Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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A SOLID ORAL DOSAGE FORM COMPRISING LINAGLIPTIN
Field of the Invention
The present invention relates to a solid oral dosage form comprising
linagliptin and at least
one binder.
Background of the Invention
Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a
selective, orally
administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as
an adjunct to
diet and exercise to improve glycemic control. DPP-4 inhibitors work by
blocking the action of
DPP-4, an enzyme which destroys the hormone incretin. There are two types of
incretin
hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-
dependent
insulinotropic peptide (GIP). These hormones are naturally produced by the
body in
response to food intake. Their function is to help the body produce more
insulin only when it
is needed and reduce the amount of glucose being produced by the liver when it
is not
needed. Linagliptin works by binding to DPP-4 and preventing it from breaking
down the
GLP-1 and GIP. This increases the levels of these hormones in the body and so
increases
their effect on controlling blood sugar.
The chemical name of linagliptin is 8-[(3R)-3-aminopiperidin-1-y1]-7-but-2-yn-
1-y1)-3-methyl-1-
[(4-methylquinazolin-2-Amethyl]-3,7-dihydro-1H-purine-2,6-dione and its
chemical structure
is shown in the Formula I.
11110) N
N \
0 N N
NH2
Formula I
W02014/026939 patent application discloses a pharmaceutical composition
comprising
linagliptin or salts thereof with mannitol, copovidone, and magnesium
stearate, a process for
the preparation of the pharmaceutical composition.
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There still remains a need in the art to provide an improved pharmaceutical
composition of
linagliptin. At this invention provides having high stability of linagliptin,
dissolution rate, and
therefore a high bioavailability and a long-term stability.
Detailed Description of the Invention
The main object of the present invention is to provide high stability of
linagliptin and a long
shelf life by the help of selection of excipients in a certain ratio.
Another aim of the present invention is to provide a pharmaceutical dosage
form comprising
linagliptin which has a long shelf life, a short disintegration time, desired
dissolution
properties and enables a high bioavailability of linaglitpin in a patient.
The term "linagliptin" as used throughout the specification refers to not only
linagliptin, but
also its other pharmaceutically acceptable salt, pharmaceutically acceptable
solvates,
pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable derivatives, pharmaceutically acceptable
polymorphs and
pharmaceutically acceptable prodrugs thereof.
The linagliptin is present as amorphous linagliptin, crystalline linagliptin
having polymorphic
form A, crystalline linagliptin having polymorphic form B and/or crystalline
linagliptin having
polymorphic form C or mixtures thereof.
In one embodiment of the invention, the linagliptin is present as a mixture of
crystalline
linagliptin having polymorphic form A and crystalline linagliptin having
polymorphic form B.
In one embodiment of the invention, the pharmaceutical solid oral dosage form
comprises
linagliptin as an active agent and at least one binder in which the weight
ratio of linagliptin to
binder is between 0.1 and 6Ø This ratio is important in order to providing
high stability of
linagliptin and improved flow properties.
In one embodiment of the invention, the weight ratio of linagliptin to binder
is between 0.3
and 3.0 or between 0.5 and 2Ø
In one embodiment of the invention, the amount of linagliptin in the
composition is between
1.0% and 10.0% by weight, preferably it is between 2.0% and 7.0%, more
preferably it is
between 2.5% and 6.0%.
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As used here in, 'particle size' means the cumulative volume size distrubition
as tested by
any conventionally accepted method such as the laser diffraction method (i.e.
Malvern
Mastersizer 2000 analysis). The term d (0.9) means the size at which %90 by
volume of the
particles are finer.
In one embodiment of the invention, linagliptin has ad (0.9) particle size
less than 100 pm,
preferably linagliptin has a d (0.9) particle size less than 50 pm. This
property provides
improved flow properties.
Suitable binders are selected from the group comprising povidone, copovidone,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose, mannitol,
gelatin, pullulan, sodium alginate or mixtures thereof.
The present invention comprises one or more binders in an amount of from about
1% to
about 20% by weight of the composition.
In general, DPP-4 inhibitors are not very stable compounds. Especially, in
solid dosage
forms, amine group containing DPP-4 inhibitors like linagliptin may react with
many
excipients or impurities of excipients. In this invention, it has been
surprisingly found that
using binder ensures high stability of linagliptin in a solid oral dosage
composition. Especially
povidone is used as binder in the present invention. Povidone has also
disintegration
property and it is used to enhance dissolution of poorly soluble drugs from
solid-dosage
forms.
In one embodiment of the invention, binder is povidone and the amount of
povidone in the
composition is 1.0% and 5.0% by weight.
In another embodiment, the pharmaceutical acceptable excipients used in the
present
invention are selected from the group consisting of fillers, disintegrants,
lubricants, and film
coating agents.
Suitable fillers are selected from the group comprising microcrystalline
cellulose, mannitol,
spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose,
fructose,
maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts,
polysaccharides,
dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin,
sucrose-maltodextrin
mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or
mixtures
thereof.
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According to one embodiment, microcrystalline cellulose is a filler which has
the best
flowability properties among the other fillers. In this invention, it further
improves the
disintegration of compositon as well as being a filler. In addition, it
further enhances the
compressibility by increasing the hardness of the tablet.
In this embodiment, the amount of microcrystalline cellulose is in the range
of 70.0 to 90 `)/0,
preferably 76.0 to 88.0 `)/0, more preferably it is 80.0 to 85.0 `)/0 by
weight of total composition.
Suitable disintegrants are selected from the group comprising sodium starch
glycolate, cross-
linked polyvinil pyrrolidone (crospovidone), povidone, croscarmellose sodium,
low-substituted
hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl
cellulose, calcium
carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum,
low
substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate,
corn starch,
alginic acid, alginates, sodium dodecyl sulphate, sodium glycine carbonate,
sodium lauryl
sulphate or mixtures thereof.
A sufficient amount of disintegrant that is neither too much nor too little to
detrimentally alter
the release of the active ingredient should be used to form solid oral dosage
forms provided
herein. However, disintegrants can be mixed with other excipient to increase
effective
disintegration of the tablet into smaller fragments.
In one embodiment of the invention, disintegrant is sodium starch glycolate,
is also known as
superdisinteg rant, and the amount of sodium starch glycolate is in the range
of 3.0% to 8.0%
and thus desired level of dissolution rate is provided.
Furthermore, the combination of povidone and sodium starch glycolate provides
desired
short disintegration time and desired dissolution properties in composition.
According to an embodiment of the present invention, the weight ratio of
sodium starch
glycolate to povidone is between 0.2 and 10.0 or 0.6 and 8Ø
According to another embodiment, the lubricant is selected from the group
comprising
sodium stearyl fumarate, magnesium stearate, polyethylene glycol (PEG), sodium
lauryl
sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate,
hydrogenated
natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid,
paraffin or mixtures
thereof, preferably sodium stearyl fumarate.
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Coating may also preferably be used for moisture protection. Suitable coating
agents are
selected from the group comprising polymethacrylates, hydroxypropyl
methylcellulose,
lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA),
polyethylene glycol
(PEG), talc, glycerine, polyvinyl alcohol-polyethylene glycol copolymers
(Kollicoat IR),
5 ethylcellulose dispersions (Sureleasee), polyvinylprolidone,
polyvinylprolidone-vinyl acetate
copolymer (PVP-VA), all kinds of Opadry , pigments, dyes, titanium dioxide,
macrogol,
coloring agent or mixtures thereof.
Suitable coloring agents are selected from the group comprising ferric oxide,
titanium
dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green,
FD&C red,
FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue,
indigotine FD&C
blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide
red, yellow,
black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or
mixtures thereof.
Preferably, the pharmaceutical composition of the present invention comprises
linagliptin or a
pharmaceutically acceptable salt thereof, povidone, sodium stearyl fumarate,
sodium starch
glycolate, microcrystalline cellulose.
Solid oral dosage is used for having effective stability and bioavailability.
Another
embodiment of the present invention is a pharmaceutical composition in the
form of a solid
oral dosage form.
In this present invention, the solid oral dosage form is tablet or capsule or
pastilles or strip.
.. In this present invention, the solid oral dosage form is tablet. Tablet may
be consisted of
separated compartments or layer.
An embodiment of this present invention, the pharmaceutical combination is
formulated as
tablets comprising film-coated tablets, compressed tablets, coated or uncoated
tablets,
multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal
tablets, sublingual
tablets, effervescent tablets, immediate release tablets, core-in-tablet,
modified release
tablets, tablet-in-tablet, orally disintegrating tablets, gastric
disintegrating tablets, chewable
tablet, dispersing tablet, lozenges.
Preferably, the pharmaceutical combination is formulated as film coated
tablet.
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In this present invention, the pharmaceutical combination can be prepared in
tablet form.
Tablet comprises at least one type of particle, for example; mini-tablets,
pellets,
agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
An embodiment of this present invention, each type of particle comprises at
least one active
agent.
In this present invention, pharmaceutical combination may comprise a film
coating if
necessary.
In this present invention, pharmaceutical combination can be prepared in
capsule form.
Capsule comprises of at least one type of particle, for example; mini-
capsules, mini-tablets,
pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures
thereof.
An embodiment of this present invention, the dosage unit form of composition
is mini-
capsules in capsule wherein the mini-capsules comprise at least one active
agent.
An embodiment of this present invention, the dosage unit form of composition
is mini-tablets
in capsule wherein a mini-tablets comprise at least one active agent.
An embodiment of this present invention, the dosage unit form of composition
is pellets in
capsule wherein pellets comprise at least one active agent.
In one embodiment of the present invention, the composition comprises;
a) 2.0 - 10.0% by weight of linagliptin
b) 80.0 - 85.0% by weight of filler
c) 1.5 - 4.0% by weight of binder
d) 3.5 - 6.0% by weight of disintegrant
e) 0.1 - 3.0% by weight of lubricant
f) 1.0 - 5.0% by weight of coating agents
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In one embodiment of the present invention, the composition comprises;
a) 1.0 - 10.0% by weight of linagliptin
b) 70.0 - 90.0% by weight of microcrystalline cellulose
c) 1.0 - 5.0% by weight of povidone
d) 3.0 - 8.0% by weight of sodium starch glycolate
e) 0.1 - 5.0% by weight of sodium stearyl fumarate
f) 0.5 - 8.0% by weight of coating agents
The pharmaceutical composition of the present invention can be prepared, using
standard
.. techniques and manufacturing processes well known in the art, such as
direct compression,
wet and dry granulation.
According to one embodiment of the present invention, it has been found that
when the
formulation is prepared with wet granulation, the formulation has desired
stability and desired
dissolution rate.
Suitable granulation solutions are selected from a group comprising pure
water, ethyl
alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl
alcohol or mixtures
thereof, preferably the granulation solution is pure water.
An embodiment of the present invention, the process for preparation of the
pharmaceutical
composition comprises the following steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate
b) Granulating povidone with pure water on a separate tank
c) Mixing step (a) mixture and step (b) mixture
d) Drying the mixture, then sieving the mixture
e) Adding sodium stearyl fumarate and then mixing
f) Then, pressing to form tablet
g) Coating tablets with coating agents.
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Example 1: Film coated tablet comprising linagliptin
( /0) amount (w/w)
Linagliptin 2.0% - 10.0%
Filler 80.0% - 85.0%
Binder 1.5% - 4.0%
Disinteg rant 3.5% - 6.0%
Lubricant 0.1% - 3.0%
Coating agents 1.0% - 5.0%
Total 100
Example 2: Solid oral dosage form comprising linagliptin
( /0) amount (w/w)
Linagliptin 1.0% - 10.0%
Microcrystalline cellulose 70.0% - 90.0%
Povidone 1.0% - 5.0%
Sodium starch glycolate 3.0% - 8.0%
Sodium stearyl fumarate 0.1% - 5.0%
Coating agents 0.5% - 8.0%
Total 100
Process for example 1 or 2:
The process for preparation of the pharmaceutical composition comprises the
following
steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate
b) Granulating povidone with pure water on a separate tank
c) Mixing step (a) mixture and step (b) mixture
d) drying the mixture, then sieving the mixture
e) Adding sodium stearyl fumarate and then mixing
f) Then, pressing to form tablet
g) Coating tablets with coating agents.
