Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/135863
PCT/EP2021/083930
A non-micronized bilastine composition
This application claims the benefit of European Patent Application
EP20383149.0 filed december 23rd, 2020.
The present invention relates to a novel composition comprising non-micronized
bilastine, a preparation
process thereof and the use of the composition in the treatment of histamine-
mediated disease processes
and allergic reactions.
Background Art
Bilastine is the international common name of 4-[244-[1-(2-ethoxyethylph-
benzimidazol-2-y11-1-
piperidinypethy1]-a,a-dimethyl-benzeneacetic acid, whose structure corresponds
to the compound of formula
(I):
COOH
\N
CH.,C,I-20CH2CH;
(I)
Bilastine is a selective H1 receptor antagonist, meaning that it is useful for
treating histamine-mediated
disease processes and allergic reactions, and especially for treating
rhinoconjunctivitis and urticaria.
Bilastine as a product per se, as well as the preparation and use thereof as
an H1 receptor antagonist has
been described in the European patent number EP0818454B1. Subsequently, the
European patent
EP1505066B1 describes three crystalline forms of bilastine. Specifically, it
describes the crystalline forms 1, 2
and 3 of bilastine, which are characterized by the infrared absorption
spectrum and crystallographic
parameters in the case of form 1. Furthermore, in the patent EP150506661,
preparation methods of
crystalline form 1 from a mixture of crystalline forms 2 and 3 are described.
However, crystalline forms 2 and 3
of bilastine are easily converted into crystalline form 1. Finally, the
European patent application
EP16829901A1 describes other crystalline forms of bilastine including Eta
crystalline form which is
characterized by X-ray diffractogram.
Bilastine is actually present in the market with the commercial drug name
Bilaxten, which is in form of
inmediate-release and orodispersible tablets. Particularly, Bilaxten contains
crystalline form 1 of bilastine in
micronized form, having a particle size distribution D90 about 6.8 pm.
As it is known, the different solid forms of a pharmaceutical active
ingredient may have different
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characteristics and offer certain advantages, for example, with respect to
stability, bioavailability, ease of the
formulation and ease of administration, among others. Since some solid forms
are more suitable for one type
of formulation, and other forms for other different formulations, the
development of novel solid forms makes it
possible to improve the characteristics of pharmaceutical formulations that
comprise them. Furthermore,
depending on therapeutic indications, one or another pharmaceutical
formulation may be preferable.
However, the particle size of the active ingredient may be also critical for
having the appropriate dissolution
profile and bioavailabilty. In fact, a reduction of the particle size of the
active ingredient may be advantegeous
for increasing its therapeutic efficacy. Micronization is the process of
reducing the average diameter of
a solid material's particles. For the purpose of the invention, the term
micronization refers to the reduction of
average particle diameters to the micrometer range.
Traditional techniques for micronizing based on friction have been widely
disclosed in the state of the art.
Such traditional methods include milling, bashing and grinding. Methods like
crushing and cutting are also
used for reducing particle diameter, but produce more rough particles compared
to the two previous
techniques and are therefore used as the early stages of the micronization
process.
Subsequently, modern methods using supercritical fluids in the micronization
process has been disclosed.
These methods induce a state of supersaturation, which leads to precipitation
of individual particles. The most
widely applied techniques of this category include the RESS process (Rapid
Expansion of Supercritical
Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method
(Particles from Gas Saturated
Solutions). These modern techniques allow greater tuneability of the process.
In fact, parameters like relative
pressure and temperature, solute concentration, and antisolvent to solvent
ratio can be varied to be adjusted
to the producer's needs. The supercritical fluid methods result in finer
control over particle diameters,
distribution of particle size and consistency of morphology. However, the
properties of the micronized active
ingredient such as particle size, size distribution, shape, surface
properties, and agglomeration behaviour and
powder flow are affected by the type of micronization technique used.
Furthermore, the use of micronized active ingredients for the preparation of
solid pharmaceutical compositions
entails some processability problems. The first problems is related to
wettability and reagglomeration by
electrostatic phenomena In particular, when a mixture containing micronized
active ingredients is
compressed into tablets, there is a possibility of agglomeration of the
micronized particles together within the
tablet due to their high surface area and high surface free energy during
compression; and also a modification
of the physical and chemical properties of the ingredients including the
active ingredients and the excipients or
carriers. In particular, a change of the polymorphisms of the active
ingredient may occur during the
micronization process or during its compression, resulting in a possible
modification of crucial bioavailability
properties (such as stability, dissolution and absorption). And, the second
problem is that micronization
processes employ higher financial resources and therefore their production is
more costly, due to an extra
process needed to obtain the desired particle size, affecting the yield and
generating more problems from a
security and process control point of view.
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Therefore, from what is known in the art it is derived that there is still the
need of providing compositions
comprising non-micronized bilastine having the apropriate dissolution rate and
bioavailability by an easy
industrially-scaling up and reproducible process.
Summary of Invention
The inventors have surprinsingly found that a composition comprising a
therapeutically effective amount of
non-micronized bilastine in combination with a pyrrolidone-based polymer,
allows having comparable
pharmacokinetic parameters on bioavailability (e.g. C., AUCo_t, AUCo¨, AUCo_
T,SS, - C max, ss, and Cmin, ss) as
commercially available Bilaxten containing bilastine micronized.
In particular, as it is demonstrated in the Experimental data, the composition
of the invention which comprises
the combination of a therapeutically effective amount of bilastine having a
particle size distribution 090 from
15 to 90 pm with a pyrrolidone-based polymer allows having the appropriate
dissolution rate and availability
for being used in therapy and being considered equivalent to Bilaxten which
contains micronized bilastine.
Furthermore, the compositions of the present invention containing non-
micronized bilastine can be prepared
by a costless, simple, industrially scale-up and reproducible method without
the processability problems
disclosed in the state of the art associated to the use of micronized active
ingredients (such as wettability and
reagglomeration by electrostatic phenomena).
Thus, a first aspect of the invention relates to a composition comprising: a
therapeutically effective amount of
bilastine having a particle size distribution D90 from 15 to 90 pm measured by
laser diffraction; and a
pyrrolidone-based polymer; together with one or more pharmaceutically
acceptable excipients or carriers.
The second aspect of the invention relates to a preparation process of the
composition of the first aspect of
the invention.
The third aspect of the invention relates to the use of the composition of the
first aspect of the invention in the
treatment of histamine-mediated disease processes and allergic reactions.
Brief Description of Drawings
FIG. 1 pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-
theta ( )) of crystalline form Eta of
bilastine.
FIG. 2 pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-
theta ( )) of crystalline form 1 of
bilastine.
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Detailed description of the invention
All terms as used herein in this application, unless otherwise stated, shall
be understood in their ordinary
meaning as known in the art. Other more specific definitions for certain terms
as used in the present
application are as set forth below and are intended to apply uniformly
throughout the specification and claims
unless an otherwise expressly set out definition provides a broader
definition.
For the purposes of the present invention, any ranges given include both the
lower and the upper end-points
of the range. Ranges given, such as temperatures, times, weights, and the
like, should be considered
approximate, unless specifically stated. The term "about" or "around" as used
herein refers to a range of
values 10% of a specified value. For example, the expression "about 15"
includes 10% of 15, i.e. from
13.5 to 16.5.
The terms "percentage (%) by weight", "weight/weight %" and "w/w%" have the
same meaning and are used
interchangeable. They refer to the percentage of each ingredient of the
composition in relation to the total
weight of the composition.
As it is mentioned above, the composition comprises a therapeutically
effective amount of bilastine having a
particle size distribution D90 from 15 to 90 pm. A "therapeutically effective
amount" of bilastine relates to the
amount of bilastine that provides a therapeutic effect after the
administration thereof. In an embodiment, the
therapeutically effective amount of bilastine is from about 5 to 50 mg,
particularly from about 10 to 40 mg,
particularly from about 10 to 30 mg and particularly from about 10 to 20 mg.
The bilastine in the compositions of the invention is not micronized, and
particular, the particle size distribution
D90 of bilastine is from about 15 to 90 pm. In an embodiment, the particle
size distribution D90 of bilastine is
from about 25 to 80 pm, particularly from about 25 to 75 pm. The term
"particle size" refers to the size of the
particles measured in pm. The measurement was performed with an appropriate
apparatus by conventional
analytical techniques such as, for example, laser diffraction. In the present
invention the particle size was
measured by a Mastersizer 3000 particle size analyzer. Such apparatus uses a
technique of laser diffraction
to measure the size of particles. It operates by measuring the intensity of
light scattered, as a laser beam
passes through a dispersed particles sample. This data is then analyzed using
the general purpose model to
calculate the size of the particles that created the scattering pattern,
assuming a spherical particle shape.
Optionally, also microscopic determination utilizing a scanning electron
microscope (SEM) may be used. But
laser diffraction is preferred.
The terms "particle size distribution" or "PSD" have the same meaning and are
used interchangeably. They
refer to the percentage of the particles within a certain size range. The term
"D90" refers to the value of
particle size distribution where at least 90% of the particles have a size
less or equal to the given value.
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Further, the term "D50" refers to the value of particle size distribution
where at least 50% of the particles have
a size less or equal to the given value. Thus, for the purpose of the
invention, a particle size distribution D90
from about 15 to 90 pm means that the 90% of the particles of bilastine have a
size less or equal to the given
value within the range from about 15 to 90 pm.
5
The composition of the invention also comprises a pyrrolidone-based polymer.
The term "pyrrolidone-based
polymer" means that the chemical structure of the monomer of the backbone of
the polymer, from which the
pyrrolidone-based polymer is made, contains a pyrrolidone. For the purpose of
the invention, a "pyrolidone-
based polymer' refers to a polymer that comprises more than 50% by weight of
polymerized pyrrolidone units
(also named monomer).
In an embodiment, the composition is one wherein the pyrrolidone-based polymer
comprises 1-vinyl-2-
pyrrolidone units, which mean that the pyrrolidone-based polymer is a
polyvinylpyrrolidone. The terms
"polyvinylpyrrolidone", "polyvidone", "povidone" and "PVP" have the same
meaning and they are used
interchangeable. In particular, the polyvinylpyrrolidone is the polymer made
from the monomer N-
vinylpyrrolidone. Polyvinylpyrrolidone is the common name of the compound 1-
ethenylpyrrolidin-2-one with
the CAS number 9003-39-8 having the following structure:
4..µN 07L-
- n
In an embodiment, the composition is one wherein the pyrrolidone-based polymer
is a cross-linked
polyvinylpyrrolidone. The terms "cross-linked polyvinylpyrrolidone",
"polyvinylpolypyrrolidone", "polyvinyl
polypyrrolidone", "PVPP", "crospovidone" and "crospolividone" have the same
meaning and they are used
interchangeable. In particular, the crospovidone is a crosslinked polymer made
from the monomer N-
vinylpyrrolidone. Crospovidone is the common name of the crosslinked
polyvinylpyrrolidone (PVP) named
crosslinked 1-ethenylpyrrolidin-2-one with has the CAS number 25249-54-1.
The terms "cross-linked" or "cross-linking" refers to the use of cross-links
to promote a difference in the
physical properties of the polymers. The term "cross-links" refers to bonds
that link one polymer chain to
another or differents parts of the same polymer and these bonds can be
covalent or ionic bonds. The term
"cross-linker' or "cross-linking agent" refers to compounds having the ability
to cross-link the polymer chains.
In the present invention, the term "percentage of crosslinking" refers to the
amount of cross-links present in
the polymer. In an embodiment, the pyrrolidone-based polymer may be any cross-
linked polyvinylpyrrolidone
with any percentage of crosslinking as measured by ASTM D2765 or by ASTM
F2214.
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In an embodiment, the composition comprises from Ito 10 % by weigth of the
pyrrolidone-based polymer. In
an embodiment, the composition comprises from 1 and 8 % by weigth of the
pyrrolidone-based polymer. In an
embodiment, the composition comprises from 2 and 8 % by weigth of the
pyrrolidone-based polymer. In an
embodiment, the composition comprises from 3 and 5 % by weigth of the
pyrrolidone-based polymer.
In an embodiment, the composition comprises bilastine having an X-ray
diffractogram that comprises
characteristic peaks at 8.4; 9.6; 12.2; 13.2; 15.1; and 19.2 - 0.2 degrees 2
theta measured with an X-ray
diffractometer with Cu Ka radiation (1.5418 A) called crystalline Eta form of
bilastine. In an embodiment, the
composition comprises Eta crystalline form of bilastine which further contains
characteristic peaks at 19.7;
20.3; 21.5; and 23.4 0.2 degrees 2 theta measured with an X-ray
diffractometer with Cu Ka radiation
(1.5418 A). In an embodiment, the composition comprises Eta crystalline form
of bilastine which further also
contains peaks at 14.0; 16.8; 17.5; 18.2 and 25.5 0.2 degrees 2 theta
measured with an X-ray
diffractometer with Cu Ka radiation (1.5418 A). In an embodiment, the
composition comprises Eta crystalline
form of bilastine having the X-ray diffractogram shown in FIG. 1.
In an embodiment, the composition comprises Eta crystalline form of bilastine
characterized in that it shows
the pattern of peaks, expressed in units of 2 theta degrees, 20 (0), in the X-
ray powder diffractogram shown in
the following table:
Intensity
('') d(A)
(')/0)
8.37 10.56 41.0
9.55 9.26 64.9
9.74 9.08 7.8
11.40 7.76 4.3
12.18 7.27 89.7
13.19 6.71 42.1
13.95 6.35 11.2
15.07 5.88 52.7
16.79 5.28 16.0
17.49 5.07 21.0
17.77 4.99 5.8
18.18 4.88 22.6
19.18 4.63 100
19.67 4.51 26.7
20.16 4.40 34.0
20.34 4.37 83.9
20.83 4.26 7.4
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21.52 4.13 25.3
23.35 3.81 66.8
24.26 3.67 4.9
24.51 3.63 7.0
24.73 3.60 6.4
25.46 3.50 11.1
The Eta crystalline form of bilastine is prepared following the processes
disclosed in the European patent
application EP16829901. In an embodiment, the process for the preparation of
the Eta crystalline form of
bilastine comprising transforming the form 1 of bilastine into the Eta
crystalline form, which comprises
dispersing crystalline form 1 in water during the time needed for the
transformation into the Eta crystalline
form of bilastine of said dispersion to take place.
In an embodiment, the composition comprises bilastine haying an X-ray
diffractogram that comprises
characteristic peaks at 12.51; 16.35; 17.24, 19.99 and 21.20 0.2 degrees 2
theta measured with an X-ray
diffractometer with Cu Ka radiation (1.5418 A) called crystalline Form I of
bilastine. In an embodiment, the
composition comprises crystalline Form I of bilastine which further contains
characteristic peaks at 10.65;
12.64, 15.58 and 25.00 0.2 degrees 2 theta measured with an X-ray
diffractometer with Cu Ka radiation
(1.5418 A). In an embodiment, the composition comprises crystalline Form I of
bilastine which further also
contains peaks at 14.14, 14.33, 17.48, 23.40 0.2 degrees 2 theta measured
with an X-ray diffractometer
with Cu Ka radiation (1.5418 A). In an embodiment, the composition comprises
crystalline Form I of bilastine
haying the X-ray diffractogram shown in FIG. 2.
In an embodiment, the composition comprises crystalline Form I of bilastine
characterized in that it shows the
pattern of peaks, expressed in units of 2 theta degrees, 20 ('), in the X-ray
powder diffractogram shown in the
following table:
20 (1) d(A) l(rolito;nsity
3.78 23.37347 1.85
10.65 8.30482 16.41
11.36 7.79036 5.29
12.51 7.07699 15.09
12.65 6.99799 15.29
12.88 6.87216 4.49
14.14 6.26446 14.38
14.33 6.179 14.24
14.57 6.08096 0.59
14.76 6.00242 5.31
15.16 5.84521 2.73
15.58 5.68938 9.96
16.35 5.42088 19.65
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16.96 5.22891 1.05
17.24 5.14283 100
17.48 5.07348 16.36
18.17 4.88233 1.24
18.52 4.79157 9.71
18.98 4.67474 3.88
19.18 4.62874 2.55
19.81 4.48233 13.59
19.99 4.44212 20.99
20.22 4.39174 2.71
20.35 4.36392 3.8
21.20 4.19182 28.2
21.46 4.14044 8.14
21.64 4.10693 1.37
22.26 3.99388 2.88
22.41 3.96769 2.08
22.68 3.92157 4.79
22,84 3.89325 1.24
23.04 3.85991 2.33
23.40 3.80223 8.78
23.91 3.7216 0.88
24.33 3.65914 1.33
24.50 3.63347 1.47
24.68 3.60783 4.18
25.00 3.56165 10.22
25.42 3.5007 2.54
25.54 3.4932 1.49
25.92 3.43473 7.2
26.36 3.37867 0.38
26.71 3.33468 1.24
27.43 3.24939 2.1
28.31 3.15014 0.51
28.54 3.12465 0.8
29.22 3.05362 7.33
29.91 2.98479 2.52
30.62 2.91733 0.4
31.00 2.88258 2.58
31.67 2.82279 0.59
31.89 2.80414 1.53
32.05 2.79766 0.99
32.25 2.77315 0.34
33.04 2.70937 1.78
33.27 2.69048 0.85
33.53 2.67076 0.84
33.76 2.65288 0.69
34.10 2.62707 1.22
34.48 2.59902 4.15
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The crystalline form I of bilastine is prepared following the processes
disclosed in the European patent
EP1505066B1. In an embodiment, the process for the preparation of the
crystalline Form 1 of bilastine
comprises dispersing crystalline form 1 in water during the time needed for
the transformation into the Eta
crystalline form of bilastine of said dispersion to take place.
The composition of the present invention comprise one or more pharmaceutically
acceptable excipients or
carriers. The term "pharmaceutically acceptable excipients or carriers" refers
to that excipients or carriers
suitable for use in the pharmaceutical technology for preparing compositions
with medical use. Said excipients
or carriers must be pharmaceutically acceptable in the sense that they must be
compatible with the rest of the
ingredients of the pharmaceutical composition. They must also be suitable for
use in contact with human or
animal tissues or organs without showing excessive toxicity, irritation,
allergic response, immunogenicity or
other problems or complications relating to a reasonable risk/benefit ratio.
The compositions of the invention can be formulated in any form that includes
any single unit dosage form
and any multiple unit dosage forms. The term "single unit" encompasses one
entity such as a single tablet, a
single granule, and a single pellet. The term "single unit dosage form"
defines a dosage form which consists
only of one unit which contains the effective amount of bilastine. The term
"multiple unit dosage form" defines
a dosage from which consists of more than one unit which contains the
effective amount of bilastine. Usually,
the multiple unit dosage forms are based on subunits such as granules, pellets
or minitablets. They are
usually delivered in hard capsules or transformed into tablets. Thus, it is
also part of the invention a unit
dosage form which comprises the composition of the present invention. In an
embodiment, the unit dosage
from which comprises the composition of the present invention is a single unit
dosage form. In an
embodiment, the unit dosage from which comprises the composition of the
present invention is a multiple unit
dosage form. The appropriate excipients and/or carriers, and their amounts,
can readily be determined by
those skilled in the art according to the type of formulation being prepared.
In an embodiment, the pharmaceutically acceptable excipients or carriers are
selected from the group
consisting of selected from the group consisting of diluent, lubricant,
binder, glidant, disintegrant and mixtures
thereof.
The terms "filler" and "diluent" have the same meaning and are used
interchangeably. They refer to any
pharmaceutically acceptable excipient or carrier (material) that fill out the
size of a composition, making it
practical to produce and convenient for the consumer to use. Materials
commonly used as filler include
calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic
calcium sulfate, calcium
carboxymethyl cellulose, cellulose, cellulose products such as
microcrystalline cellulose and its salts, dextrin
derivatives, dextrin, dextrose, fructose, lactitol, lactose, starches or
modified starches, magnesium carbonate,
magnesium oxide, maltitol, maltodextrins, maltose, mannitol, sorbitol, starch,
sucrose, sugar, xylitol, erythritol
and mixtures thereof. In an embodiment, the composition of the invention is
one wherein the pharmaceutically
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acceptable excipients or carriers comprises one or more fillers. In an
embodiment, the composition of the
invention is one wherein the pharmaceutically acceptable excipients or
carriers comprises one or more fillers
selected from the group consisting of microcrystalline cellulose or sugar
alcohols like mannitol. In an
embodiment, the composition of the invention is one wherein the
pharmaceutically acceptable excipients or
5 carriers comprise one or more filler in an amount from about 35 to 90% by
weight of the composition,
particularly from about 50 to 90% by weight of the composition, particularly
from about 70 to 90% by weight of
the composition.
The term "lubricant" refers to a substance that prevents composition
ingredients from clumping together and
10 from sticking to the tablet punches or capsule filling machine and
improves flowability of the composition
mixture. Materials commonly used as a lubricant include sodium oleate, sodium
stearate, sodium benzoate,
sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate,
calcium stearate, magnesium
stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or
fatty acid, zinc, polyethylene
glycol, talc and mixtures thereof. The presence of a lubricant is particularly
preferred when the composition is
a tablet to improve the tableting process. In an embodiment, the composition
of the invention is one wherein
the pharmaceutically acceptable excipients or carriers comprises one or more
lubricants selected from the
group consisting of magnesium stearate, ascorbic acid and sodium stearyl
fumarate. In an embodiment, the
composition of the invention is one wherein the pharmaceutically acceptable
excipients or carriers comprise
one or more lubricants in an amount from 0.1 to 5% by weight of the
composition, particularly from 0.5 to 5%
by weight of the composition, particularly from about 0.5 to 3% by weight of
the composition.
The term "binder" refers to any pharmaceutically acceptable compound having
binding properties. Materials
commonly used as binders include povidone such as polyvinylpyrrolidone K30,
ethyl cellulose polymers,
methylcellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, L-
hydroxypropyl cellulose (low
substituted), hydroxypropylmethyl cellulose (HPMC), sodium carboxymethyl
cellulose, carboxymethylene,
carboxymethylhydroxyethyl cellulose and other cellulose derivatives, starches
or modified starches and
mixture thereof. In an embodiment, the composition of the invention is one
wherein the pharmaceutically
acceptable excipients or carriers comprise one or more binders. In an
embodiment, the composition of the
invention is one wherein the pharmaceutically acceptable excipients or
carriers comprise one or more binders
selected from the group consisting of polyvinylpyrrolidone, ethyl cellulose
and hydroxypropylmethyl cellulose.
In an embodiment, the composition of the invention is one wherein the
pharmaceutically acceptable excipients
or carriers comprise one or more binders in an amount from 0 to 10% by weight
of the composition,
particularly from 1 to 10% by weight of the composition, particularly from 1
to 7% by weight of the
composition, particularly from about 2.5 to 6% by weight of the composition.
The term "glidant" refers to a substance which improves the flow
characteristics of powder mixtures in the dry
state. Materials commonly used as a glidant include magnesium stearate,
colloidal silicon dioxide or talc. In an
embodiment, the composition of the invention is one wherein the
pharmaceutically acceptable excipients or
carriers comprises one or more glidants. In an embodiment, the composition of
the invention is one wherein
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the pharmaceutically acceptable excipients or carriers comprises one or more
glidants selected from the
group consisting of colloidal silicon dioxide and talc. In an embodiment, the
composition of the invention is one
wherein the pharmaceutically acceptable excipients or carriers comprise one or
more glidants in an amount
from 0 to 5% by weight of the composition, particularly from 0.1 to 5% by
weight of the composition,
particularly from 0.2 to 5% by weight of the composition, particularly from
about 0.5 to 3% by weight of the
composition.
The term "disintegrant" refers to a substance that expand and dissolve when
wet causing the tablet to break
apart in the body and release the active ingredient for absorption. Materials
commonly used as disintegrants
include cross-linked polymers like, for example,crospovidone and
croscarmellose sodium, and modified
starches like sodium starch glycolate.
In an embodiment, the composition of the invention is one wherein the
pharmaceutically acceptable excipients
or carriers further comprises at least one or more disintegrants differents
from pyrrolidone-based polymer. In
an embodiment, the composition of the invention is one wherein the
pharmaceutically acceptable excipients or
carriers comprises at least one disintegrant different from a pyrrolidone-
based polymer selected from the
group consisting of croscarmellose and sodium starch glycolate. In an
embodiment, the composition of the
invention is one wherein the pharmaceutically acceptable excipients or
carriers comprise one or more
disintegrants different from a pyrrolidone-based polymer in an amount from 0
to 10, particularly from 0 to 5%
by weight, particularly from about 0.1 to 5 % by weight of the composition.
Additionally, the composition of the present invention may contain other
ingredients, such as colorants,
sweeteners, aromas, and other components known in the state of the art for use
in solid formulations. For
example, sweeteners may be selected from the group consisting of sucralose,
acesulfame K, aspartame,
neohesperidin and dihydrochalcone. Aromas may be selected from the group
consisting of grape aroma,
strawberry aroma and raspberry aroma.
In an embodiment, the composition of the present invention comprises:
a therapeutically effective amount of bilastine having a particle size
distribution 090 from 15 to 90 pm; and
from 1 to 10% by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 35 to 90 % by weight of a filler;
from 0 to 5 % by weight of a glidant;
from 0 to 10% by weight of binder;
from 0 to 10 % by weight of a disintegrant different from a pyrrolidone-based
polymer;
from 0.1 to 5 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment, the composition of the present invention is in a form of
tablet.
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In an embodiment, the composition of the present invention is form of a tablet
and comprises:
a therapeutically effective amount of bilastine having a particle size
distribution D90 from 15 to 90 pm; and
from 1 to 10% by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 35 to 90 % by weight of a filler;
from 0 to 5 % by weight of a glidant;
from 0 to 10% by weight of binder;
from 0 to 10 % by weight of a disintegrant different from a pyrrolidone-based
polymer;
from 0.1 to 5 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment the composition of the present invention is in a form of
immediate release tablet and an
orodispersible tablet (abbreviated as ODT).
In an embodiment, the composition of the present invention is in a form
immediate release tablet. For the
purpose of the invention, the term "Immediate release" composition refers to a
composition which releases the
active ingredient substantially immediately upon contact with gastric juices
and will result in substantially
complete dissolution within about 1 hour. Immediate release (IR) components
can also be referred to as
instant release. When used in association with the dissolution profiles
discussed herein, the term "immediate
release" refers to the composition which delivers the active ingredient over a
period of time less than 1 hour.
In an embodiment, the composition of the present invention is in form of an
immediate release tablet
comprising:
a therapeutically effective amount of bilastine having a particle size
distribution 090 from 15 to 90 pm; and
from 1 to 10% by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 35 to 90 % by weight of a filler;
from 0.1 to 5 % by weight of a glidant;
from 0.1 to 5 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment, the composition of the present invention is in form of an
immediate release tablet
comprising:
a therapeutically effective amount of bilastine having a particle size
distribution D90 from 15 to 90 pm; and
from 2 to 8 % by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 50 to 90 % by weight of a filler;
from 0.2 to 5 % by weight of a glidant;
from 0.5 to 5 % by weight of a lubricant; and
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optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition
In an embodiment, the composition of the present invention is in form of an
immediate release tablet
comprising:
a therapeutically effective amount of bilastine having a particle size
distribution 090 from 15 to 90 pm; and
from 3 to 5 % by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 70 to 90 % by weight of a filler;
from 0.5 to 3 % by weight of a glidant;
from 0.5 to 3 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition
In an embodiment, the composition is in form of a orodispersible tablet (ODT).
The terms "orodispersible"
tablet, "quick disintegrating" tablet, "mouth dissolving" tablet, "porous"
tablets and the abbreviature "ODT"
have the same meaning and they can be used interchangeable. In particular, the
term "orodispersible" tablet
refers to non-coated tablets for placing in the mouth which disintegrate
quickly before they are swallowed. In
particular, it is established that the time under which they must disintegrate
in the disintegration test for tablets
and capsules, according to the Ph. Eur. 2.9.1. 1s3 minutes (cf. European
Pharmacopoeia (Ph.Eur.) 5th
edition, Supplement 5.2, published in June 2004). The orodispersible tablet of
the present inventionis
advantageously used in cases where administration without water is necessary,
cases of administration to
patients who have difficulty in swallowing tablets, or cases of administration
to the elderly or to children where
there is a fear of blocking the throat if it is unusual tablet form.
In an embodiment, the composition of the present invention is in form of an
orodispersible tablet comprising:
a therapeutically effective amount of bilastine having a particle size
distribution D90 from 15 to 90 pm; and
from 1 to 10% by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 35 to 90 % by weight of a filler;
from 1 to 10 % by weight of a binder;
from 0.1 to 5 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment, the composition of the present invention is in form of an
orodispersible tablet comprising:
a therapeutically effective amount of bilastine having a particle size
distribution D90 from 15 to 90 pm; and
from 2 to 8 % by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 50 to 90 % by weight of a filler;
from 1 to 7 % by weight of a binder;
from 0.5 to 5 % by weight of a lubricant; and
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optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment, the composition of the present invention is in form of an
orodispersible tablet comprising:
a therapeutically effective amount of bilastine having a particle size
distribution D90 from 15 to 90 pm; and
from 3 to 5 % by weight of a pyrrolidone-based polymer, particularly
crospovidone;
from 70 to 90 % by weight of a filler;
from 2.5 to 6 % by weight of a binder;
from 0.5 to 3 % by weight of a lubricant; and
optionally other pharmaceutically acceptable excipients or carriers
being the sum of the components up to 100% by weight of the composition.
It is also part of the invention, a process for the preparation of the
compositions in form of tablets of the
invention. In an embodiemnt, the process for the preparation of the immediate
release tablets of the present
invention comprises:
a) preparing a pre-mixture comprising bilastine or a pharmaceutically
acceptable salt thereof, Crospovidone
and a part of the filler (particularly about 20% of the total amount of the
filler);
f) optionally, sieving the pre-mixture obtained in step a) and each one of the
remaining excipients (including
the remaining quantity of the filler) separately by a sieve having a sieve
diameter from 750 to 1250 pm;
b) mixing the pre-mixture obtained in step a) with the remaining excipients
including the crospovidone and
except for the lubricant;
c) adding the lubricant to the mixture obtained in step b); and
d) compressing the mixture obtained in step (c) to form tablets; and (e)
optionally, coating the tablets obtained
in step (d).
In an embodiment, the process for the preparation of the orodispersible
tablets of the present invention
comprises:
a') preparing a first pre-mixture comprising the flavour, the sweetener and a
part of the filler (particularly about
10% of the total amount of the filler);
a") preparing a second pre-mixture comprising bilastine or a pharmaceutically
acceptable salt thereof,
Crospovidone and a part of the remaining part of the filler (particularly
about 40-50% of the total amount of the
filler);
f') optionally, sieving the first and the second pre-mixture obtained in step
a') and a"), and each one of the
remaining excipients (including the remaining quantity of the filler)
separately by a sieve having a sieve
diameter from 750 to 1250 pm;
b') mixing the first and the second pre-mixture with the remaining excipients
including the crospovidone the
remaining quantity of the filler and except for the lubricant;
c') adding the lubricant to the mixture obtained in step b'); and
d') compressing the mixture obtained in step (c') to form tablets; and (e')
optionally, coating the tablets
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obtained in step (d').
In an embodiment, each one of the steps (a), (a') and (a") of the process for
preparation of the composition of
the invention is performed at room temperature. In an embodiment, each one of
the steps (a), (a') and (a") of
5 the process for preparation of the composition of the invention is
performed manually at lab step or in a
double cone or tumbler mixer at industrial scale.
In an embodiment, each one of the steps (b), (b'), (c) and (c') of the process
for preparation of the composition
of the invention is performed at room temperature. In an embodiment, each one
of the steps (b), (b'), (c) and
10 (c') of the process for preparation of the composition of the invention
is performed in a double cone or tumbler
mixer.
In an embodiment, the process comprises step (f) or (f'). In an embodiment,
each one of steps (f) or (V) are
performed by the use of a sieve of 1000 pin for sieving the pre-mixtures,
mixture and excipients excpet for the
lubricant which is sieve throught a sieve of 250 pm of diameter.
In an embodiment, the compressing steps (d) and (d') of the process for
preparation of the composition of the
invention is performed using an eccentric tableting machine for lab-scale
process and rotary tableting machine
for industrial scale. In an embodiment, the compressing steps (d) and (d') of
the process for preparation of the
composition of the invention is performed in order to obtain tablets having a
hardness about 55 to 95N.
As it is mentioned above, the composition of the invention allows having the
appropriate dissolution rate and
availability for being used in therapy and considered equivalent to Bilaxten
which include micronized bilastine.
In an embodiment, the composition of the invention is an immediate release
tablet which exhibits a dissolution
profile according to which at least 85% by weight of the bilastine or a
pharmaceutically acceptable salt thereof
is dissolved in 15 min, wherein: the dissolution profile is measured using a
USP type I apparatus (basket),
placing the composition in 900mL of phosphate buffer having pH 6.8, at 37 C
and 50 rpm.
In an embodiment, the composition of the invention is an orodispersible tablet
which exhibits a dissolution
profile according to which at least 85% by weight of the bilastine or a
pharmaceutically acceptable salt thereof
is dissolved in 15 min, wherein: the dissolution profile is measured using a
USP type I apparatus (basket),
placing the composition in 900mL of phosphate buffer having pH 6.8, at 37 C
and 50 rpm. A skilled person
must differenciate between disintegration (according to the Ph. Eur. 2.9.1. is
3 minutes) and dissolution
profile.
In an embodiment, the composition of the invention, exhibits a maximum plasma
concentration (Cmax) and an
area under the time/plasma concentration curve from time 0 to 36 hours (AUC (0-
36)) from 80 to 125%
refering to the Bilaxten reference product, in a confidence interval of 90% .
The term "Cmax" refers to the
maximum concentration of bilastine in the blood following a single-dose
administration of the composition.
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The term "AUC" refers to the area under the time/plasma concentration curve
after an oral single-dose
administration of the composition of the present invention. AUCO-infinity
denotes the area under the plasma
concentration versus time curve from time 0 to infinity and AUCo-t denotes the
area under the plasma
concentration versus time curve from time 0 to time t.
Other aspect of the invention relates to the use of the composition of the
invention in treatment of histamine-
mediated disease processes and allergic reactions. This aspect could be also
formulated as the use of a
composition of the invention as defined above for the preparation of a
medicament for the prophylaxis and/or
treatment of the histamine-mediated disease processes and allergic reactions.
It also relates to a method for
the prophylaxis and/or treatment of a mammal suffering or is susceptible to
suffer from a histamine-mediated
disease processes and allergic reactions,wherein the method comprises
administering to said mammal an
effective amount of the composition of the present invention. In an
embodiment, the histamine-mediated
disease processes and allergic reactions are selected from the group
consisting of the symptomatic treatment
of seasonal allergic rhinoconjunctivitis, the symptomatic treatment of
perennial allergic rhinoconjunctivitis and
the treatment of urticaria. All the embodiments disclosed above for the
composition of the first aspect of the
invention also apply for its use.
Throughout the description and claims the word "comprise" and variations of
the word, are not intended to
exclude other technical features, additives, components, or steps.
Furthermore, the word "comprise"
encompasses the case of "consisting of". Additional objects, advantages and
features of the invention will
become apparent to those skilled in the art upon examination of the
description or may be learned by practice
of the invention. The following examples and drawings are provided by way of
illustration, and they are not
intended to be limiting of the present invention. Reference signs related to
drawings and placed in
parentheses in a claim, are solely for attempting to increase the
intelligibility of the claim, and shall not be
construed as limiting the scope of the claim. Furthermore, the present
invention covers all possible
combinations of particular and preferred embodiments described herein.
Examples
Methods:
- X-ray Powder diffractogram (XRPD) method
The X-ray powder diffractogram has been obtained by using an X-ray
diffractometer with Cu Ka radiation
(1.5418 A) in a PANalytical X'Pert PRO MPD powder diffractometer with a radius
of 240 millimeters, in a
convergent beam configuration with a focusing mirror and transmission geometry
with flat samples inserted
between low absorbent films. The samples in powder form were inserted between
polyester films with a
thickness of 3.6microns.
The experimental conditions were as follows:
Cu Ka radiation (a= 1.5418 A).
Working power: 45 kV ¨ 40 mA.
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Incident beam slits that define a beam height of 0.4 millimeters
Incident and diffracted beam slits of 0.02 radian SoIler
Detector PIXcel: active length = 3.347 2theta/theta scans of 2 to 40 2theta
with a step size of 0.026 2theta
and a measurement time of 76 seconds per step.
The diffractograms obtained show the pattern of X-ray powder diffraction
(intensity
(counts) vs. angle 2-theta ( )).
- Determination of the particle size distribution (PSD) of Bilastine by laser
diffraction
2mg of sample were taken to measure the PSD of every API sample
Instrument conditions
Instrument: Malvern Laser Diffraction Masterizer 3000
Accesory: Dry Smapler Aero S
Measuring range: 0.001-3500pm
Sensitivity: Normal
Particle Type: Non-spherical
Material Refraction Index: 1.59
Material Absorption Index: 0.01
Dispersant: Air
Dispersant Air Pressure: 2 bar
Background measuring time: 5 seconds
Sample meauring time: 5 seconds
Number of measurements: 3
Obscuration Range: 1-5%
Feed rate: 30%
Hoper opening: 2.5
Micronization method for Bilastine Form I
Wet molturation of sample
Instrument: Pilot micronizer with Jetmill technology lnox 316
Feed hoper: 0.5L
Mirror polish: Ra < 0.2 pm
Dosage speed: 30g/h
Chamber pressure: 2.0 bar
PSD analysis of the commercial tablets Bilaxten by SEM
Tablets were dispersed in water (approx. 1:5 w/v ratio) and shaken manually
for 2 minutes to dissolve the
soluble contents in water. The mixture was centrifuged for 1 min at 5000 rpm.
The supernatant containing
soluble ingredients was discarded. Sample from the sediment was dried, mounted
on glass slide, and
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observed under microscope for particle size analysis. The API and tablet
samples were subjected to similar
sample preparation and analyzed.
Particle size of API in the tablets was determined with a pre-calibrated stage
micrometer using
optical/polarized hot stage microscope (Leica DMLP, Leica, Germany) equipped
with a controlled heating and
cooling stage (LTS350, Linkam) and an imaging system (VTO 232, JVC ¨ Digital
camera and Linksys 32
imaging software, Linkam, England). A small amount of powder was mounted on
glass slide and observed
under the microscope in dry state. Sample was observed at 500X magnification
with a least count of 3.5
micron.
Identification of API
For particle size analysis, API particles were differentiated from other
ingredients present in tablets through
microscopy. This was done based on difference in the melting point of the drug
and excipients. API particles
could be differentiated by hot-stage microscopy.
Particle size of API was recorded by measuring the length along the longest
axis of individual particles. PSD
of separated individual API particles was measured and aggregated API
particles were not considered for
measurement. Particle size of about 300 particles was determined and data was
grouped into class intervals.
1. Compositions
The values of the D90 of the crystalline form of Bilastine used for the
preparation of the compositions of
Examples 1-3 of the present invention and of the comparative Examples using
the method as defined above
were disclosed below in each one of the Tables 1 and 2.
1.1. Compositions of the invention
The qualitative and quantitative composition of the immediate release tablets
(IR-tablets of Examples 1 and 3)
and orodispersible tablets (ODT of Example 2) of the present invention are
shown in Table 1, wherein the
amount of each of the components are expressed in weight percent:
Table 1
Examples (% w/w)
Function Ingredient/D90 (pm) Example 1 Example 2
Example 3
(IR-Tablet) (ODT)
(IR-Tablet)
Bilastine crystaline form I
16
(090: 57 pm)
Active ingredient
Bilastine crystaline form Eta
6.7 16
(D90: 29.9 pm)
Disintegrant-
Crospovidone
pyrrolidone-based 5 3.0
5
(type A)
polymer
Ethylcellulose
binder 4.0
(ethocel std 10 FP)
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microcrystalline cellulose
77.6 77.6
Filler (Avicel PH-102)
Mannitol CD 85.1
Glidant colloidal silicon dioxide 0.5
0.5
Lubricant Magnesium stearate 0.9 1.0
0.9
Sweetener Sucralose granular 0.1
aroma Red grapes aroma 0.1
Total weight 100 100
100
1.2. Comparative compositions
The qualitative and quantitative comparative composition of the commercially
available immediate realease
tablet of micronized bilastine (Bilaxten) (Comparative Example 1) and the
qualitative comparative composition
of the commercially available orodispersible tablet of micronized bilastine
(Bilaxten) (Comparative Example 2)
falling outside the scope of the present invention are shown in Table 2,
wherein the amount of each of the
components are expressed in weight percent:
Table 2
Examples ( /0 w/w)
Function Ingredient/D90 (pm) IR-Comparative
Example 1
Bilastine crystaline form I
Active ingredient/ 16
(D90: 6.8 pm)
Disintegrant Sodium starch glycolate 5
Filler Microcrystalline cellulose 77.6
Glidant Colloidal silicon dioxide 0.5
Lubricant Magnesium stearate 0.9
Total weight 100
Table2-cont.
ODT-Comparative Example 2
Function
(% w/w)
Bilastine crystaline form I
Active ingredient/
(D90: 6.8 pm)
Disintegrant Croscarmellose sodium
Filler Mannitol
Lubricant Sodium stearyl fumarate
Sweetener Sucralose
flavour Red grade flavour
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1.3. Preparation process
1.3.1. Immediate release compositions
The immediate release compositions of the invention (Examples 1 and 3) defined
in Table 1 were prepared
following the general process 1 as defined below using the ingredients and the
amounts specified in the
5 table.
Meanwhile, the comparative immediate realease tablet (Comparative Example 1)
defined in Table 2 was
prepared following the general process 1 as defined below using the
ingredients and the amounts specified in
the table, but further comprises a previous step which comprises micronizing
the bilastine crystaline form I
10 until having the D90 about 6.8 pm. The micronization process of the
bilastine was also disclosed herein
below.
General process 1
The process comprises performing the following 5 consecutive steps: 1) Pre-
blending, 2) Screening, 3)
15 Blending, 4) Lubrication and 5) Tableting. Pre-blending and screening
steps were performed manually at
laboratory scale; blending and lubrication steps were performed in a double
cone mixer; and tableting step
was performed in an eccentric tableting machine.
The general process 1 is disclosed herein below.
1) Pre-blending Step. Bilastine (20mg), Crospovidone and a part of the filler
(20.6% of the total quantity of the
20 filler) were premixed to obtain a pre-mixture.
2) Screening Step. The pre-mixture obtained in step 1 and the remaining
excipients (including the remaining
quantity of the filler) except for the lubricant were screened by a 1000 pm
sieve.
3) Blending Step. The pre-mixture obtained in step 2) and the excipients
(including the remaining quantity of
the filler) except for the lubricant were added to a 1L double cone blender
and the resulting mixture was mixed
during 20 minutes at 18 rpm.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was
added to the mixture obtained
in step 3) and mixed for 5 minutes at 18 rpm in the same double cone mixer.
5) Tableting Step. The lubricated mixture obtained in step 4) was tableted in
an eccentric tableting machine to
obtain biconvex and unscored roundimmediate release tablets.
1.3.2. Orodispersible compositions
The orodispersible composition of the invention (Example 2) defined in Table 1
was prepared following the
general process 2 as defined below using the ingredients and the amounts
specified in the table.
Meanwhile, the comparative orodispersible tablet (Comparative Example 2)
defined in Table 2 was prepared
following the general process 2 as defined below using the ingredients and the
amounts specified in the table,
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but further comprises a previous step which comprises micronizing the
bilastine crystaline form I until having
the the D90 about 6.8 pm. The micronization process of the bilastine was also
disclosed herein below.
General process 2
The process comprises perfomring the following 5 consecutive steps: 1) Pre-
blending, 2) Screening, 3)
Blending, 4) Lubrication and 5) Tableting. Pre-blending and screening steps
were performed manually at
laboratory scale; blending and lubrication steps were performed in a double
cone mixer; and tableting step
was performed in an eccentric tableting machine.
The process is disclosed herein below.
1) Pre-blending Step. Two pre-mixtures were performed. The first pre-mixture
was prepared by manually
premixing the flavour, the sweetener and a part of the filler (10.6% of the
total quantity of the filler); and the
second pre-mixture was prepared by manually premixing Bilastine (10mg),
Crospovidone and a second part
of the filler (44.8% of the total quantity of the filler).
2) Screening Step. The first and the second pre-mixtures obtained in previous
step and the remaining
excipients (including the remaining quantity of the filler) except for the
lubricant were screened by a 1000 pm
sieve.
3) Blending Step. The two pre-mixtures obtained in step 2) and the screened
excipients (including the
remaining quantity of the filler) except for the lubricant were added to a 1L
drum blender and mixed during 20
minutes at 23-24 rpm.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was
added to the mixture obtained
in step 3) and mixed for 5 minutes at 23-24 rpm in the same blender.
5) Tableting Step. The lubricated mixture obtained in step 5) was tableted in
an eccentric tableting machine to
obtain biconvex and unscored round orodispersible tablets.
2. Dissolution Test
The dissolution profile of the compositions of Examples 1-3 of the present
invention and the comparative
Examples 1 and 2 was measured.
Conditions of the dissolution bath
- Paddle speed: 50 rpm
- Temperature of dissolution medium: 37.0 C - 0.5 C
- Dissolution Medium: sodium acetate buffer
- Vessel volume: 900 mL
- Vessel pH: 4.5
- Sample volume: 10 mL
-Time point (min): 5, 10, 15, 20 and 30.
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-no of units: 1
Method:
To the set dissolution apparatus having a 900mL of dissolution medium as
defined above to each of 6 glass
vessels and under the above mentioned conditions, a tablet of the test sample
was added into each basket
lower down hood, taking care to exclude the air bubbles from the surface of
the tablet and immediately start
the apparatus.
After that, at each time point, 10 mL of the test sample from each of 6 glass
vessels were withdrawn and
filtered through 0.22p polyvinylidene fluoride filter (PVDF filter). Further,
the withdrawn volume at each time
point is replaced by adding an equal quantity of fresh dissolution medium at
37.0 C 0.5 C.
Conditions of the chromatographic analysis
- Column: Acquity BEH C18 1.7 pm (100 x 2.1 mm) or equivalent
- Mobile Phase A: Acetonitrile HPLC grade: Methanol HPLC grade (50:50)
- Mobile Phase B: 5 mM Ammonium hydrogen carbonate (pH=10)
Dissolve 0.40 g of ammonium hydrogen carbonate in about 900 mL of water of
water, HPLC grade. Stir it until
complete dissolution and adjust to pH=10.0 0.5 with 30% ammonium hydroxide.
Dilute to 1000 mL with
water, HPLC grade and filter through 0.22 pm GHP filter.
- Mobile phase: Mobile Phase A/Mobile Phase B (55:45) (isocratic)
- Flow: 0.4 mL/min
- Column temperature: 30 C
- Wavelength detection: 220 nm
- Injection volume: 2 pL- Loop: 2 pL
- Sample Loop Option: Full loop
- Sample temperature: Room temperature
- Retention time: Bilastine: about1.1 min
- Run time: 2 min
Results
The weight percent of bilastine released from the compositions of Example 1-3
of the present invention and
the comparative Examples 1 and 2 submitted to the above-mentioned dissolution
conditions at the time
points; as well as the relative standard deviation is shown in Tables below.
Table 4 shows the percentage of bilastine released from the inmediate release
tablets of Examples 1 and 3,
and from the commercially available inmediate release tablet of comparative
Example 1, expressed as % by
weight of bilastine dissolved in the time given.
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Table 4
Time Points Bilastine release (Y0) / RSD (%)
(minutes) Example 1 Example 3 Comparative
Example 1
70.4 70.4 59.6
85.9 81.5 77.7
93.3 87.3 87.4
97.1 91.1 92.1
100.4 95.4 97.4
45 ND ND ND
ND = not determined
Table 5 shows the percentage of bilastine released from the orodispersible
tablet of Example 2, and from the
5 commercially available orodispersible tablet of comparative Example 2,
expressed as % by weight of bilastine
dissolved in the time given.
Table 5
Time Points Bilastine release ('%) I RSD (%)
(minutes) Example 2 Comparative
Example 2
5 43.75 58.9
10 81.83 85.0
15 91.3 93.2
20 94.45 96.6
30 97.11 99.4
45 98.12 100.7
The results of the dissolution profile disclosed in the above-mentioned Tables
showed that the compositions
10 of the present invention comprising a therapeutically effective amount
of non-micronized bilastine in
combination with a pyrrolidone-based polymer has comparable target dissolution
profile as commercially
available Bilaxten containing micronized bilastine. In particular, the target
dissolution profile of the inmediate
release bilastine composition comprises at least 85% dissolution at 15
minutes. And, the target dissolution
profile of the orodispersible tablet bilastine composition comprises at least
85% dissolution at 15 minutes.
Thus, the compositions of the present invention allows controlling the release
of the non-micronized bilastine
having the appropriate dissolution rate and availability for being used in
therapy and considered equivalent to
commercially available Bilaxten which include micronized bilastine.
Furthermore, the use of the combination of
non-micronized bilastine in combination with a pyrrolidone-based polymer
avoids the disadvantages of
processability of micronized active ingredients.
CA 03200779 2023- 5- 31
