations thereof. In one embodiment, suitable pH modifiers may optionally be
incorporated in the compositions of the present invention including, but are not limited to
tartaric acid, malic acid, fumaric acid, maleic acid, aspartic acid or citric acid.
In a further embodiment the controlled release gastroretentive dosage forms of the
present invention may be in the form of a monolithic system, an expanding bilayered or
multilayered or in-lay system for oral administration which is adapted to deliver the drug
at a predetermined rate. In one embodiment, the direct thrombin inhibitor is incorporated
in monolithic matrix type in the controlled release gastroretentive formulation. In another
embodiment, the direct thrombin inhibitor is incorporated in the form of a bilayered
gastroretentive dosage form that consists of a drug layer and a gastroretentive
expanding layer wherein the drug is released at a predetermined rate from the drug
layer.
In a further embodiment pharmaceutical controlled release gastroretentive composition
in the form of an expanding bilayered system for oral administration is provided to deliver
direct thrombin inhibitor from a first layer immediately upon reaching the gastrointestinal
tract, and to deliver same or different active, from a second layer, in a sustained manner
over a specific time period. The second layer is also adapted to provide expanding
nature for the dosage system, thereby making the dosage system have greater retention
in the stomach. In yet another embodiment, the controlled release gastroretentive
dosage form is in the form of a trilayered system consisting of a drug layer compressed
between a first gastroretentive layer and a second gastroretentive layer wherein direct
thrombin inhibitor is released at a predetermined rate from the drug layer. In a further
embodiment the controlled release gastroretentive dosage form of the present invention
comprises direct thrombin inhibitor treated with a release controlling agent. In a further
embodiment the controlled release gastroretentive dosage form of the present invention
comprises solubilized direct thrombin inhibitor treated with a release controlling agent.
The dosage forms of the present invention ensure desired gastroretention and controlled
or sustained release of direct thrombin inhibitor thereby improving the oral bioavailability.
In yet another embodiment, the gastroretentive dosage form is in the form of a trilayered
system consisting of a drug layer compressed between a gastroretentive layer and a
barrier layer wherein direct thrombin inhibitor is released at a predetermined time from
the drug layer. The barrier layer acts as a barrier modulating the release and is partially
impermeable, for a predeterminable time, to the active ingredient contained in the
adjacent drug layer. In one embodiment the excipients employed for the preparation of
said barrier layer include but are not limited to, glyceryl monostearate and derivative
thereof, semisynthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate,
glyceryl behenate, cetyl alcohol, glycerin, cellulose derivatives, ethylcellulose,
methylcellulose, sodium carboxymethylcellulose, polymethacrylates,
polyvinylpyrrolidone, stearic acid, talc, sodium benzoate, boric acid, polyoxyethylene
glycols, colloidal silica and the like. Further for the preparation of barrier layer,
plasticizers may be employed such as but not limited to hydrogenated vegetable oils,
fatty alcohols, fatty acids, glycerides and triglycerides and their substituted forms,
polyoxyethylene glycols and derivatives thereof and the like. In one embodiment the
barrier layer may also be characterized in that it can act as a barrier modulating the
release and can rapidly swell, i.e. can rapidly increase in volume, and have bioadhesive
properties allowing dosage form retention and adhesion to gastrointestinal mucosa.
In a further embodiment controlled release gastroretentive dosage form of the present
invention is in the form of an in-lay system comprising a drug containing tablet which is
placed in another tablet comprising a blend of excipients that ensure gastric retention. In
this system the drug containing tablet is small and is covered from all sides except at
least one side with a blend of excipient that ensure the gastric retention.
In yet another illustrative embodiment according to the invention, the controlled release
formulation with improved bioavailability may be optionally coated. Surface coatings may
be employed for aesthetic purposes or for dimensionally stabilizing the dosage form. The
coating may be carried out using any conventional technique employing conventional
ingredient. A surface coating can, for example, be obtained using a quick-dissolving film
using conventional polymers such as, but not limited to, hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, poly
methacrylates or the like or combinations thereof. Tablets of the present invention may
vary in shape including, but not limited to, oval, triangle, almond, peanut, parallelogram,
pentagonal. It is contemplated within the scope of the invention that the dosage form can
be encapsulated. Tablets in accordance with the present invention may be manufactured
using conventional techniques of common tableting methods known in the art such as
direct compression, dry granulation, wet granulation and extrusion/ melt granulation.
Further, in one embodiment, the present invention provides a process of preparing a
controlled release formulation comprising: preparing solubilized direct thrombin inhibitor
by treatment with solubility enhancing agent; blending said solubilized direct thrombin
inhibitor with at least one release controlling agent, and at least one pharmaceutically
acceptable excipient; lubricating the blend to form a lubricated blend; compressing the
blend to form a monolithic tablet. In another embodiment, the present invention provides
a process of preparing a controlled release gastroretentive formulation comprising:
preparing solubilized direct thrombin inhibitor by treatment with solubility enhancing
agent; blending said solubilized direct thrombin inhibitor with at least one release
controlling agent, at least one swelling agent and at least one pharmaceutically
acceptable excipient; lubricating the blend to form a lubricated blend; compressing the
blend to form a monolithic tablet. Furthermore, the present invention also provides a
process of preparing a controlled release gastroretentive dosage form of direct thrombin
inhibitor comprising: preparing solubilized direct thrombin inhibitor by treatment with
solubility enhancing agent; blending said solubilized direct thrombin inhibitor with at least
one release controlling agent and at least one pharmaceutically acceptable excipient,
lubricating the blend to form drug layer blend; blending at least one swelling agent, at
least one pharmaceutically acceptable excipient, lubricating the blend to form a
gastroretentive layer blend; and compressing the drug layer and the gastroretentive layer
to form a bilayer tablet.
The controlled release gastroretentive dosage form of the present invention that may be
coated/ uncoated, single layer or multilayered composition, gradually swells upon contact
with the gastric fluid. The time taken for swelling may vary from about 15 minutes to
about 4 hours. In one embodiment, the time taken for swelling is within about 15 minutes
to about 3 hours. In another embodiment, the time taken for swelling is within about 15
minutes to about 2 hours.
Two dimensions of the dosage form namely length and width expand to more than about
8 mm after swelling within 2 hours in media simulating typical gastric environment (0.1
hydrochloric acid). In one embodiment, the length and width of the dosage form expand
to more than about 10 mm after swelling within 2 hours in media simulating typical
gastric environment (0.1N hydrochloric acid). In another embodiment, the length and
width of the dosage form expand to more than about 2 mm after swelling within 2 hours
in media simulating typical gastric environment (0.1N hydrochloric acid). The present
invention provides controlled release formulations of direct thrombin inhibitor that are
more than about 1 to about 4 times more bioavailable than the conventional immediate
release dosage forms. The controlled release formulations according to the present
invention allow for controlled release of direct thrombin inhibitor. In one embodiment the
direct thrombin inhibitor is released over a period of more than about 4 hours. In a further
embodiment the direct thrombin inhibitor is released over a period of about 6 hours. In
one embodiment the direct thrombin inhibitor is released over a period of about 8 hours.
In another embodiment the direct thrombin inhibitor released over a period of about 12
hours. In another embodiment the direct thrombin inhibitor released over a period of
about 24 hours.
Further, within the purview of the present invention, are included formulations that
comprise a combination of direct thrombin inhibitor with other drugs or active agents
which may be delivered in an immediate release or modified release manner, including
not limited to, atorvastatin, dipyridamole, mopidamole and the like or combinations
thereof.
In a further embodiment is provided the use of pharmaceutical composition of direct
thrombin inhibitor for the manufacture of a medicament for reducing the risk of stroke
and systemic embolism in patients with non-valvular atrial fibrillation and/or preventing
venous thromboembolic events in adult patients who have undergone elective total hip
replacement surgery or total knee replacement surgery. Further, the present invention
provides a method for reducing the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation and/or preventing venous thromboembolic events in adult
patients who have undergone elective total hip replacement surgery or total knee
replacement surgery, comprising administering to the subject in need thereof
pharmaceutical compositions of direct thrombin inhibitors of the present invention.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are
intended to be included within the scope of the present invention. The invention is
further illustrated by the following examples, which are for illustrative purposes and
should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Controlled release gastroretentive tablet of dabigatran etexilate
mesylate
Preparation of gastroretentive tablet of dabigatran etexilate mesylate
Table 1: Composition of gastroretentive tablet of dabigatran etexilate mesylate
Ingredients mg/tablet
Dabigatran etexilate mesylate equivalent to 75 mg of 86.48
dabigatran etexilate
Stearoyl macrogol glyceride, USP/NF (Gelucire 50/13®) 80
Vitamin E TPGS, USP/NF (d-a-tocopheryl polyethylene 40
glycol 1000 succinate)
Polyethylene oxide, USP/NF 180
Hydroxy propyl methyl cellulose, USP/NF (Methocel K100M) 90
Microcrystalline cellulose, USP/NF 120.52
Povidone , USP/NF 32
Crospovidone, USP/NF 200
Sodium bicarbonate, USP/NF 40
Citric acid, USP/NF 16
Magnesium stearate, USP/NF 10
Total 895
Procedure: StearoyI macrogol glyceride and Vitamin E TPGS was melted and dabigatran
etexilate mesylate, part of microcrystalline cellulose was added to the same. The mass
was then sized and screened to obtain granules of dabigatran etexilate mesylate. These
granules were then blended with other excipients except lubricant, then lubricated and
compressed to form gastroretentive tablet.
Example 2: Controlled release gastroretentive tablet of dabigatran etexilate
mesylate
A. Preparation of controlled release drug layer
Table 2: Composition of controlled release drug layer
Procedure: All the excipients except the lubricant were blended. This blend was then
lubricated to form lubricated drug layer blend.
B. Preparation of gastroretentive layer
Table 3: Composition of gastroretentive layer
Procedure: All ingredients except lubricant were dry mixed. The blend was then
lubricated using magnesium stearate to form the gastroretentive layer blend.
A bilayer gastroretentive tablet of dabigatran etexilate mesylate was prepared by
compressing the drug layer blend and the gastroretentive layer blend.
CLAIMS
We claim:
1) A controlled release formulation comprising at least one direct thrombin
inhibitor, at least one release controlling agent and at least one
pharmaceutically acceptable excipient.
2) The controlled release formulation of claim 1, wherein the direct thrombin
inhibitor is dabigatran, argatroban, inogatran, melagatran, ximelagatran,
hirudin, bivalirudin, lepirudin, or desirudin.
3) The controlled release formulation of claim 2 , wherein the direct thrombin
inhibitor is in the form of a free acid, a free base, a pharmaceutically
acceptable prodrug, a pharmaceutically acceptable salt, a pharmaceutically
acceptable salt of prodrug, an active metabolite, a polymorph, a precursor, a
derivative, an analog, an amorphous form, a diastereomer, a diastereomeric
mixtures, a solvate, a hydrate, an enantiomer, an optical isomer, a tautomer,
a racemic mixture or any combination thereof.
4) The controlled release formulation of claim 2, wherein the direct thrombin
inhibitor is dabigatran etexilate mesylate.
5) The controlled release formulation of claim , wherein the release controlling
agent is polymeric release controlling agent, non-polymeric release controlling
agent or any combination thereof.
6) The controlled release formulation of claim 5, wherein the polymeric release
controlling agent is cellulose derivative, saccharide or polysaccharide,
poly(oxyethylene)-poly(oxypropylene) block copolymer, vinyl derivative or
polymer or copolymer thereof, polyalkylene oxide and derivative thereof,
maleic copolymer, acrylic acid derivative, or any combination thereof.
7) The controlled release formulation of claim 5, wherein the non-polymeric
release modifier is a fatty acid, long chain alcohol, fat, oil, wax, phospholipid,
eicosonoid, terpene, steroid, resin or any combination thereof.
8) The controlled release formulation of claim 1, wherein the formulation further
comprises at least one swelling agent.
9) The controlled release formulation of claim 8, wherein the swelling agent is at
least one hydrophilic polymer.
10) The controlled release dosage from of claim 9, wherein the hydrophilic
polymer is polyalkylene oxide, cellulosic polymer, acrylic acid and methacrylic
acid polymer or ester thereof, polyethylene oxide, maleic anhydride polymer;
polymaleic acid, poly(acrylamide); poly(olefinic alcohol), poly(N-vinyl lactam),
polyol, polyoxyethylated saccharide, polyoxazoline, polyvinylamine,
polyvinylacetate, polyimine, starch and starch-based polymer, polyurethane
hydrogel, chitosan, polysaccharide gum, alginate, zein, shellac-based
polymer, polyacrylic acid, maltodextrin, pre-gelatinized starch, polyvinyl
alcohol, or any combination thereof.
) The controlled release formulation of claim 1, wherein the pharmaceutically
acceptable excipient is a solubility enhancing agent, p-glycoprotein inhibitor,
swelling enhancer, permeation enhancer, binder, lubricant, diluent,
disintegrant, glidant, stabilizer, pH modifier, preservative, colorant or any
combination thereof.
12) The controlled release formulation of claim 1, wherein the formulation is in the
form of a matrix controlled-release system, coated controlled release system,
coated-matrix controlled release system, osmotic controlled-release system,
multiparticulate controlled-release system, non-gastroretentive controlled
release system.
13) The controlled release formulation of claim 1, wherein the formulation is in
the form of gastroretentive dosage form.
14) The controlled release formulation of claim 13, wherein the gastroretentive
dosage form is in the form of a monolithic system, an expanding bilayered or
multilayered or in-lay system.
15) The controlled release formulation of claim 14, wherein the bilayered
gastroretentive dosage form comprises (a) a direct thrombin inhibitor layer
and (b) a gastroretentive layer.
16) The controlled release formulation of claim 15, wherein the direct thrombin
inhibitor layer comprises at least one direct thrombin inhibitor, at least one
release controlling agent, at least one pharmaceutically acceptable excipient,
and optionally at least one swelling agent; and the gastroretentive layer
comprises at least one swelling agent and at least one pharmaceutically
acceptable excipient.
17) The controlled release formulation of claim 13, wherein the dosage form is
retained in the upper gastrointestinal tract for a time period of about 30 min to
about 2 hours.
18) The controlled release formulation of claim 1, wherein the dosage form
releases at least one direct thrombin inhibitor over a period of up to about 24
hours.
19) The controlled release formulation of claim 1, wherein the formulation further
comprises one or more active agents.