FORM 2
THE PATENT ACT, 1970
(39 Of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10; rule13)
TITLE OF THE INVENTION
A STABLE SOLID ORAL DOSAGE FORM OF DABIGATRAN
APPLICANT(S)
(a) Name: GLENMARK PHARMACEUTICALS LIMITED
(b) Nationality: Indian
(c) Address: B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai, Maharashtra, India – 400026.
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the
manner in which it is to be performed.
2
A STABLE SOLID ORAL DOSAGE FORM OF DABIGATRAN
RELATED APPLICATIONS
This application claims the benefit of Indian Provisional Application No.
202321058899 filed on September 1, 2023; which is hereby incorporated by5
reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a stable solid oral dosage form containing
pharmaceutical composition comprising dabigatran etexilate or pharmaceutically10
acceptable salt and at least one pharmaceutically acceptable excipient, wherein said
dosage form is capable of reducing the nitrosamine genotoxic impurities. In
particular, the invention relates to a stable solid oral capsule comprising dabigatran
etexilate and at least one pharmaceutical excipient with reduced nitrosamine
impurities. The present invention also relates to a process for preparing said15
pharmaceutical composition to lower the risk of stroke and blood clots.
BACKGROUND OF THE INVENTION
The word nitrosamine first caught the attention of the pharmaceutical world
and the drug regulatory agencies back in 2018 with the discovery of N-20
nitrosodimethylamine (NDMA) in valsartan drug products.
This led to the detection of complex so-called nitrosamine drug-substance-
related impurities (NDSRIs) which are formed due to the reaction between
secondary or tertiary amine groups present in APIs or API impurities, which are
prone to nitrosation and nitrites present as impurities, in excipients or packaging or25
residual solvents (albeit present in miniscule amounts).
The ICH M7 (R1) guideline categorizes N-nitroso compounds in the “cohort
of concern” of highly potent mutagenic carcinogens, which are associated with
significantly high carcinogenic and mutagenic potential. This finding led to the
implementation of stringent controls, in the form of guidance documents, by the30
different regulatory agencies across the globe on controlling the amount of
3
nitrosamine impurity in drug products being approved by them since it poses a
threat to the health and safety of patients.
N-Nitrosamines are a class of chemical compounds with the general
structure shown in Figure 1. The essential feature of N-nitroso compounds is the
N–N=O structure.5
Figure 1
Nitrosamines are metabolized in liver and their metabolic by-products have
the potential to irreversibly change the DNA.
Investigations revealed sources of nitrosamine in drug products to be either10
the API, manufacturing processes of the API as well as the drug product, excipients
as well as packaging or even printing ink and storage conditions. Investigations
revealed tetrazole, which is an intermediate in synthesis of certain angiotensin
receptor blockers, which utilizes nitrite in the presence of aqueous acid, to be the
root cause behind NDMA contamination found in valsartan, losartan and irbesartan.15
High storage temperatures led to increased degradation of ranitidine and thus
increased NDMA levels in ranitidine drug products. Residual dimethylamine in
metformin API and residual nitrite and nitrate in excipients used in manufacture of
metformin tablets were recognized as the source of NDMA contamination in
metformin tablets. Thus, these lessons have pointed out that the root causes for20
nitrosamine contamination can arise from a myriad of sources. This leads to
manufacturers getting entrapped in solving a complex maze of experiments in order
to detect the true reason behind the nitrosamine generation.
Nitroso group
4
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.5
Dabigatran is currently available as dabigatran etexilate mesylate under the
brand name Pradaxa® from Boehringer Ingelheim as immediate release oral
capsules of 75 mg, 110 mg and 150 mg strengths for twice daily administration.
Dabigatran etexilate mesylate is stable in the solid state and not sensitive to light
irradiation but it undergoes degradation by hydrolytic pathways in the presence of10
moisture. It is also acid sensitive. Due to these physicochemical and
biopharmaceutical properties of dabigatran etexilate mesylate, some attempts have
been made to provide compositions of Dabigatran etexilate mesylate that are stable
and/or provide desirable in vitro release and bioavailability.
N-nitroso dabigatran (hereinafter referred to as NDAB), which has the15
chemical structure as shown in Figure 2, has the potential to increase the risk of
cancer in patients, who consume such drug products for an extended treatment
regime, when exposed to it for prolonged duration to levels higher than acceptable
limits.
20
Figure 2
Multiple dabigatran products had uncontrolled and increased levels of
NDAB and could not meet the level of NDAB prescribed by drug regulatory
agencies.
5
US 9,925,174, discloses pharmaceutical compositions of dabigatran for oral
administration in the form of pellets comprising (a) substantially spherical core
material comprised of one or more pharmaceutically acceptable organic acids such
as tartaric acid; and (b) an active substance layer containing one or more binders
along with an optional separating agent between the organic acid core and the active5
layer. But, US 9,925,174 does not disclose about levels of NDAB in the finished
drug product or about efforts undertaken to control the NDAB level in such finished
products.
There is thus a need to develop stable solid oral dosage forms of dabigatran
etexilate or its pharmaceutically acceptable salt, with controlled and reduced levels10
of NDAB and associated manufacturing processes which leads to control of such
genotoxic and carcinogenic NDAB impurity.
SUMMARY OF THE INVENTION
The present disclosure provides an improved and stable solid oral dosage15
form of dabigatran etexilate or its pharmaceutically acceptable salt wherein said
dosage form contains less than 3 PPM of nitrite(NO2-
).
The invention in one embodiment relates to a stable solid oral dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable20
excipient, wherein the said dosage form has nitrite (NO2-
) content of less than 3
PPM.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable25
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 3 PPM.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 3 PPM,30
6
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored
for 6 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable5
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 3 PPM,
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored
for 6 months at 25°C ± 2 °C and 60 ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or10
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 2 PPM,
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored
for 6 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form15
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 2 PPM,
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored
for 6 months at 25°C ± 2 °C and 60 ± 5% RH.20
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 1 PPM,
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored25
for 6 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 1 PPM,30
7
and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored
for 6 months at 25°C ± 2 °C and 60 ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable5
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 0.5 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 6 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or10
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 0.5 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 6 months at 25°C ± 2 °C and 60 ± 5% RH.
Another embodiment relates to a stable solid oral capsule dosage form15
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 3 months at 40°C ± 2 °C and 75% ± 5%RH.20
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)25
impurity, when stored for 3 months at 25°C ± 2 °C and 60 ± 5% RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of30
8
less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 2 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable5
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or10
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.5 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 3 months at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form15
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.5 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 2 months at 40°C ± 2 °C and 75% ± 5%RH.20
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, and / or less than 0.5 ppm of N-Nitroso-dabigatran (NDAB)25
impurity, when stored for 1 month at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form, wherein said dosage form30
9
has less than 0.45 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored for
1 month at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable5
excipient, wherein said solid oral capsule dosage form, wherein said dosage form
has less than 0.35 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored for
1 month at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or10
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form, wherein said dosage form
has less than 0.25 ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored for
1 month at 40°C ± 2 °C and 75% ± 5%RH.
Another embodiment relates to a stable solid oral capsule dosage form15
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein capsule is hydroxy propyl methyl cellulose based capsule shell,
wherein the capsule shell is devoid of carrageenan and / or potassium chloride.
Another embodiment relates to a stable solid oral capsule dosage form20
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein capsule is gelatin based capsule / or polyethylene glycol based
gelatin capsule.
Another embodiment relates to a stable solid oral capsule dosage form25
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein the capsule shell is devoid of carrageenan and / or potassium
chloride.
Another embodiment relates to a stable solid oral capsule dosage form30
containing pharmaceutical composition comprising dabigatran etexilate or
10
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said dosage form has nitrite (NO2-
) content of less than 0.5 PPM.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable5
excipient, wherein said composition has nitrite (NO2-
) content of less than 0.5 PPM.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said capsule shell has nitrite (NO2-
) content of less than 0.5 PPM.10
It is surprisingly found in present invention, the role of nitrite (NO2-
) content
in generation or increase of N-Nitroso-dabigatran (NDAB) impurity. It is found that
reducing the levels of nitrite (NO2-
) content from the capsule shell and the
excipients in the dabigatran composition reduces the generation of N-Nitroso-
dabigatran (NDAB) impurity.15
DETAILED DESCRIPTION OF THE INVENTION
The various aspects and embodiments will now be fully described herein.
These aspects and embodiments may, however, be embodied in many different
forms and should not be construed as limiting; rather, these embodiments are20
provided so the disclosure will be thorough and complete, and will fully convey the
scope of the present subject matter to those skilled in the art. All publications,
patents and patent applications cited herein, whether supra or infra, are hereby
incorporated by reference in their entirety.
The term singular forms "a," "an" and "the" include plural references unless25
the context clearly dictates otherwise.
In one embodiment, the present invention relates to pharmaceutical dosage
form of dabigatran for oral administration in the form of pellets comprising (a)
substantially spherical core material comprised of one or more pharmaceutically
acceptable organic acids such as tartaric acid; and (b) an active substance layer30
containing one or more binders and optionally a separating agent, that encloses said
11
core material. The separating agent layer or insulating layer separates the acid core
from the active substance containing layer, wherein said composition has nitrite
(NO2-
) content of less than 3 PPM.
The composition of the present invention comprises a mixture of at least
two types of particles and optionally at least one pharmaceutically acceptable5
excipient, with first type of particles comprising dabigatran etexilate and second
type of particles comprising at least one organic acid, wherein said composition has
nitrite (NO2-
) content of less than 3 PPM.
The term "particle" as used herein is intended to mean any solid or semi-
solid portion of a substance or a composition having defined physical boundaries.10
Examples of particles include, but are not limited to, powder, granules, pellets,
beads, mini tablets or the like. The granules may be prepared by methods such as,
but not limited to, wet granulation, melt granulation, dry granulation or roll
compaction or the like. In an embodiment of the present invention, pellets may be
prepared using extrusion spheronization. The inert carrier can be selected from, but15
not limited to, beads, pellets, spheres or similar particles that do not contain an
active ingredient. Non-limiting examples of inert carrier include microcrystalline
cellulose, sugar or silicon dioxide. In yet another embodiment, the particles of the
present invention, in the powder form, may be incorporated in the compositions of
the present invention.20
The term "dosage form" is as used herein is intended to mean a
pharmaceutical composition which is suitable for administration to a patient. The
compositions of the present invention can be in the form of capsules, tablets, mini
tablets, dry suspension for reconstitution, powder or granule for solution or
suspension, granules, tablet in capsules, pellets in capsule, granules in capsules,25
capsule in capsule and the like or any combinations thereof. Depending of the final
dosage form the compositions of the present invention may comprise appropriate
pharmaceutically acceptable excipients such as those mentioned above or some
additional ones such as, but not limited to, sweeteners, flavors, colorants and the
like or combinations thereof. Further it is contemplated within the scope of the30
invention that the dosage form can be encapsulated or coated. In one embodiment,
12
the composition of the present invention is in the form of a capsule. Capsules
include, for example, hard capsules of hydroxypropyl methylcellulose and the like.
In a further embodiment, the compositions of the present invention may be
manufactured using conventional techniques known in the art.
The term "stable solid oral dosage form" means solid oral dosage form5
which exhibits any one or all of the following conditions: (i) solid oral dosage form
exhibits substantial chemical stability, when stored for 1 month or 2 month or 3
month or 6 months at 40°C ± 2 °C and 75% ± 5%RH; (ii) solid oral capsule dosage
form containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable10
excipient, wherein said dosage form has less than 0.75 ppm of N-Nitroso-dabigatran
(NDAB) impurity, when stored for 1 month or 2 month or 3 month or 6 month at
40°C ± 2 °C and 75% ± 5% RH (iii) solid oral dosage form exhibits substantial
chemical stability, when stored for 1 month or 2 month or 3 month or 6 month or 9
month or 12 month or 18 month or 24 months at 25°C ± 2 °C and 60% ± 5% RH;15
(iv) solid oral capsule dosage form containing pharmaceutical composition
comprising dabigatran etexilate or pharmaceutically acceptable salt and at least one
pharmaceutically acceptable excipient, wherein said dosage form has less than 0.75
ppm of N-Nitroso-dabigatran (NDAB) impurity, when stored for 1 month or 2
month or 3 month or 6 month or 9 month or 12 month or 18 month or 24 month at20
25°C ± 2 °C and 60% ± 5% RH.
The “stable solid oral capsule” means the capsule shell which has a
pharmaceutical composition of dabigatran etexilate and/or its pharmaceutically
acceptable salts along with one or more excipients enclosed within it; and which
exhibits any one or all of the following conditions: (i) substantial chemical stability,25
when stored for 1 month or 2 month or 3 month or 6 months at 40°C ± 2 °C and
75% ± 5%RH; (ii) has less than 0.75 ppm of N-Nitroso-dabigatran (NDAB)
impurity, when stored for 1 month or 2 month or 3 month or 6 month at 40°C ± 2
°C and 75% ± 5% RH (iii) exhibits substantial chemical stability, when stored for
1 month or 2 month or 3 month or 6 month or 9 month or 12 month or 18 month or30
24 months at 25°C ± 2 °C and 60% ± 5% RH; (iv) has less than 0.75 ppm of N-
13
Nitroso-dabigatran (NDAB) impurity, when stored for 1 month or 2 month or 3
month or 6 month or 9 month or 12 month or 18 month or 24 month at 25°C ± 2 °C
and 60% ± 5% RH.
Capsule shell can have hydroxypropylmethyl cellulose as the base. Capsule
shell is preferably free of carrageenan and/or potassium chloride.5
The compositions of the present invention are stable, easy to prepare, and
provide the desired in-vitro and in-vivo release of the active. The compositions of
the present invention, comprise dabigatran etexilate. Dabigatran etexilate may be
used in the compositions of the present invention as the free base (3-[(2-{4-
(hexyloxycarbonylamino-imino-methyl)- phenylamino]methyl}-1 -methyl-1 H-10
benzimidazol-5-carbonyl)-pyridin-2-yl-amino- propionic acid ethyl ester) or in the
form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates thereof.
The term dabigatran etexilate is employed in this specification to designate any of
the above- mentioned forms except when the term is further qualified (i.e.
dabigatran etexilate mesylate). Whenever it is necessary to designate the free base15
of dabigatran etexilate the term "dabigatran etexilate (free base)" is employed.
The term "pharmaceutically acceptable salt" refers to those salts which are,
according to medical judgement, suitable for use in contact with the tissues of
humans and other mammals without undue toxicity, irritation, allergic response and
the like. Pharmaceutically acceptable salts are well known in the art.20
In one embodiment the amount of dabigatran etexilate (expressed as
dabigatran etexilate mesylate) in the composition can vary from about 20 weight %
to about 90 weight %, based on the total weight of the composition. In another
embodiment the amount of dabigatran etexilate in the composition can vary from
about 25 weight % to about 85 weight %, based on the total weight of the25
composition. In still another embodiment, the amount of dabigatran etexilate in the
composition can vary from about 30 weight % to about 75 weight %, based on the
total weight of the composition.
In one embodiment the compositions of the present invention may be in the
form of unit dose forms comprising from 50 mg to 200 mg of dabigatran etexilate30
14
mesylate, preferably from 75 mg to 150 mg, more preferably 75 mg, 110 mg or 150
mg.
In one embodiment of the present invention dabigatran etexilate is used in
the form of the mesylate salt, i.e. dabigatran etexilate mesylate.
The pharmaceutically acceptable excipients that may be incorporated in the5
composition of the present invention include, but are not limited to, organic acid,
binders, disintegrants, diluents, surfactants, glidants, lubricants, and the like or
combinations thereof.
Organic acids that may be employed in the present composition include, but
are not limited to, tartaric acid, fumaric acid, succinic acid, citric acid, malic acid,10
glutamic acid, aspartic acid and the like or combinations thereof including the
hydrates and acid salts thereof.
In one embodiment the organic acid is present in the composition of the
present invention in an amount of about 2% by weight to about 95% by weight of
the composition. In another embodiment the organic acid is present in the15
composition of the present invention in an amount of about 5% by weight to about
90% by weight of the composition. In a further embodiment the organic acid is
present in the composition of the present invention in an amount of about 10% by
weight to about 85% by weight of the composition.
The term "disintegrant" as used herein is intended to mean a compound used20
in solid dosage formulations to promote the disruption of the solid mass into smaller
particles which are more readily dispersed or dissolved. Exemplary disintegrants
include, by way of example and without limitation, natural, modified or
pregelatinized starch, modified starches (such as sodium starch glycolate) and
partially pregelatinized starches (such as Starch 1500), crospovidone,25
croscarmellose sodium, low substituted hydroxypropyl cellulose and the like,
combinations thereof and other such materials known to those of ordinary skill in
the art.
The term "binders" as used herein is intended to mean substances used to
cause adhesion of powder particles in granulations. Examples of suitable binders30
include, but are not limited to celluloses such as microcrystalline cellulose,
15
modified celluloses (such as low substituted hydroxypropyl cellulose,
hydroxypropyl cellulose (or HPC or hyprolose), hydroxypropyl methylcellulose (or
HPMC or hypromellose), hydroxyethylcellulose, hydroxyethyl methylcellulose,
ethyl cellulose, cellulose gum, xanthan gum, sugars (such as sucrose, glucose,
amilose, maltodextrin, dextrose and the like), starches such as corn or potato starch5
partially pregelatinized starches (such as Starch 1500), polyvinyl acetate (Kollicoat
SR), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR),
copovidone, cross-linked polyvinylpyrrolidone, acrylic acid polymer (Carbopol),
poloxamer, polycarbophil, polyethylene oxide, polyethylene glycol, and the like,
combinations thereof and other material known to those of ordinary skill in the art.10
The term "diluent" or "filler" as used herein is intended to mean inert
substances used as fillers to create the desired bulk, flow properties, and
compression characteristics in the preparation of solid dosage formulations.
Examples of suitable diluents include, but are not limited to microcrystalline
cellulose, co-processed microcrystalline celluloses (such as Avicel CI-611, Avicel15
RC-581, Avicel RC591, Avicel CE, Avicel DG, Avicel HFE), lactose, sucrose,
xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium
hydroxide, dibasic calcium phosphate, kaolin, calcium sulphate, carrageenan,
chitosan, pectinic acid, sodium alginate, magnesium aluminium silicate, calcium
carbonate and the like, combinations thereof and other such materials known to20
those of ordinary skill in the art. The term "lubricant" as used herein is intended to
mean substances used in solid dosage formulations to reduce friction during
compression of the solid dosage. Such compounds include, but are not limited to,
magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, mineral oil
and sodium stearyl fumarate, combinations thereof and other such materials known25
to those of ordinary skill in the art.
The term "glidant" as used herein is intended to mean agents used in solid
dosage formulations to improve flow-properties during tablet compression and to
produce an anti-caking effect. Such compounds include, but not limited to, colloidal
silica, silica gel, precipitated silica, calcium silicate, magnesium silicate, Corn30
starch, talc and their combinations thereof.
16
The term "surfactant" as used herein is intended to mean substances used to
reduce the surface tension of the aqueous solutions comprising them. Examples of
surfactants include, but are not limited to, sodium docusate, glyceryl monooleate,
polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl
sulfate, sorbic acid, sorbitan fatty acid ester, mixtures thereof and other such5
materials known to those of ordinary skill in the art.
Further the oral pharmaceutical compositions of the present invention
comprise a mixture of at least two types of particles and optionally at least one
pharmaceutically acceptable excipient, wherein optionally at least one type of
particles are coated with a protective coating layer or seal coating layer or barrier10
coating layer. In one embodiment, the first type of particles is coated with a
protective coating layer or seal coating layer or barrier coating layer. In another
embodiment, the second type of particles is coated with a protective coating layer
or seal coating layer or barrier coating layer. In yet another embodiment, the first
and the second type of particles are coated with a protective coating layer or seal15
coating layer or barrier coating layer. The term "protective coating layer" or “seal
coating layer” or “barrier coating layer” as used herein is intended to mean a layer
of a polymeric or a non-polymeric material disposed on the surface of a particle
core in order to avoid direct contact of the particle core with its environment.
In one embodiment, protective coating layer is formed of a polymeric or a20
non- polymeric pharmaceutically acceptable agent or any combination thereof.
The polymeric pharmaceutically acceptable agents used for the protective
coating layer include, but are not limited to, cellulose derivatives, vinyl derivatives,
polymers and copolymers, gums, acrylic or methacrylic acid polymers, copolymers,
esters or derivatives thereof, and the like or combinations thereof. Cellulose25
derivatives that may be employed, include, but are not limited to, methylcellulose,
hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxymethyl cellulose, ethylcellulose, hydroxypropyl ethylcellulose,
carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl
hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose,30
hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl
17
cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose,
sodium carboxymethyl cellulose, and the like or combinations thereof. Vinyl
derivatives, polymers and copolymers thereof that may be employed include, but
are not limited to copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol
(Kollicoat IR), polyvinylpyrrolidone or combinations thereof. Gums that may be5
employed include, but are not limited to, gum arabic, alginates, guar gum, locust
bean gum, carrageenan, pectin, xanthan gum, gellan gum, acacia, arabic gum,
maltodextrin, galactomannan, karaya, and the like, or combinations. Acrylic or
methacrylic acid polymers, copolymers, esters or derivatives thereof, that may be
employed include, but are not limited to, a) copolymer formed from monomers10
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 and15
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 Eudragit20
NE40D (ethylacrylate methymethacrylate copolymer), Eudragit RD 100
(ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the
like or any combinations thereof.
The non-polymeric pharmaceutically acceptable agents used for the
protective coating layer include, but are not limited to C8-C22 fatty acids, C8-C2225
fatty alcohols, fats, in particular mono-, di- or triesters of glycerol and C8-C22 fatty
acids, waxes, and the like, or combinations thereof. Fatty acids that may be
employed include, but are not limited to, decenoic acid, docosanoic acid, stearic
acid, palmitic acid, lauric acid, myristic acid, hydrogenated palm kernel oil,
hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil,30
hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil,
18
hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures
thereof. Long chain monohydric alcohols that may be employed include, but are not
limited to, cetyl alcohol, stearyl alcohol and mixtures thereof. Waxes that may be
employed include, but are not limited to, spermaceti wax, carnauba wax, Japan wax,
bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax,5
sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum
wax, carbowax, glyceryl monostearate, glyceryl distearate, glyceryl tristearate,
glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl
dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl trimyristate, glyceryl
monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate and10
the like, or mixtures thereof.
In a further embodiment, in addition to polymeric or non-polymeric
pharmaceutically acceptable agent or any combination thereof, the protective
coating layer or seal coating layer may optionally further comprise one or more
pharmaceutically acceptable excipients such as, but not limited to, plasticizer, anti-15
tacking agent, pigment, and the like, or combinations thereof. A plasticizer that may
be employed includes, but is not limited to, triethyl citrate, acetyl triethyl citrate,
propylene glycol, polyethylene glycol, acetyl tributyl citrate, acetylated
monoglycerides, glycerin, triacetin, phthalate esters (e.g., diethyl phthalate, dibutyl
phthalate), castor oil, sorbitol and dibutyl sebacate or a combination thereof. An20
anti-tacking agent that may be employed includes, but is not limited to, talc, or
glyceryl monostearate. A pigment such as, but not limited to, titanium dioxide, iron
oxide, or a mixture thereof may be employed.
The protective coating layer or seal coating layer may be optionally applied
onto at least one type of particles of the present invention. For example, the25
protective coating layer or seal coating layer is applied onto the first type of particles
which comprise dabigatran etexilate in the form of free base or in the form of
pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof. In a
preferred embodiment of the present invention the protective coating layer or seal
coating layer is coated onto the second type of particles which comprise at least one30
pharmaceutically acceptable organic acid. In a particular embodiment said coating
19
layer comprises hydroxypropyl methyl cellulose and talc. In another embodiment
said coating layer comprises hydroxypropyl cellulose and talc. In another
embodiment, both particles are coated with the said protective coating layer or seal
coating layer.
The protective coating layer or seal coating layer may be optionally applied5
onto at least a type of particles of the present invention in any suitable equipment
where coating can be achieved, such as, but not limited to, coating pan,
conventional film coating apparatus or a fluidized bed apparatus, or the like.
Furthermore, in one embodiment, the protective coating layer can be applied from
an aqueous or organic solution or dispersion. In another embodiment, the particles10
being coated with the protective coating layer may be coated to a weight gain of
about 2% to about 50% by weight. In one embodiment, in order to reduce any
damage to the protective coating layer during transfer into capsules, the particles
coated with the protective coating layer may be further seal coated with
conventional pharmaceutically acceptable film forming agents which may15
optionally be combined with plasticizers or pigments. Suitable film forming agents
include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, acrylic and methacrylic acid polymers, copolymers or esters, and
the like or combinations thereof. Plasticizers or pigments as discussed above may
optionally be used with the film forming agents.20
In another embodiment, the compositions of the present invention comprise
a mixture of at least two types of particles and optionally at least one
pharmaceutically acceptable excipient. In a further embodiment, the first type of
particles comprising dabigatran etexilate may optionally further comprise at least
one pharmaceutically acceptable excipient. In another embodiment, the second type25
of particles comprising at least one organic acid, may optionally further comprise
at least one pharmaceutically acceptable excipient. In yet another embodiment, at
least two types of particles that are present in the pharmaceutical composition
optionally further comprise at least one pharmaceutically acceptable excipient.
In another aspect the present invention provides a process for the30
preparation of a composition comprising the two types of particles described above
20
comprising the step of mixing said first type of particles and said second type of
particles with a at least one pharmaceutically acceptable excipient. In a particular
embodiment of the present invention said first type of particles are prepared by
granulation.
In one embodiment the process of preparing the compositions of the present5
invention comprises the steps of:
(i) protective layer is applied to this organic acid containing core material.
This can be done by conventional methods, e.g. by applying an aqueous dispersion
of the water-soluble, pharmaceutically acceptable polymer, optionally with the
addition of plasticizers, separating agents and/or pigments, in a fluidized bed, in10
coating pans or in conventional film coating apparatus.
(ii) the active substance is applied from a dispersion containing binder
and optionally separating agent. The volatile dispersant is removed during or after
the process by drying. Suitable binders in the dispersion may be for example
hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,15
hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copoly
mers of N-vinylpyrrolidone and vinyl acetate or combinations of these polymers.
Preferably, hydroxypropylcellulose or copolymers of N vinylpyrrolidone and
vinyl acetate are used. Suitable separating agents include e.g. talc or silicic acid;
preferably, talc is used. The dispersants may be for example ethanol, 2-propanol,20
acetone or mixtures of these solvents with one another or with water, preferably
2-propanol. The application of active substance to the core material may be carried
out by established methods known in pharmaceutical technology, e.g. in coating
pans, conventional film coating apparatus or by the fluidized bed method. Then a
further screening process may be carried out.25
(iii) To reduce any increased abrasion during transfer into capsules or to
increase the shelf life the system may finally be coated with a coating of a
pharmaceutically conventional film forming agent, plasticizer and optionally
pigment. This may be done by conventional methods as mentioned earlier in the
description of the application of the insulating layer.30
21
(iv) When core material with an average diameter of 0.4 – 2.0 mm is
used, the process described above produces pellets containing active substance,
which can then be packed into hard capsules, for example. To do this, a number
of these units corresponding to the required dosage are packed into hard capsules
in a standard capsule filling machine. Suitable hard capsules include, for example,5
hard gelatin capsules or PEG based gelatin capsules or hard capsules of hydroxy
propyl methylcellulose (HPMC); HPMC capsules are preferred. The active
substance content of the pharmaceutical composition is 5 to 60 % w/w, preferably
20 to 50 % w/w; the content of the pharmaceutically acceptable organic acid is
usually between 10 and 90 % w/w, preferably between 20 and 80 % w/w.10
In another embodiment, the capsule shells are devoid of carrageenan.
In another embodiment, the capsule shells are devoid of potassium
chloride.
In another embodiment the process of preparing the compositions of the
present invention comprises the steps of:15
(i) blending dabigatran etexilate and at least one pharmaceutically
acceptable excipient such as diluent;
(ii) granulating the blend of step (i) with a binder solution to form granules
of the active agent;
(iii) coating the organic acid pellets with a protective coating layer;20
(iv) blending the granules of step (ii) with the coated pellets of step (iii) to
form a mixture of at least two types of particles;
(v) optionally blending the mixture of at least two types of particles of step
(iv) with at least one pharmaceutically acceptable excipient;
(vi) filling the lubricated mixture of step (viii) into suitable hard capsules.25
In another embodiment the process of preparing the compositions of the
present invention comprises the steps of:
(i) coating dabigatran etexilate and at least one pharmaceutically acceptable
excipient over the inert core;
(ii) coating organic acid pellets with a protective coating layer;30
(iii) blending the pellets of step (i) and (ii);
22
(iv) filling the mixture of step (iii) into suitable hard capsules.
In another embodiment, the present invention relates to pharmaceutical
composition of dabigatran for oral administration in the form of pellets comprising
(a) substantially spherical core material comprised of one or more pharmaceutically
acceptable organic acids such as tartaric acid in weight percentage ranging from 35-5
45%; and (b) an active substance layer containing one or more binders and
optionally a separating agent, that encloses said core material. The separating agent
layer or insulating layer which separates the acid core from the active substance
containing layer, is present in amounts ranging between 0.75-2 weight percentages
of the final filled weight of the finished product. The insulating layer can be selected10
from cellulosic polymers such as hydroxypropyl cellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose; gum Arabic,
polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or
combinations of these polymers. This layer can further comprise saccharide
polymers such as maltodextrin in 2-4 weight percentages along with the insulating15
layer polymer and other suitable excipients. The drug layer is layered over the
barrier layer. The drug layer can also comprise other pharmaceutically suitable
excipients. Such pellets were then filled in capsule shells.
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or20
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, wherein said dosage form has less than 0.75 ppm of N-Nitroso-
dabigatran (NDAB) impurity, when stored for 2 months at accelerated conditions
at 40°C ± 2 °C and 75% ± 5%RH.25
Another embodiment relates to a stable solid oral capsule dosage form
containing pharmaceutical composition comprising dabigatran etexilate or
pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient, wherein said solid oral capsule dosage form has nitrite (NO2-
) content of
less than 3 PPM, wherein said dosage form has less than 0.75 ppm of N-Nitroso-30
23
dabigatran (NDAB) impurity, when stored for 2 months at 25°C ± 2 °C and 60% ±
5%RH.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 3 ppm5
and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 3 ppm10
and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of
carrageenan.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable15
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 3 ppm
and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of
potassium chloride.
Another embodiment of the invention comprises a stable solid oral capsule20
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 3 ppm
and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of both
carrageenan and potassium chloride.25
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl
propyl methyl cellulose and has nitrite (NO2-
) content less than 3 ppm and N-
nitroso-dabigatran (NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C30
and 75% ± 5% relative humidity for 3 months.
24
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate or its pharmaceutically acceptable salt, wherein the
solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose
and has nitrite (NO2-
) content less than 1 ppm and N-nitroso-dabigatran (NDAB)
content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative5
humidity for 3 months.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 1 ppm
and N-nitroso-dabigatran (NDAB) content less than 0. 5 ppm; wherein the capsule10
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of
carrageenan.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 1 ppm15
and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of
potassium chloride.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable20
excipient, wherein the solid oral capsule has nitrite (NO2-
) content less than 1 ppm
and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm; wherein the capsule
comprises a capsule shell of hydroxypropylmethylcellulose and is devoid of both
carrageenan and potassium chloride.
Another embodiment of the invention comprises a stable solid oral capsule25
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl
propyl methyl cellulose and is devoid of carrageenan and has nitrite (NO2-
) content
less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75 ppm when
stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.30
25
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate or its pharmaceutically acceptable salt, wherein the
solid oral capsule comprises a capsule shell of hydroxyl propyl methyl cellulose
and is devoid of carrageenan and has nitrite (NO2- ) content less than 1 ppm and N-
nitroso-dabigatran (NDAB) content less than 0.5 ppm when stored at 40°C ± 2 °C5
and 75% ± 5% relative humidity for 3 months.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl
propyl methyl cellulose and is devoid of potassium chloride and has nitrite (NO2-
)10
content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75
ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl15
propyl methyl cellulose and is devoid of potassium chloride and has nitrite (NO2-
)
content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than 0.75
ppm when stored at 40°C ± 2°C and 75% ± 5% relative humidity for 3 months.
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable20
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl
propyl methyl cellulose and is devoid of both carrageenan and potassium chloride
and has nitrite (NO2-
) content less than 3 ppm and N-nitroso-dabigatran (NDAB)
content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative
humidity for 3 months.25
Another embodiment of the invention comprises a stable solid oral capsule
comprising dabigatran etexilate and at least one pharmaceutically acceptable
excipient, wherein the solid oral capsule comprises a capsule shell of hydroxyl
propyl methyl cellulose and is devoid of both carrageenan and potassium chloride
and has nitrite (NO2-
) content less than 3 ppm and N-nitroso-dabigatran (NDAB)30
26
content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative
humidity for 3 months.
In yet another embodiment, the invention relates to use of a HPMC based
capsule shell, to formulate a stable capsule dosage form of dabigatran etexilate
mesylate with one or more pharmaceutically acceptable excipient, with a nitrite5
content nitrite (NO2-
) content less than 3 ppm and N-nitroso-dabigatran (NDAB)
content less than 0.75 ppm when stored at 40°C ± 2°C and 75% ± 5% relative
humidity and when stored at 25°C ± 2°C and 60% ± 5% relative humidity.
In yet another embodiment, the invention relates to use of a HPMC based
capsule shell, to formulate a stable capsule dosage form of dabigatran etexilate10
mesylate with one or more pharmaceutically acceptable excipient, with a nitrite
content nitrite (NO2-
) content less than 1 ppm and N-nitroso-dabigatran (NDAB)
content less than 0.5 ppm when stored at 40°C ± 2°C and 75% ± 5% relative
humidity and when stored at 25°C ± 2°C and 60% ± 5% relative humidity.
15
EXAMPLES
Manufacturing Process
The inert core of organic acid was coated with polymer or Acacia or film
former either alone or in combination with suitable excipients.
An additional separation protective layer can be given to the above20
granulated organic acid or insulated organic acid with suitable protective layer of
polymer or film former alone or in combination with suitable excipients to give
additional protection from inert organic acid.
Dabigatran Etexilate Mesylate drug granules/pellets/particles were prepared
using inert core with suitable binder or suspension or dispersion consisting of25
suitable excipients for drug deposition with the process of mixing with suitable
excipients or drug loading with binder / dispersion or granulation with binder or
blending or compaction or extrusion or fluid bed microencapsulation process.
Drug particles can be further separated with barrier or seal coating to give
additional protection to drug with suitable polymers or film-formers with suitable30
excipients to give desirable insulation.
27
The above insulated organic acid and/or granulated drug and / or seal coated
drug were lubricated with suitable lubricant like talc in suitable blender at suitable
time to ensure uniform mixing of lubricant with uniform layer on insulated organic
acid or granulated particle or seal coated drug.
Different permutation combinations of drug layer or portions with organic5
acid layer were filled into capsule shells.
It was also surprisingly discovered that stable oral capsule compositions of
dabigatran etexilate and/or its pharmaceutically acceptable salts when enclosed
within hydroxypropyl methylcellulose capsule shells which were devoid of
carrageenan and/or potassium chloride and which had low levels of nitrite,10
displayed the lowest NDAB levels in comparison with capsule compositions of
dabigatran etexilate and/or its pharmaceutically acceptable salts which are enclosed
within hydroxypropyl methylcellulose capsule shells containing carrageenan and/or
potassium chloride.
Solid oral capsule dosage forms of dabigatran etexilate mesylate were15
manufactured with formula as depicted in Table-1. Such formulations were then
filled in capsule shells of hydroxypropyl methylcellulose, which were devoid of
carrageenan and potassium chloride and the solid oral capsules were tested for their
nitrite content and NDAB content. Such formulations were also filled in
hydroxypropyl methylcellulose capsule shells containing carrageenan and20
potassium chloride and the solid oral capsules were tested for their nitrite content
and NDAB content. The comparative nitrite and NDAB contents of such capsule
dosage forms are depicted in Table-2.
Table-1: Example-1 Disclose Oral Capsule Formulations of Dabigatran Etexilate
Mesylate.25
Ingredients & Stages Example-1
A) Tartaric acid Pellets Stage % w/w
Tartaric Acid Pellets 24.79
Acacia 5.90
Hydroxypropyl Cellulose -
28
Ingredients & Stages Example-1
Talc 0.30
Purified Water q.s
Ethanol q,s
Isopropyl Alcohol -
Lubrication
Talc 0.31
Lubricated Pellets Weight -
A) Maltodextrin Coating -
Maltodextrin -
Talc -
Purified Water -
Ethanol -
Lubrication
Talc -
Lubricated Pellets Weight
B) Dabigatran Stage:
Sugar Spheres (#25-30) 19.44
B1) Barrier Coat
Hypromellose 0.85
Talc 0.13
Isopropyl Alcohol q.s
Methylene Chloride q.s
B2) Dabigatran Coating
Dabigatran Etexilate Mesylate 38.65
Hydroxypropyl Cellulose 8.94
Iso Propyl Alcohol q.s
Lubrication
Talc 0.70
Lubricated Pellets Weight -
29
Ingredients & Stages Example-1
B3) Dabigatran Granules
Dabigatran Etexilate Mesylate -
Maltodextrin -
Binder Solution -
Hydroxypropyl Cellulose -
Butylated Hydroxy Toluene -
Lubrication -
Talc -
Lubricated Blend Weight -
Total Fill Weight 100.00
Table-2: Effect of capsule shell composition on N-Nitroso-dabigatran (NDAB)
levels in drug product.
Capsule Shell Composition Nitrite
content(PPM)
NDAB Content
(PPM)
Hydroxypropyl methylcellulose
Carrageenan
Potassium chloride
H2 O
26.9 0.492
Hydroxypropyl methylcellulose
H2 O
<0.4 0.065
The capsule dosage forms of Example-1 encapsulated in capsule shell5
comprising hydroxypropyl methylcellulose but devoid of carrageenan and
potassium chloride were further tested for stability and its results are shown in
Table-3.
Table-3: N-Nitroso-dabigatran (NDAB) levels in PPM of Example-1.10
30
Storage
period
Storage
condition
Dissolution Assay N-Nitroso-
Dabigatran-
Etexilate
NLT 80% (Q)in
45minutes
92.0-
105.0%
NMT 0.769 ppm
Initial NA 105 101.7 0.096
1M 25C/60%RH 104 99.8 0.122
40C/75%RH 105 101.5 0.188
2M 25C/60%RH 104 101.6 0.079
40C/75%RH 104 101.4 0.086
3M 25C/60%RH 105 101.5 0.113
40C/75%RH 104 101.5 0.127
Another solid oral capsule dosage forms of dabigatran etexilate mesylate
were also manufactured with formula as depicted in Table-4. Such formulations
were then filled in capsule shells comprising hydroxypropyl methylcellulose, which
were devoid of carrageenan and potassium chloride. The NDAB levels of such5
finished dosage forms are depicted in Table-5.
Table-4: Example-2 Disclose Oral Capsule Formulation of Dabigatran Etexilate
Mesylate.
Ingredients & Stages Example 2
A) Tartaric acid Pellets Stage % w/w
Tartaric Acid Pellets 24.98
Acacia
Hydroxypropyl Cellulose 0.90
Talc 0.25
Purified Water -
Ethanol -
Isopropyl Alcohol q.s
Lubrication -
31
Ingredients & Stages Example 2
Talc -
Lubricated Pellets Weight -
A) Maltodextrin Coating -
Maltodextrin 5.74
Talc 0.34
Purified Water q.s
Ethanol q.s
Lubrication
Talc 0.23
Lubricated Pellets Weight
B) Dabigatran Stage: -
Sugar Spheres (#25-30) -
B1) Barrier Coat
Hypromellose -
Talc -
Isopropyl Alcohol -
Methylene Chloride -
B2) Dabigatran Coating
Dabigatran Etexilate Mesylate -
Hydroxypropyl Cellulose -
Iso Propyl Alcohol -
Lubrication -
Talc -
Lubricated Pellets Weight -
B3) Dabigatran Granules
Dabigatran Etexilate Mesylate 38.95
Maltodextrin 27.21
Binder Solution -
Hydroxypropyl Cellulose 0.56
32
Ingredients & Stages Example 2
Butylated Hydroxy Toluene 0.17
Lubrication -
Talc 0.68
Lubricated Blend Weight -
Total Fill Weight 100.00
Table-5: N-Nitroso-dabigatran (NDAB) levels in PPM of Example-2.
Storage
period
Storage
condition
Dissolution Assay N-Nitroso-
Dabigatran-
Etexilate (NDAB)
NLT 80%
(Q)in
45minutes
92.0-
105.0%
NMT 0.769 ppm
Initial NA 105 101.0 0.31
1M 25C/60%RH - - 0.31
40C/75%RH - - 0.25
Although the invention herein has been described with reference to
particular embodiments, it is to be understood that these embodiments are merely5
illustrative of the principles and application of the present invention. It is therefore
to be understood that numerous modifications may be made to the illustrative
embodiments and that other arrangements may be devised without departing from
the spirit and scope of the present invention as described above.
All publications, patents, and patent applications cited in this application are10
herein incorporated by reference to the same extent as if each individual
publication, patent, or patent application was specifically and individually indicated
to be incorporated herein by reference.
15
33
We Claim:
1. A stable solid oral capsule dosage form comprising dabigatran etexilate and at
least one pharmaceutically acceptable excipient, wherein the solid oral capsule
has nitrite content less than 3 ppm and N-nitroso-dabigatran (NDAB) content5
less than 0.75 ppm.
2. A stable solid oral capsule dosage form according to claim 1, wherein the solid
oral capsule has nitrite content less than 3 ppm and N-nitroso-dabigatran
(NDAB) content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ±10
5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ±
5% relative humidity for 3 months.
3. A stable solid oral capsule dosage form according to claim 1, wherein the
capsule has nitrite content less than 1 ppm when stored at 40°C ± 2 °C and 75%15
± 5% relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ±
5% relative humidity for 3 months.
4. A stable solid oral capsule dosage form according to claim 1, wherein the
capsule has N-nitroso-dabigatran (NDAB) content less than 0.5 ppm when20
stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 3 months and when
stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3 months.
5. A stable solid oral capsule dosage form according to claim 1, wherein the
capsule comprises a capsule shell of hydroxyl propyl methyl cellulose.25
6. A stable solid oral capsule dosage form according to claim 1, wherein the
capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is
devoid of carrageenan.
30
34
7. A stable solid oral capsule dosage form according to claim 1, wherein the
capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and is
devoid of potassium chloride.
8. A stable solid oral capsule dosage form according to claim 1, wherein the5
capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has
nitrite content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less
than 0.75 ppm.
9. A stable solid oral capsule dosage form according to claim 1, wherein the10
capsule comprises a capsule shell of hydroxyl propyl methyl cellulose and has
nitrite content less than 1 ppm and N-nitroso-dabigatran (NDAB) content less
than 0.5 ppm.
10. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate15
a stable solid oral capsule dosage form of dabigatran etexilate and at least one
pharmaceutically acceptable excipient wherein the stable solid oral capsule has
nitrite content (NO2-
) less than 3 ppm and N-nitroso-dabigatran (NDAB)
content less than 0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative
humidity and when stored at 25°C ± 2 °C and 60% ± 5% relative humidity.20
11. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate
a stable solid oral capsule dosage form of dabigatran etexilate as claimed in
claim 10 wherein the stable solid oral capsule has nitrite (NO2-
) content less
than 1 ppm and N-nitroso-dabigatran (NDAB) content less than 0.5 ppm when25
stored at 40°C ± 2 °C and 75% ± 5% relative humidity and when stored at 25°C
± 2 °C and 60% ± 5% relative humidity.
12. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate
a stable solid oral capsule dosage form of dabigatran etexilate as claimed in30
claim 10 wherein the capsule shell is devoid of carrageenan.
35
13. Use of capsule shell comprising hydroxypropylmethyl cellulose, to formulate
a stable solid oral capsule dosage form of dabigatran etexilate as claimed in
claim 10, wherein the capsule shell is devoid of potassium chloride.
5
14. A stable solid oral capsule dosage form comprising dabigatran etexilate and at
least one pharmaceutically acceptable excipient, wherein the solid oral capsule
comprises a capsule shell of hydroxyl propyl methyl cellulose and has nitrite
content less than 3 ppm and N-nitroso-dabigatran (NDAB) content less than
0.75 ppm when stored at 40°C ± 2 °C and 75% ± 5% relative humidity for 310
months and when stored at 25°C ± 2 °C and 60 ± 5% relative humidity for 3
months, wherein the capsule shell is devoid of carrageenan and potassium
chloride.
15. A stable solid oral capsule dosage form according to claim 14, wherein the15
solid oral capsule comprises a capsule shell of hydroxyl propyl methyl
cellulose and has nitrite content less than 1 ppm and N-nitroso-dabigatran
(NDAB) content less than 0.5 ppm when stored at 40°C ± 2 °C and 75% ± 5%
relative humidity for 3 months and when stored at 25°C ± 2 °C and 60 ± 5%
relative humidity for 3 months, wherein the capsule shell is devoid of20
carrageenan and potassium chloride.