DESCRIPTION
STABLE PARTICULATE PHARMACEUTICAL COMPOSITION OF SOLIFENACIN
OR SALT THEREOF
Technical Field
The present invention relates to a stable particulate
pharmaceutical composition obtained by using solifenacin or
a salt thereof and a specific binder, a process for producing
the same, a disintegrating tablet in buccal cavity comprising
the particulate pharmaceutical composition, and a method of
stabilizing the particulate pharmaceutical composition.
Background Art
Solifenacin is represented by the following formula (I) :
[Chemical formula 1]

and its chemical name is (1R, 3'R)-3'-quinuclidinyl-1-
phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate.
It has been reported that a series of quinuclidine
1

derivatives including solifenacin and salts thereof have a
highly selective antagonism to a muscarinic M3 receptor, and
is useful as a preventive/therapeutic agent for urologic
diseases such as nervous pollakiuria, neurogenic bladder,
nocturia, unstable bladder, bladder spasms and chronic
cystitis or respiratory diseases such as chronic obstructive
lung diseases, chronic bronchitis, asthma and rhinitis (see
Patent document 1).
In Example 8 in the Patent document 1, a process for
producing solifenacin hydrochloride is disclosed, and it is
described that a crystal deposited in a mixed solvent composed
of acetonitrile and diethyl ether had a melting point of 212
to 214°C and showed a specific rotation [a] 25D of 98 .1 (c = 1. 00,
EtOH).
However, in the Patent document 1, there is no
description or even indication on an amorphous form of
solifenacin or a salt thereof, or that when solifenacin
succinate is formulated into a pharmaceutical preparation by
a standard formulation method, the solifenacin succinate,
which is an active ingredient, is significantly degraded with
time in the produced pharmaceutical preparation.
In Non-patent document 1 issued by Ministry of Health,
Labour and Welfare in June 2003, specification setting for
pharmaceutical preparations, that is, concepts of degradation
products (impurities) in pharmaceutical preparations accepted
2

in a stability test is described. According to this document,
in the case where the amount of a drug substance to be
administered per day is less than 10 mg, the threshold for which
the confirmation of the safety of the degradation products in
the pharmaceutical preparation is required is the lower of the
1.0% in terms of the percentage of the degradation products
contained in the drug substance and the 50 μg in terms of the
total intake of the degradation products per day. In the case
where the amount of a drug substance to be administered per
day is 10 mg or more and 100 mg or less, the threshold for which
the confirmation of the safety of the degradation products in
the pharmaceutical preparation is required is the lower of the
0.5% in terms of the percentage of the degradation products
contained in the drug substance and the 200 μg in terms of the
total intake of the degradation products per day. Therefore,
in general, the standard value of the amount of degradation
products, which can be set without confirming the safety of
the degradation products, is, for example, in the case of a
pharmaceutical preparation in which the content of the drug
substance is 5 mg, 1.0% or lower in terms of the percentage
of the degradation products contained in the drug substance,
and, for example, in the case of a pharmaceutical preparation
in which the content of the drug substance is 10 mg, 0.5% or
lower in terms of the percentage of the degradation products
contained in the drug substance.
3

At present, pharmaceutical preparations of solifenacin,
which are going to be sold on the market based on the results
of the current clinical studies, are a 2.5 mg tablet, a 5 mg
tablet and a 10 mg tablet. In order for such pharmaceutical
preparations to have stability as described in the Non-patent
document 1, it is considered that the amount of a major
degradation product of solifenacin succinate (hereinafter
referred to as F1) relative to the total amount of the
solifenacin succinate and the degradation products has to be
set to 0.5% or lower, and more preferably, there is a need to
control it at 0.4% or lower including differences and errors
among lots of the products and at the time of testing.
On the other hand, it is known that solifenacin and a
salt thereof has very high solubility in various solvents and
very strong bitterness and astringency. Therefore, in order
to develop a pharmaceutical preparation with high convenience
such as a particle or powder incorporated in a disintegrating
tablet in buccal cavity of solifenacin or a salt thereof, there
is a need to mask the bitterness and astringency. Thus, there
was a need to apply a film-coating method using a polymeric
substrate. More specifically, in the case where a drug
substance is film coated with a polymeric substrate, there is
a need to uniformly coat the surface of the drug substance.
Thus, the drug substance had to be spherical fine particles
with similar particle size.
4

[Patent document 1] EP Patent No. 801067
[Non Patent document 1] PFSB/ELD Notification No.
0624001 "Revision of the Guideline on the Impurities in the
Medicinal Products with New Active Ingredients"
Disclosure of the invention
Problems that the Invention is to Solve
As described above, there was a need to provide a stable
particulate pharmaceutical composition of solifenacin or a
salt thereof, which is in a spherical shape suitable for film
coating and in which degradation with time can be inhibited
when a pharmaceutical preparation of solifenacin or a salt
thereof is supplied to clinical fields.
Means for Solving the Problems
Upon developing solifenacin succinate as an excellent
therapeutic agent for frequent urination or urinary-
incontinence, the present inventors coated drug substances
with a standard binder (polyvinylpyrrolidone (hereinafter
abbreviated as PVP) or hydroxypropylmethyl cellulose
(hereinafter abbreviated as HPMC)), which a person skilled in
the art generally conducts by the fluidized-bed granulation
method or the like, and conducted a preliminary stability test
for the resulting pharmaceutical preparations for over 2 months
under accelerated test conditions (conditions of 40°C, 75% RH
(relative humidity) and in an airtight bottle), which is one
5

of the standard stability tests. As a result, a decrease in
the residual ratio of solifenacin succinate was observed, and
it was indicated that at 6 months after the initiation of
storage, which is the time of the final determination in the
accelerated test, the ratio of the production amount of F1 (the
oxidized form of the solifenacin succinate) to the total amount
of the solifenacin succinate and degradation products exceeds
0.4% (for more details, refer to the following Table 1). It
was found that it is difficult to obtain a pharmaceutical
preparation having a pharmaceutically sufficient stability by
such a standard formulation method.
At such a technical level, the present inventors have
made intensive studies for stabilizing a pharmaceutical
preparation of solifenacin, and as a result, they found beyond
expectation that solifenacin in an amorphous form formed in
the production process of the pharmaceutical preparation is
the major cause of degradation of the active ingredient with
time, and the use of a standard binder such as HPMC is largely
associated with the formation of the amorphous form of
solifenacin.
To obtain a granular substance in which the bitterness
and astringency of solifenacin are masked, the present inventor
considered that a method in which a fine particle (particulate
pharmaceutical composition) is prepared by spraying a solution
of drug substance on a core particle composed of, for example,
6

crystalline cellulose, and the fine particle is film coated
with an appropriate polymeric substance is effective. To
prepare such a fine particle, it is necessary to perform
spraying after solifenacin or a salt thereof is dissolved once,
however, it was found that solifenacin is liable to be
amorphized at this time, and further, a problem specific to
solifenacin that degradation products occur when it is
converted from the amorphous form to the crystalline form
arises. That is, in the case where a particulate
pharmaceutical composition is produced after a part of or the
whole of solifenacin is dissolved in a solvent, it was found
that it is very difficult to ensure the stability of
solifenacin.
Under such circumstances, the present inventors first
found that when a substance having an ethylene oxide chain such
as polyethylene glycol (another name: macrogol, hereinafter
sometimes abbreviated as PEG) is used as a binder, a
pharmaceutical preparation in which degradation of
solifenacin with time can be inhibited by inhibiting the
retention of an amorphous form of solifenacin is produced
beyond expectation although PEG itself is a substance which
is generally used for the purpose of amorphizing a drug
substance.
Further, upon developing and producing a stable
particulate pharmaceutical composition of solifenacin or a
7

salt thereof suitable for film coating, the present inventors
came up with the idea that, for example, in the case where
dissolved solifenacin is sprayed on a core particle together
with a polymeric substance (binder) such as PEG, whether or
not the solifenacin can retain an amorphous form after the
spraying may depend on the fluidity of solifenacin in the
polymeric substance (binder). Therefore, they made intensive
studies and paid attention on physical values (a glass
transition point (hereinafter abbreviated as Tg) or a melting
point (hereinafter abbreviated as mp) ) specific to a polymer
that may affect the fluidity of the drug substance as for a
binder to be used in spraying the core particle. As a result,
they found that when a binder having a high Tg was used for
the particulate pharmaceutical composition, the initial value
for a related substance, which becomes a degradation index,
was low, however, as for the stability thereafter, it was
unstable. On the other hand, when a specific binder having
a Tg lower than a given value was used for the particulate
pharmaceutical composition, they found beyond expectation
that the initial value for a related substance and the value
for a related substance generated thereafter were both low and
stable, and moreover, the particle size was uniform and
spherical, which is suitable for film coating.
Further, as a result of intensive studies, they found
that when a crystallization-promoting treatment such as a
8

humidification and drying treatment is performed, a more stable
particulate pharmaceutical composition is produced, thus the
present invention has been completed.
That is, the present invention relates to:
1. a stable particulate pharmaceutical composition,
comprising solifenacin or a salt thereof and a binder having
an action of stabilizing solifenacin or a salt thereof;
2. the pharmaceutical composition according to the above
1, wherein the binder having an action of stabilizing
solifenacin or a salt thereof is a binder having an action of
inhibiting retention of an amorphous form of solifenacin or
a salt thereof;
3. the pharmaceutical composition according to the above
1 or 2, characterized in that the binder is a binder having
a glass transition point or melting point is lower than 174°C;
4. the pharmaceutical composition according to the above
3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, polyethylene
oxide, a polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl
cellulose, methacrylic acid copolymer L, methacrylic acid
copolymer LD, methacrylic acid copolymer S, cornstarch,
aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate
copolymer RS and maltose;
5. the pharmaceutical composition according to the above
9

3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose and maltose;
6. the pharmaceutical composition according to the above
3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer and
hydroxypropyl cellulose;
7. a stable particulate pharmaceutical composition of
solifenacin or a salt thereof, which can be obtained by using
a mixture in which solifenacin or a salt thereof and a binder
having an action of stabilizing solifenacin or a salt thereof
are codissolved and/or suspended;
8. the pharmaceutical composition according to the above
7, wherein the binder having an action of stabilizing
solifenacin or a salt thereof is a binder having an action of
inhibiting retention of amorphous form of solifenacin or a salt
thereof;
9. the pharmaceutical composition according to the above
7 or 8, characterized in that the binder is a binder having
a glass transition point or melting point is lower than 174°C;
10. the pharmaceutical composition according to the
above 9, wherein the binder is one or more substances selected
from the group consisting of polyethylene glycol, polyethylene
10

oxide, a polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl
cellulose, methacrylic acid copolymer L, methacrylic acid
copolymer LD, methacrylic acid copolymer S, cornstarch,
aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate
copolymer RS and maltose;
11. the pharmaceutical composition according to the
above 9, wherein the binder is one or more substances selected
from the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose and maltose;
12. the pharmaceutical composition according to the
above 9, wherein the binder is one or more substances selected
from the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer and
hydroxypropyl cellulose;
13. the pharmaceutical composition according to any one
of the above 1 to 12, the stability of which is enhanced by
further performing a crystallization-promoting treatment; and
14 . a disintegrating tablet in buccal cavity, comprising
the pharmaceutical composition according to any one of the
above 1 to 13.
In general, as an index of fluidity, thermodynamic
parameters specific to a substance such as a glass transition
point (Tg, unit: °C) or a softening point (unit: °C) based on
11

an amorphous region in a polymer and a melting point (mp, unit:
°C) based on a crystalline region in a polymer are used in many
cases. These values indicate temperature showing a change in
the thermodynamic state of a substance, however, because the
molecular motion is suppressed at a temperature lower than Tg,
the substance is in a state close to a crystalline state or
a glass state, whereby the plasticity is liable to decrease.
However, when the temperature of the substance is Tg or higher,
the degree of the activity of the molecule increases, whereby
the substance is in a rubber like state and the flexibility
increases. Further, a state in which by an increase in the
temperature, a crystalline region of a polymer is degraded to
exhibit fluidity means melting of the polymer. By taking this
into consideration, when a drug substance in an amorphous state
exists in a polymer at a certain temperature, the higher the
Tg of the polymer is, the more difficult the polymer itself
flows. Therefore, it is liable to exist in an amorphous form,
which is in an initial state, and on the contrary, it means
that the lower the Tg of the polymer is, the sooner the crystal
is deposited (Int. J. Pharm. 282 (2004) 151-162). On the other
hand, as for a low-molecular compound, because the structure
of the substance is crystalline, it does not have a Tg in many
cases, therefore, in terms of a parameter showing a change in
the thermal mobility, a melting point was used as an index for
a low-molecular compound. As for a polymer, Tg, which is a
12

temperature at which the change appears faster, was used.
Further, the present invention relates to:
15 . a method of stabilizing solifenacin or a salt thereof
by subjecting a pharmaceutical composition comprising
solifenacin or a salt thereof and a binder having an action
of stabilizing solifenacin or a salt thereof to a
crystallization-promoting treatment; and
16. a method of transferring an amorphous form of
solifenacin or a salt thereof to a crystalline form thereof
by subjecting a stable particulate composition comprising
solifenacin or a salt thereof and a binder having an action
of stabilizing solifenacin or a salt thereof to a
crystallization-promoting treatment.
Hereinafter, the composition of the present invention
will be described in detail.
Examples of the "salt of solifenacin" to be used in the
present invention include solifenacin hydrochloride described
in the Patent document 1, acid addition salts with mineral acids
such as hydrobromic acid, hydriodic acid, sulfuric acid, nitric
acid and phosphoric acid or with organic acids such as formic
acid, acetic acid, propionic acid, oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, lactic acid, malic
acid, citric acid, tartaric acid, carbonic acid, picric acid,
methanesulfonic acid, ethanesulfonic acid and glutamic acid,
and quaternary ammonium salts. Among these, solifenacin
13

succinate is preferred in consideration of being provided as
a pharmaceutical product.
The "solifenacin or a salt thereof" to be used in the
present invention can be easily obtained by or in accordance
with the method described in the Patent document 1 or by a
standard method.
The "crystal" or the "crystalline form" of solifenacin
or a salt thereof means a literal interpretation of a substance
of solifenacin or a salt thereof having a crystallographically
crystalline structure. However, in the present invention, it
means a substance different from an "amorphous form" which
shows significant degradability with time of solifenacin when
it is contained in an amount within the range which exerts no
influence on the stability of the product in the pharmaceutical
preparation. On the other hand, the "amorphism" or the
"amorphous form" of solifenacin or a salt thereof in the present
invention means a substance having a crystallographically
amorphous structure. However, in the present invention, it
means a substance different from a "crystal" or a "crystalline
form" which shows extremely little degradability with time of
solifenacin when it is contained in an amount exceeding the
range which exerts no influence on the stability of the product
in the pharmaceutical preparation.
The mixing amount of solifenacin or a salt thereof to
be used in the present invention is generally selected suitably
14

according to the type of drug substance or the medicinal use
thereof (indication), however, it is not particularly limited
as long as it is a therapeutically effective amount or a
prophylactically effective amount. Specifically, it is from
0.01 mg to 100 mg, preferably from 0.5 mg to 50 mg, more
preferably from 0.5 mg to 10 mg, and most preferably from 0.5
mg to 4 mg in terms of the daily amount of solifenacin or a
salt thereof.
Further, the mixing amount of solifenacin or a salt
thereof in the disintegrating tablet in buccal cavity of the
present invention may be any as long as an effective amount
per administration unit of the pharmaceutical preparation is
contained, however, it is preferably from 0.001% by weight to
97% by weight, more preferably from 0.05% by weight to 50% by
weight, further more preferably from 0.05% by weight to 10%
by weight, and most preferably from 0.05% by weight to 4% by
weight.
The "binder having an action of stabilizing solifenacin
or a salt thereof" to be used in the present invention means
a binder that can inhibit degradation with time of solifenacin
or a salt thereof, and specifically means a binder that can
inhibit degradation with time of solifenacin or a salt thereof
by the action of inhibiting retention of an amorphous form.
In addition, in the case where a binder that does not have an
action of stabilizing solifenacin or a salt thereof alone, for
15

example, even a binder such as HPMC or PVP, is used together
with the binder to be used in the present invention for the
purpose of enhancing the action as a binder, it can be used
in an amount within the range which does not exceed the
specification setting of the stability of the pharmaceutical
preparation, which is an object of the present invention.
The "action of inhibiting retention of an amorphous form"
as used in the present invention refers to an action of making
the compound difficult to exist in an amorphous state and/or
an action capable of making the compound easy to be transformed
from the amorphous form to the crystalline form.
Further, the binder having an action of stabilizing
solifenacin or a salt thereof or an action of inhibiting
retention of an amorphous form to be used in the present
invention is a binder capable of reducing the amount of F1 of
solifenacin to 0.5% or lower, more preferably a binder capable
of reducing the amount of Fl to 0.4% or lower. Specifically,
it is a binder having a Tg or mp lower than 174°C, preferably
a binder having a Tg or mp of 0°C or higher and lower than 174°C,
more preferably a binder having a Tg or mp of 0°C or higher
and lower than 156°C, further more preferably a binder having
a Tg or mp of 0°C or higher and lower than 137°C, and most
preferably a binder having a Tg or mp of 10°C or higher and
lower than 137°C. The specific type as the binder is not
particularly limited as long as it has a Tg of above-mentioned
16

range, however, preferred examples thereof include a substance
having an ethylene oxide chain, hydroxypropyl cellulose,
hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol,
a methacrylic acid copolymer, an aminoalkyl methacrylate
copolymer, a starch and maltose. However, from the viewpoint
of the production process, among the above-mentioned binders,
polyvinyl alcohol, a methacrylic acid copolymer, an aminoalkyl
methacrylate copolymer and a starch have a weak binding force,
therefore, it is considered that coating of a particle is
difficult. Accordingly, it is more preferably a substance
having an ethylene oxide chain such as PEG, polyethylene oxide
or a polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose or maltose,
further more preferably PEG, a polyoxyethylene/
polyoxypropylene block copolymer or hydroxypropyl cellulose,
particularly preferably PEG or hydroxypropyl cellulose, and
most preferably PEG. As for such a binder, the molecular weight
type, the degree of polymerization or the like is not
particularly limited as long as the object of the present
invention to inhibit the amorphization of solifenacin or a salt
thereof can be attained by the addition of the binder. However,
as for the molecular weight type, the weight average molecular
weight is preferably within the range from 400 to 1,000,000,
and more preferably the weight average molecular weight is
within the range from 2,000 to 200,000. In addition, the
17

binders described above can be used in combination of two or
more types.
The substance having an ethylene oxide chain as used
herein is not particularly limited as long as it has an ethylene
oxide chain. The molecular weight type thereof, the degree
of polymerization thereof or the like is not particularly
limited as long as the object of the present invention to
inhibit the amorphization of solifenacin or a salt thereof can
be attained by the addition of the substance. However, as for
the molecular weight type, the weight average molecular weight
is preferably within the range from 400 to 1, 000, 000, and more
preferably, the weight average molecular weight is within the
range from 2,000 to 200, 000. The substances having an ethylene
oxide chain may be used alone or by mixing two or more types.
In the present invention, specific examples of the substance
having an ethylene oxide chain include PEG, polyethylene oxide,
a polyoxyethylene/polyoxypropylene block copolymer and the
like. However, in the present invention, among these, PEG and
a polyoxyethylene/polyoxypropylene block copolymer are
preferred, and PEG is particularly preferred. As the PEG, PEG
in a solid form at normal temperature is preferred. Specific
examples include Macrogol 4000 (Japanese Pharmacopoiea,
molecular weight: from 2,600 to 3,800, brand name: Macrogol
4000/ Sanyo Chemical Industries, Ltd., NOF Corporation, Lion
Corporation, and the like), Macrogol 6000 (Japan
18

Pharmaceopoiea, molecular weight: from 7,300 to 9,300, brand
name: Macrogol 6000/ Sanyo Chemical Industries, Ltd., NOF
Corporation, Lion Corporation, and the like), Macrogol 20000
(Japan Pharmacopoeia, molecular weight: from 15, 000 to 25, 000,
brand name: Macrogol 20000/ Sanyo Chemical Industries, Ltd.,
NOF Corporation, Lion Corporation, and the like) , polyethylene
glycol 8000 (USP/ NF, molecular weight: from 7,000 to 9,000,
brand name: Polyethylene glycol 8000/ The Dow Chemical Company,
and the like), and the like. The weight average molecular
weight of PEG is preferably within the range from 400 to 40, 000,
more preferably within the range from 2,000 to 25,000, and
further more preferably within the range from 2, 000 to 10, 000.
The polyoxyethylene/polyoxypropylene block copolymer of
the present invention is a copolymer of propylene oxide and
ethylene oxide, and various types exist depending on the
composition ratio thereof, however, it may has a composition
ratio so as to have a property of inhibiting the amorphization
of solifenacin or a salt thereof. Specifically,
polyoxyethylene (105) polyoxypropylene (5) glycol,
polyoxyethylene (160) polyoxypropylene (30) glycol (another
name: Pluronic F68) or the like is used.
The "mixture in which solifenacin or a salt thereof and
a binder having an action of stabilizing solifenacin or a salt
thereof are codissolved and/or suspended" as used in the
present invention means a mixture in which a binder having an
19

action of stabilizing solifenacin or a salt thereof is
dissolved together with a solution obtained by dissolving
solifenacin or a salt thereof in a solvent such as water.
However, it is not always necessary that the whole of
solifenacin or a salt thereof be dissolved in a solvent, and
as long as a particle containing a drug substance suitable for
coating such as masking of bitterness, which is performed
thereafter, can be obtained with the resulting mixture, such
a mixture to given a particle obtained by using the mixture
in a suspended state in which a part of solifenacin or a salt
thereof is dissolved in a solvent is also included.
The composition, which "can be obtained by using" a
mixture in which solifenacin or a salt thereof and a binder
having an action of stabilizing solifenacin or a salt thereof
are codissolved, in the present invention is a particle
containing a drug substance suitable for coating such as
masking of bitterness . Examples thereof include a composition
obtained by spray coating a core particle of such as crystalline
cellulose with a drug substance in a solution form, a
composition that can be obtained not by spraying a drug
substance in a liquid form, but by mixing a mixture obtained
by codissolving these substances with an insoluble core
particle and depositing the drug substance to arrange the drug
substance uniformly around the insoluble core particle, and
the like. Further, examples of a product prepared by a method
20

without using a core particle include a powder itself obtained
by spray-drying or freeze-drying a solution of a drug substance
and a binder, and such a powder can be used for a particle
containing a drug substance to be used for masking bitterness
or the like. However, in view of the production efficiency,
a composition that can be obtained by spray-coating a core
particle with a mixture in which solifenacin or a salt thereof
and a binder having an action of stabilizing solifenacin or
a salt thereof are codissolved is preferred.
The "stable particulate pharmaceutical composition" as
used in the present invention is a particle that can be obtained
by using solifenacin or a salt thereof or the like, and is not
particularly limited as long as it is a stable particle in which
degradation with time is inhibited. The term "stable" as used
herein specifically means a particle in which the production
amount of Fl of solifenacin or a salt thereof is 0.5% or lower,
more preferably 0.4% or lower. Further, in the case where the
pharmaceutical composition of the present invention is a
particle such as a granule, the particle size of the particulate
pharmaceutical composition is not particularly limited as long
as the longest diameter is 2 mm or less. As for the case where
it is incorporated in a disintegrating tablet in buccal cavity,
the particle size is not particularly limited as long as there
is not an unpleasant gritty sensation like sand when it is taken,
however, it is preferably prepared at an average particle size
21

of 350 μm or less. The more preferred average particle size
is from 1 to 350 μm, and the particularly preferred average
particle size is from 20 to 350 μm. In view of the particle
size distribution, it is not particularly limited as long as
it is a particle suitable for coating such as masking of
bitterness, however, preferably, 80% of the total weight is
distributed between 1 and 350 μm, more preferably 80% of the
total weight is distributed between 50 and 300 μm, and
particularly preferably 80% of the total weight is distributed
between 100 and 250 μm.
Further, the shape of the particulate composition of the
present invention is not particularly limited as long as it
is in a state where coating such as masking of bitterness can
be performed, however, in terms of the coating efficiency, it
is preferably in a spherical shape, that is, the sphericity
thereof is preferably as close to 1 as possible.
In the case where the particulate pharmaceutical
composition of the present invention is a granule, the mixing
amount of the binder in the particulate pharmaceutical
composition is not particularly limited as long as it is an
amount that enables the coating with solifenacin or a salt
thereof and attains the object of the present invention.
However, it is preferably from 0.01 to 91% by weight, and more
preferably from 0.5 to 75% by weight of the total particulate
pharmaceutical composition. The most preferred mixing amount
22

is from 5 to 50% by weight. Further, by taking the mixing amount
of the binder in the case where the pharmaceutical composition
of the present invention is a particle such as a granule into
consideration relative to the 1 part by weight of solifenacin
or a salt thereof in a crystalline form and an amorphous form,
it is preferably at a ratio ranging from 1 to 1,000% by weight,
more preferably at a ratio ranging from 5 to 500% by weight,
and further more preferably at a ratio ranging from 10 to 100%
by weight.
The particulate pharmaceutical composition of the
present invention is prepared with solifenacin or a salt
thereof in a solution state. However, in the case where a core
particle is spray coated with a solifenacin solution, examples
of the core particle include sodium chloride, microcrystalline
cellulose, calcium carbonate, lactose, maltose and mannitol,
and preferred examples thereof include microcrystalline
cellulose, lactose, mannitol and the like. More preferred are
microcrystalline cellulose and lactose. In the present
invention, among a group of these substances, one type or two
or more types can be used in combination.
Further, the crystallization-promoting treatment as
used herein is not particularly limited as long as it is a
treatment of promoting crystallization, and examples thereof
include a humidification treatment, a microwave irradiation
treatment, an ultrasonic irradiation treatment, a
23

low-frequency irradiation treatment, a thermal electron
irradiation treatment and the like. Further, the
humidification treatment refers to a treatment in which, for
example, a humidification treatment at a temperature of from
20 to 30°C and at a humidity of from 60 to 85% RH for 6 to 24
hours is carried out, and then drying at a temperature of from
30 to 40°C and at a humidity of from 30 to 40% RH for 2 to 6
hours is carried out. The microwave irradiation treatment
cannot be limited in general, however, for example, a microwave
with a wavelength of from 10 MHz to 25 GHz can be used. Further,
the treatment time depends on the degree of crystallization
at an initial stage and a selected base material, however, for
example, the treatment can be carried out for 10 seconds to
60 minutes. The irradiation per se may be carried out
continuously or intermittently, and at any timing after any
particulate composition is produced.
The ultrasonic irradiation treatment cannot be limited
in general, however, for example, an ultrasonic wave with a
frequency of from 10 kHz to 600 kHz can be used. Further, the
treatment time depends on the degree of crystallization at an
initial stage and a selected base material, however, for
example, the treatment can be carried out for 10 seconds to
24 hours. The irradiation per se may be carried out
continuously or intermittently, and at any timing after any
particulate composition is produced.
24

As the crystallization-promoting treatment, a
humidification treatment, a microwave irradiation treatment
and an ultrasonic irradiation treatment are preferred.
In the particulate pharmaceutical composition of the
present invention, any of a variety of pharmaceutical
excipients is suitably used and formulated into a
pharmaceutical preparation. Examples of such a
pharmaceutical excipient include lactose and the like.
Further, another additive can be used within the range that
does not impair the object of the present invention as long
as it is a pharmaceutically and pharmacologically acceptable
one. For example, a disintegrating agent, an acidifier, a
foaming agent, an artificial sweetener, a flavor, a lubricant,
a coloring agent, a stabilizing agent, a buffering agent, an
antioxidant, a surfactant or the like can be used, and there
is no particular limitation. Examples of the disintegrating
agent include cornstarch, potato starch, carmellose calcium,
carmellose sodium, low-substitution degree hydroxypropyl
cellulose and the like. Examples of the acidifier include
citric acid, tartaric acid, malic acid and the like. Examples
of the foaming agent include sodium bicarbonate and the like.
Examples of the artificial sweetener include saccharin sodium,
dipotassium glycyrrhizinate, aspartame, stevia, somatin and
the like. Examples of the flavor include lemon, lemon-lime,
orange, menthol and the like. Examples of the lubricant
25

include magnesium stearate, calcium stearate, a sucrose fatty-
acid ester, talc, stearic acid and the like. Examples of the
coloring agent include yellow iron sesquioxide, red iron
sesquioxide, food yellow No. 4 and No. 5, food red No. 3 and
No. 102, food blue No. 3 and the like. Examples of the buff ering
agent include citric acid, succinic acid, fumaric acid,
tartaric acid, ascorbic acid or a salt thereof, glutamic acid,
glutamine, glycine, asparatic acid, alanine, arginine, or a
salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide,
phosphoric acid, boric acid or a salt thereof and the like.
Examples of the antioxidant include ascorbic acid, sodium
nitrite, sodium sulfite, sodium hydrogen sulfite, sodium
edetate, erythorbic acid, tocopherol acetate, tocopherol,
butylhydroxyanisol, dibutylhydroxytoluene, propyl gallate
and the like. Examples of the surfactant include sodium lauryl
sulfate, a polyoxyethylene sorbitan fatty acid ester
(polysorbate 80) , polyoxyethylene hydrogenated castor oil and
the like. As for the pharmaceutical excipient, the
above-mentioned substances can be suitably added alone or in
combination of two or more types in an appropriate amount.
The "content of the amorphous form" as used in the present
invention means the ratio relative to the total of the amorphous
form and the crystalline form of solifenacin or a salt thereof.
Examples of the pharmaceutical preparation using the
above-mentioned particle include a powder, a granule, a pill,
26

a tablet, a capsule, an disintegrating tablet in buccal cavity,
a dry syrup and the like, however, particularly, an
disintegrating tablet in buccal cavity is preferred.
Hereinafter, a disintegrating tablet in buccal cavity
containing the particulate pharmaceutical composition of the
present invention will be described.
The "disintegrating tablet in buccal cavity" in the
present invention means a tablet which is disintegrated in the
buccal cavity with substantially saliva only within 2 minutes,
preferably within 1 minute, more preferably within 30 seconds
in the case where the tablet is taken without having any water,
and a pharmaceutical preparation similar to the tablet.
The particulate pharmaceutical composition of the
present invention can be incorporated in such a disintegrating
tablet in buccal cavity, for example, a disintegrating tablet
in buccal cavity can be prepared by applying the particulate
pharmaceutical composition as the drug substance of a known
disintegrating tablet in buccal cavity described in any of
International Publication No. 95-20380 (corresponding to US
Patent No. 5576014), International Publication No. 2002-92057
(corresponding to US Patent Application Publication No.
2003/099701), US Patent No. 4305502, US Patent No. 4371516,
Japanese Patent No. 2807346 (corresponding to US Patent No.
5466464), JP-A-5-271054 (corresponding to European Patent No.
553777), JP-A-10-182436 (corresponding to US Patent No.
27

5958453), Japanese Patent No. 3412694 (corresponding to US
Patent No. 5223264) and International Publication No. WO
98/02185 (corresponding to US Patent No. 6287596), using the
base material of a disintegrating tablet in buccal cavity
described in any of the publications, and following the method
described in any of the publications. In this way, as the
disintegrating tablet in buccal cavity containing the
particulate pharmaceutical composition, the disintegrating
tablets in buccal cavity described in Japanese Patent No.
3412694 (corresponding to US Patent No. 5223264) and
JP-A-2003-55197 can be exemplified, and the particulate
pharmaceutical composition of the present invention can be
incorporated in such a disintegrating tablet in buccal cavity.
In general, the disintegrating tablet in buccal cavity
as illustrated above is classified roughly into a mold type,
a humidified type and a standard tablet type, and the
particulate pharmaceutical composition of the present
invention may be incorporated in any type of disintegrating
tablet in buccal cavity. The mold type of disintegrating
tablet in buccal cavity is prepared, for example, by filling
a mold with a solution or suspension of such as an excipient
and drying it as disclosed in Japanese Patent No. 2807346
(corresponding to US Patent No. 5466464). The mold type of
disintegrating tablet in buccal cavity containing the
particulate pharmaceutical composition of the present
28

invention can be prepared, for example, by filling a blister
package with a solution or suspension of the particulate
pharmaceutical composition of the present invention, an
excipient such as a saccharide and a binder such as gelatin
or agar and removing moisture by a method such as f reeze-drying,
reduced-pressure drying or low-temperature drying. The
humidified type of disintegrating tablet in buccal cavity is
prepared by humidifying an excipient such as a saccharide, and
performing tableting at a low pressure and then drying it as
described in Japanese Patent No. 3069458 (corresponding to US
Patent No. 5501861 and US Patent No. 5720974). Therefore, for
example, the particulate pharmaceutical composition of the
present invention and an excipient such as a saccharide are
humidified with a small amount of water or a mixed solution
of water and an alcohol, and the resulting humidified mixture
is molded at a low pressure, and then drying the molded mixture,
whereby the humidified type of disintegrating tablet in buccal
cavity can be prepared.
In the case of the standard tablet type, it is prepared
through a standard tableting step as disclosed in International
Publication No. 95-20380 (corresponding to US Patent No.
5576014), International Publication No. 2002-92057
(corresponding to US Patent Application Publication No.
2003/099701), JP-A-10-182436 (corresponding to US Patent No.
5958453), JP-A-9-48726, JP-A-8-19589 (corresponding to US
29

Patent No. 5672364), Japanese Patent No. 2919771, and Japanese
Patent No. 3069458 (corresponding to US Patent No. 5501861 and
US Patent No. 5720974). In order to prepare the standard tablet
type of disintegrating tablet in buccal cavity containing the
particulate pharmaceutical composition of the present
invention, for example, the particulate pharmaceutical
composition of the present invention and an excipient such as
a saccharide with low moldability are granulated by using a
solution or suspension of a saccharide with high moldability
or a water-soluble polymer, and then the resulting granulated
substance is compression molded to form a compression-molded
substance, or further the resulting compression-molded
substance is subjected to humidification and drying, whereby
the disintegrating tablet in buccal cavity can be prepared as
disclosed in International Publication No. 95-20380
(corresponding to US Patent No. 5576014) and Japanese Patent
No. 2919771. Further, in order to prepare the standard tablet
type of disintegrating tablet in buccal cavity as shown in
International Publication No. 99-47124 (corresponding to US
Patent No. 6589554), for example, the particulate
pharmaceutical composition of the present invention and an
excipient such as a crystalline saccharide are compression
molded by using an amorphous saccharide, and the resulting
substance is subjected to humidification and drying, whereby
the disintegrating tablet in buccal cavity can be prepared.
30

Further, in order to prepare the standard tablet type of
disintegrating tablet in buccal cavity as disclosed in
International Publication No. 2002-92057 (corresponding to US
Patent Application Publication No. 2003/099701), for example,
a mixture of the particulate pharmaceutical composition of the
present invention and an excipient with a saccharide with a
melting point lower than that of the excipient is compression
molded, and the resulting substance is heated to form a
cross-linkage by the melt-solidified product of the saccharide
with a lower melting point, whereby the disintegrating tablet
in buccal cavity can be prepared. By the humidification and
drying or the heating treatment as described above, the tablet
strength of such a disintegrating tablet in buccal cavity can
be improved.
As the excipient to be used in the disintegrating tablet
in buccal cavity of the present invention, a standard excipient
can also be used, however, particularly, a pharmaceutically
acceptable saccharide is preferably used. In a technique
utilizing the moldability of a saccharide, a saccharide with
low moldability can be used. When a technique for improving
the tablet strength by the crystalline/amorphous property of
a saccharide and humidification and drying is used, a
crystalline saccharide can be used. When a technique for
forming a cross-linkage by the melt-solidified product of a
saccharide is used, a saccharide with a high melting point can
31

be used in addition to a standard excipient.
The "saccharide with low moldability" means a saccharide
that provides a tablet hardness of from 0 to 2 kp when, for
example, 150 mg of the saccharide is tableted at a tableting
pressure of from 10 to 50 kg/cm2 using a punch with a diameter
of 8 mm. The "saccharide with high moldability" means a
saccharide that provides a tablet hardness of 2 kp or greater
by the same method. The saccharide with low moldability is
a pharmaceutically acceptable one, and examples thereof may
include lactose, mannitol, glucose, sucrose, xylitol,
erythritol and the like. These saccharides can be used alone
or by suitably combining two or more types. The saccharide
with high moldability is a pharmaceutically acceptable one,
and examples thereof may include maltose, maltitol, sorbitol,
trehalose and the like. Also, these saccharides can be used
alone or by suitably combining two or more types.
The "crystalline saccharide" is a pharmaceutically
acceptable one, and examples thereof may include mannitol,
maltitol, erythritol, xylitol and the like. These saccharides
can be used alone or by suitably combining two or more types.
The "amorphous saccharide" is a pharmaceutically acceptable
one, and examples thereof may include lactose, sucrose, glucose,
sorbitol, maltose, trehalose and the like. Also, these
saccharides can be used alone or by suitably combining two or
more types.
32

Further, an "excipient with a melting point higher than
that of a saccharide with a low melting point" is a
pharmaceutically acceptable one, and can be selected from, for
example, xylitol, trehalose, maltose, sorbitol, erythritol,
glucose, sucrose, maltitol, mannitol and the like. These
saccharides can be used alone or by suitably combining two or
more types. The "saccharide with a low melting point" is a
pharmaceutically acceptable one, and can be selected from, for
example, xylitol, trehalose, maltose, sorbitol, erythritol,
glucose, sucrose, maltitol, mannitol and the like. Also,
these saccharides can be used alone or by suitably combining
two or more types. As the binder for the disintegrating tablet
in buccal cavity, maltitol, copolyvidone, erythritol and the
like can be exemplified. Also, these binders can be used alone
or by suitably combining two or more types.
When a water-soluble polymer is used in place of a
saccharide with high moldability, preferred are, for example,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
povidone, polyvinyl alcohol, gum arabic powder, gelatin,
purulan, and the like.
The mixing amount of the excipient to be used in the
disintegrating tablet in buccal cavity containing the
particulate pharmaceutical composition of the present
invention is suitably adjusted according to the mixing amount
of the particulate pharmaceutical composition of the present
33

invention and/or the size of the tablet and the like, however,
it is preferably from 20 to 1000 mg in general, more preferably
from 50 to 900 mg and particularly preferably from 100 to 800
mg per tablet.
Further, the mixing amount of the saccharide with high
moldability, the water-soluble polymer, the amorphous
saccharide, or the saccharide with a low melting point is not
particularly limited as long as is it suitably selected and
used according to the respective techniques, however, it is
preferably from 0.5 to 40% by weight, more preferably from 2
to 30% by weight, and particularly from 5 to 20% by weight of
the weight of the excipient, or it is preferably from 1 to 20%
by weight of the total pharmaceutical preparation.
As for the type of another optional additive, the
formulation or the mixing amount thereof, or the like, the
description of the above-mentioned patent documents for the
disintegrating tablets in buccal cavity is cited as the
description of this specification.
Further, in the case where the particulate
pharmaceutical composition of the present invention is
incorporated in the disintegrating tablet in buccal cavity,
the particulate pharmaceutical composition can be
incorporated in an amount corresponding to 0 . 5 to 90% by weight,
preferably 1 to 80% by weight, and more preferably 5 to 60%
by weight of the total disintegrating tablet in buccal cavity.
34

Hereinafter, a process for producing the particulate
pharmaceutical composition of the present invention will be
described.
In order to obtain the particulate pharmaceutical
composition of the present invention, solifenacin or a salt
thereof and a binder having an action of stabilizing
solifenacin or a salt thereof are dissolved or suspended by
agitation in water or a mixed solution obtained by adding an
organic solvent such as ethanol to water using a stirrer,
whereby a drug substance solution is prepared. In this case,
water or the organic solvent contained in the drug substance
solution can be appropriately set. As a technique for
powderization (granulation) of the drug substance solution of
solifenacin or a salt thereof, for example, a freeze-drying
method, a spray-drying method, a high-shared agitation
granulation method, a fluidized bed granulation method, a
tumbling granulation method and the like can be exemplified.
As long as the method enables the powderization (granulation)
of solifenacin after it is dissolved, both the device and the
technique are not particularly limited, however, particularly
preferred are a spray-drying method and a fluidized bed
granulation method. Specifically, an appropriate additive
particle (for example, crystalline cellulose (particle), a
purified sucrose spherical granule, a sucrose starch spherical
granule or the like) to be a core is spray coated with the drug
35

substance solution, whereby the particulate composition of the
present invention can be obtained.
As the device to be used upon the spray coating, for
example, a fluidized bed granulator (FLO-1, manufactured by
Glatt Co., Ltd.), a spray dryer (DL41, manufactured by Yamato
Scientific Co. Ltd.) and the like can be exemplified.
Hereinafter, a process for producing the disintegrating
tablet in buccal cavity containing the particulate
pharmaceutical composition of the present invention will be
described.
When the case of the disintegrating tablet in buccal
cavity described in International Publication No. 95-20380
(corresponding to US Patent No. 5576014) is cited, the steps
of mixing the particulate pharmaceutical composition of the
present invention and a saccharide with low moldability;
spraying the resulting mixture using a saccharide with high
moldability as a binder to perform coating and/or granulation;
and subjecting the resulting granulated matter to compression
molding can be adopted. Further, in order to heighten the
hardness of the prepared molded matter, humidification and
drying steps can be adopted. The "humidification" is
determined by the apparent critical relative humidity of the
saccharide to be contained, but it is humidified generally to
the critical relative humidity or higher. For example, the
humidity is from 30 to 100 RH %, preferably from 50 to 90 RH %.
36

In this case, the temperature is preferably from 15 to 50°C,
more preferably from 20 to 40°C. The treating time is from 1
to 36 hours, preferably from 12 to 24 hours. The "drying" is
not particularly limited as long as it is a step of removing
moisture absorbed by the humidification. For example, as a
drying temperature condition, it can be set to 10 to 100°C,
preferably 20 to 60°C, more preferably 25 to 40°C. The treating
time can be set to 0.5 to 6 hours, preferably 1 to 4 hours.
In the case of the disintegrating tablet in buccal cavity
described in International Publication No. 2002-92057
(corresponding to US Patent Application Publication No.
2003/099701), the particulate pharmaceutical composition of
the present invention, an excipient with a high melting point
and a saccharide with a low melting point are mixed, and the
resulting mixture is sprayed by using a binder for
disintegrating tablet in buccal cavity to perform coating
and/or granulation, and then, the granulated matter can be
subjected to compression molding. As the spraying condition,
for example, when a fluidized bed granulator (FLO-1,
manufactured by Glatt Co., Ltd.) is used, the concentration
of the solution of solifenacin is not limited as long as it
gives a viscosity capable of sending the solution with a pump,
however, it is preferably from 0.01 to 30% (w/w) in terms of
the solid content concentration. The spraying rate is not
limited as long as spray drying can be done, however, it is
37

preferably from 0.1 to 20 g/min. The spraying temperature is
not particularly limited as long as it can be set so as to give
a product temperature of from 10 to 60°C. These spraying
conditions vary depending on the production scale and the type
of device, however, they are not particularly limited as long
as they provide a particulate composition. Further, in the
case where an excipient with a high melting point and a
saccharide with a low melting point are combined, in order to
heighten the hardness of the prepared molded matter, a heating
step can be adopted. The "heating" is determined by the melting
point of the saccharide with a low melting point contained
therein. However, it is generally heated to a temperature not
lower than the melting point of the saccharide with a low
melting point and lower than the melting point of the excipient
with a high melting point. The treating time can be set to
0.5 to 120 minutes, and preferably 1 to 60 minutes.
Further, the method of stabilizing the particulate
pharmaceutical composition of the present invention and the
method of converting an amorphous form of solifenacin or a salt
thereof to a crystalline form in the particulate pharmaceutical
composition of the present invention can be carried out for
the particulate composition of the present invention produced
as described above by using the above-mentioned
crystallization-promoting treatment method.
38

Brief Description of the Drawings
[Fig. 1] Fig. 1 shows the results of powder X-ray
diffraction for solifenacin succinate in a crystalline form;
PEG 8000 (brand name: Macrogol 6000, manufactured by Sanyo
Chemical Industries, Ltd.); a spray-dried product of
solifenacin succinate prepared by using PEG 8000; a spray-dried
product of solifenacin succinate prepared by using HPMC (brand
name: TC-5E, manufactured by Shinetsu Chemical Co. , Ltd. ) ; and
a spray-dried product of solifenacin succinate prepared by
using polyvinylpyrrolidone (brand name: PVP K90, manufactured
by BASF, hereinafter abbreviated as PVP), respectively.
[Fig. 2] Fig. 2 shows the results of powder X-ray
diffraction for a coated product obtained by coating
crystalline cellulose (brand name: Celphere, manufactured by
Asahi Chemical Industry Co., Ltd.) with PEG 8000 (brand name:
Macrogol 6000, manufactured by Sanyo Chemical Industries,
Ltd. ) in Example 3; and a coated product obtained by using HPMC
in Comparative example 1.
[Fig. 3] Fig. 3 shows the relationship between the
production amount of F1, which is a major degradation product
of solifenacin, and the Tg or mp of a binder used in combination
after a two-month storing period (O: without humidification
treatment, •: with humidification treatment).
39

Best Mode for Carrying Out the Invention
A particulate pharmaceutical composition of solifenacin
or a salt thereof in the present invention will be described
in detail. Hereinafter, the present invention will be
described in more detail with reference to Examples and
Comparative examples, however, the present invention is not
construed as being limited to these.
Example 1
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using HPC-SL as a
binder
Ten parts of solifenacin succinate and 3.4 parts of
hydroxypropyl cellulose (brand name: HPC-SL, manufactured by
Nippon Soda Co., Ltd., hereinafter abbreviated as HPC) were
dissolved by agitation in a mixed solution of 26.6 parts of
water and 26.6 parts of methanol using a stirrer (MGM-66,
manufactured by SHIBATA), whereby a drug substance solution
was prepared. Then, 60 parts of crystalline cellulose (brand
name: Celphere, manufactured by Asahi Chemical Industry Co.,
Ltd. ) were put into a fluidized bed granulator (FLO-1,
manufactured by Glatt Co. , Ltd. ) , and Celphere was spray coated
with the drug substance solution at an intake air temperature
of 50°C, an air flow volume of 1.00 m3/min, a binder
solution-spraying rate of 4.0 g/min, and a spraying air
40

pressure of 3. 0 kg/cm2, whereby a particulate composition of
the present invention was obtained.
Example 2
The particulate composition obtained in Example 1 was
subjected to a crystallization treatment by humidification at
25°C and 75% for 12 hours, and then drying at 30°C and 40% for
3 hours, whereby a particulate composition of the present
invention was obtained.
Example 3
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using PEG 6000 as a
binder
Ten parts of solifenacin succinate and 3.4 parts of PEG
(brand name: Macrogol 6000, manufactured by Sanyo Chemical
Industries, Ltd.) were dissolved by agitation in a mixed
solution of 26. 6 parts of water and 26.6 parts of methanol using
a stirrer (MGM-66, manufactured by SHIBATA), whereby a drug
substance solution was prepared. Then, 60 parts of Celphere
(manufactured by Asahi Chemical Industry Co., Ltd.) were put
into a fluidized bed granulator (FLO-1, manufactured by Glatt
Co., Ltd.), and Celphere was spray coated with the drug
substance solution at an intake air temperature of 50°C, an
air flow volume of 0.97 m3/min, a binder solution-spraying rate
of 10 g/min, and a spraying air pressure of 3.0 kg/cm2, whereby
a particulate composition of the present invention was
41

obtained.
Example 4
The particulate composition obtained in Example 3 was
subjected to a crystallization treatment by humidification at
25°C and 75% for 12 hours, and then drying at 30°C and 40% for
3 hours, whereby a particulate composition of the present
invention was obtained.
Example 5
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using maltose as a
binder
Ten parts of solifenacin succinate and 3.4 parts of
maltose (brand name: SunMalto S, manufactured by Sanwa
Cornstarch Co., Ltd.) were dissolved by agitation in a mixed
solution of 26. 6 parts of water and 26. 6 parts of methanol using
a stirrer (MGM-66, manufactured by SHIBATA), whereby a drug
substance solution was prepared. Then, 60 parts of Celphere
(manufactured by Asahi Chemical Industry Co., Ltd.) were put
into a fluidized bed granulator (FLO-1, manufactured by Glatt
Co., Ltd.), and Celphere was spray coated with the drug
substance solution at an intake air temperature of 60°C, an
air flow volume of 0.98 m3/min, a binder solution-spraying rate
of 3. 0 g/min, and a spraying air pressure of 3. 0 kg/cm2, whereby
a particulate composition of the present invention was
obtained.
42

Example 6
The particulate composition obtained in Example 5 was
subjected to a crystallization treatment by humidification at
25°C and 75% for 12 hours, and then drying at 30°C and 40% for
3 hours, whereby a particulate composition of the present
invention was obtained.
Example 7
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using HEC as a binder
Ten parts of solifenacin succinate and 3.4 parts of
hydroxyethyl cellulose (brand name: HEC SE400, manufactured
by Daicel Chemical Industries, Ltd.) were dissolved by
agitation in a mixed solution of 26.6 parts of water and 26.6
parts of methanol using a stirrer (MGM-66, manufactured by
SHIBATA), whereby a drug substance solution was prepared.
Then, 60 parts of Celphere (manufactured by Asahi Chemical
Industry Co., Ltd.) were put into a fluidized bed granulator
(FLO-1, manufactured by Glatt Co., Ltd.), and Celphere was
spray coated with the drug substance solution at an intake air
temperature of 60°C, an air flow volume of 0.98 m3/min, a binder
solution-spraying rate of 3.0 g/min, and a spraying air
pressure of 3.0 kg/cm2, whereby a particulate composition of
the present invention was obtained.
Example 8
The particulate composition obtained in Example 7 was
43

subjected to a crystallization treatment by humidification at
25°C and 75% for 12 hours, and then drying at 30°C and 40% for
3 hours, whereby a particulate composition of the present
invention was obtained.
Example 9
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using Pluronic as a
binder
Ten parts of solifenacin succinate and 3.4 parts of
Pluronic F68 (brand name: Lutrol F68, manufactured by BASF)
were dissolved by agitation in a mixed solution of 26.6 parts
of methanol and 26.6 parts of water using a stirrer (MGM-66,
manufactured by SHIBATA), whereby a drug substance solution
was prepared. Then, 60 parts of crystalline cellulose (brand
name: Celphere, manufactured by Asahi Chemical Industry Co.,
Ltd.) were put into a fluidized bed granulator (FLO-1,
manufactured by Glatt Co. , Ltd. ) , and the crystalline cellulose
was spray coated with the drug substance solution at an intake
air temperature of 54°C, an air flow volume of 0.94 m3/min, a
binder solution-spraying rate of 3.0 g/min, and a spraying air
pressure of 3.0 kg/cm2, whereby a particulate composition of
the present invention was obtained.
Example 10
A coated product obtained by coating crystalline cellulose with
solifenacin succinate and PEG
44

Ten parts of solifenacin succinate and 1 part of PEG
(brand name: Macrogol 6000, manufactured by Sanyo Chemical
Industries, Ltd.) were dissolved by agitation in a mixed
solution of 16 parts of water and 16 parts of methanol using
a stirrer (MGM-66, manufactured by SHIBATA), whereby a drug
substance solution was prepared. Then, 60 parts of
crystalline cellulose (brand name: Celphere, manufactured by
Asahi Chemical Industry Co., Ltd.) were put into a fluidized
bed granulator (FLO-1, manufactured by Glatt Co., Ltd.), and
the crystalline cellulose was spray coated with the drug
substance solution at an intake air temperature of 45°C, an
air flow volume of 1.0 m3/min, a binder solution-spraying rate
of 2 . 0 g/min, and a spraying air pressure of 2. 0 kg/cm2, whereby
a particulate powder was obtained.
Example 11
A coated product obtained by coating crystalline cellulose with
solifenacin succinate and PEG
Ten parts of solifenacin succinate and 10 parts of PEG
(brand name: Macrogol 6000, manufactured by Sanyo Chemical
Industries, Ltd.) were dissolved by agitation in a mixed
solution of 70 parts of water and 70 parts of methanol using
a stirrer (MGM-66, manufactured by SHIBATA), whereby a drug
substance solution was prepared. Then, 60 parts of
crystalline cellulose (brand name: Celphere, manufactured by
Asahi Chemical Industry Co., Ltd.) were put into a fluidized
45

bed granulator (FLO-1, manufactured by Glatt Co., Ltd.), and
the crystalline cellulose was spray coated with the drug
substance solution at an intake air temperature of 60°C, an
air flow volume of 1 m3/min, a binder solution- spraying rate
of 6. 5 g/min, and a spraying air pressure of 3. 0 kg/cm2, whereby
a particulate powder was obtained.
Example 12
In the case where a different solvent composition was used
A coated product obtained by coating crystalline cellulose with
solifenacin succinate and PEG
Ten parts of solifenacin succinate and 3.4 parts of PEG
(brand name: Macrogol 6000, manufactured by Sanyo Chemical
Industries, Ltd.) were dissolved by agitation in 53.2 parts
of water using a stirrer (MGM-66, manufactured by SHIBATA),
whereby a drug substance solution was prepared. Then, 60 parts
of crystalline cellulose (brand name: Celphere, manufactured
by Asahi Chemical Industry Co. , Ltd. ) were put into a fluidized
bed granulator (FLO-1, manufactured by Glatt Co., Ltd.), and
the crystalline cellulose was spray coated with the drug
substance solution at an intake air temperature of 80°C, an
air flow volume of 0.97 m3/min, a binder solution-spraying rate
of 7 . 0 g/min, and a spraying air pressure of 3. 0 kg/cm2, whereby
a particulate powder was obtained.
Example 13
A coated product obtained by coating crystalline cellulose with
46

solifenacin succinate and PEG (the content of drug substance:
50%)
Ten parts of solifenacin succinate and 3.4 parts of PEG
(brand name: Macrogol 6000, manufactured by Sanyo Chemical
Industries, Ltd.) were dissolved by agitation in 26.6 parts
of methanol and 26.6 parts of water using a stirrer (MGM-66,
manufactured by SHIBATA), whereby a drug substance solution
was prepared. Then, 60 parts of crystalline cellulose (brand
name: Celphere, manufactured by Asahi Chemical Industry Co.,
Ltd. ) were put into a fluidized bed granulator (FLO-1,
manufactured by Glatt Co. , Ltd.), and the crystalline cellulose
was spray coated with the drug substance solution at an intake
air temperature of 54°C, an air flow volume of 0.94 m3/min, a
binder solution-spraying rate of 3.0 g/min, and a spraying air
pressure of 3.0 kg/cm2, whereby a particulate powder was
obtained. Further, the resulting powder was overcoated with
another drug solution prepared at the above-mentioned
formulation ratio by using the same device and the same
conditions, whereby a particulate powder with a higher content
of drug substance (the content of drug substance: 50%) was
obtained.
Comparative example 1
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using HPMC as a
binder
47

Ten parts of solifenacin succinate and 3.4 parts of
hydroxypropylmethyl cellulose 2910 (brand name: TC-5E,
manufactured by Shinetsu Chemical Co., Ltd., hereinafter
abbreviated as HPMC) were dissolved by agitation in a mixed
solution of 26. 6 parts of water and 26. 6 parts of methanol using
a stirrer (MGM-66, manufactured by SHIBATA), whereby a drug
substance solution was prepared. Then, 60 parts of Celphere
(manufactured by Asahi Chemical Industry Co., Ltd.) were put
into a fluidized bed granulator (FLO-1, manufactured by Glatt
Co., Ltd.), and Celphere was spray coated with the drug
substance solution at an intake air temperature of 50°C, an
air flow volume of 0. 94 m3/min, a binder solution-spraying rate
of 7 . 0 g/min, and a spraying air pressure of 3. 0 kg/cm2, whereby
a particulate composition was obtained.
Comparative example 2
The particulate composition obtained in Comparative
example 1 was subjected to a crystallization treatment by
humidification at 25°C and 75% for 12 hours, and then drying
at 30°C and 40% for 3 hours, whereby a particulate composition
was obtained.
Comparative example 3
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using PVP as a binder
Ten parts of solifenacin succinate and 3.4 parts of
polyvinylpyrrolidone (brand name: PVP K90, manufactured by
48

BASF, hereinafter abbreviated as PVP) were dissolved by
agitation in a mixed solution of 26.6 parts of water and 26.6
parts of methanol using a stirrer (MGM-66, manufactured by
SHIBATA), whereby a drug substance solution was prepared.
Then, 60 parts of Celphere (manufactured by Asahi Chemical
Industry Co., Ltd.) were put into a fluidized bed granulator
(FLO-1, manufactured by Glatt Co., Ltd.), and Celphere was
spray coated with the drug substance solution at an intake air
temperature of 50°C, an air flow volume of 0.97 m3/min, a binder
solution-spraying rate of 6 g/min, and a spraying air pressure
of 3. 0 kg/cm2, whereby a particulate composition was obtained.
Comparative example 4
The particulate composition obtained in Comparative
example 3 was subjected to a crystallization treatment by
humidification at 25°C and 75% for 12 hours, and then drying
at 30°C and 40% for 3 hours, whereby a particulate composition
was obtained.
Comparative example 5
A coated product obtained by coating a crystalline cellulose
core particle with solifenacin succinate using methyl
cellulose as a binder
Ten parts of solifenacin succinate and 3.4 parts of
methyl cellulose (brand name: Metolose SM100, manufactured by
Shinetsu Chemical Co., Ltd., hereinafter abbreviated as MC)
were dissolved by agitation in a mixed solution of 53.2 parts
49

of water and 53.2 parts of methanol using a stirrer (MGM-66,
manufactured by SHIBATA), whereby a drug substance solution
was prepared. Then, 60 parts of Celphere (manufactured by
Asahi Chemical Industry Co., Ltd.) were put into a fluidized
bed granulator (FLO-1, manufactured by Glatt Co., Ltd.), and
Celphere was spray coated with the drug substance solution at
an intake air temperature of 55°C, an air flow volume of 0.97
m3/min, a binder solution-spraying rate of 5 g/min, and a
spraying air pressure of 3.0 kg/cm2, whereby a particulate
composition was obtained.
Comparative example 6
The particulate composition obtained in Comparative
example 5 was subjected to a crystallization treatment by
humidification at 25°C and 75% for 12 hours, and then drying
at 30°C and 40% for 3 hours, whereby a particulate composition
was obtained.
Experimental examples

First, the interaction between the drug substance and
the polymers was evaluated.
The results of powder X-ray diffraction for spray-dried
products comprising PEG and the drug substance used in Example,
HPMC or PVP and the drug substance used in Comparative examples
(as a device, using RINT 1400: tube bulb: Cu, tube voltage:
50

40 kV, tube current: 40 mA, scanning rate: 3000°/min (Rigaku.
Denki Co. ) ) are shown in Fig. 1. As the controls, the results
for only solifenacin succinate in a crystalline form and PEG
are shown together. As a result, any of the products prepared
by using PEG shown in Examples exhibits peaks originating in
solifenacin succinate in a crystalline form, and it was
confirmed that the drug substance in the powder exists as a
crystalline form. On the contrary, the samples shown in
Comparative examples exhibit a halo pattern typical of an
amorphous structure, which revealed that the drug substance
exists as an amorphous state.
Further, in Fig. 2, the results of powder X-ray
diffraction for the coated product obtained by coating Celphere
with PEG shown in Example this time (Example 3) and the coated
product obtained by using HPMC shown in Comparative example
1 (as a device, using RINT 2000: tube bulb: Cu, tube voltage:
50 kV, tube current: 300 mA, scanning rate: 60000°/min (Rigaku.
Denki Co.)) are shown. As shown in the drawing, even in the
coated products, it was confirmed that the sample using PEG
exhibits the crystalline peaks originating in solifenacin.

The results of a preliminary stability test for these
particulate compositions are shown in Tables 1 and 2. The
serial measurements of amounts of degradation products after
the compositions were stored for a certain period of time were
51

performed by high performance liquid chromatography, and the
maximum value among the obtained respective amounts of
degradation products is shown (i.e., the production amount of
F1, which is a major degradation product). In a test under
severe conditions of 40°C and 75% RH, as for the case of using
HPMC shown in Comparative example 1, when the humidification
treatment was not performed, the degradation product was
observed at 0.34% in only a 2-month time course change, which
is 8-fold the concentration at the initiation of storage of
0.04%. Further, as for the case of using PVP shown in
Comparative example 3, when the humidification treatment was
not performed, the degradation product was observed at 0.53%
in a 2-month time course change, which exceeds the standard
of 0.4%. Further, as for the case of using MC shown in
Comparative example 5, when the humidification treatment was
not performed, the degradation product was observed at 0.74%
in only a 2-month time course change, which is 12-fold the
concentration at the initiation of storage of 0.06%. Even in
the case where the humidification treatment was performed to
promote crystallization, the amount of degradation product for
any of Comparative examples 2, 4 and 6 is largeer than that
for any of Examples . In the case of using HPMC, the degradation
product was observed at 0.92% in only a 2-month time course
change, which is 13-fold the concentration at the initiation
of storage of 0.07%. Further, in the case of using MC, the
52

degradation product was observed at 11.75% in only a 2-month
time course change, which is 11-fold the concentration at the
initiation of storage of 1.09%.
On the other hand, as for the samples shown in Examples
1 to 7, whether or not the humidification treatment was
performed, the amounts of degradation product at 2 months were
0.2% or lower, and the absolute values were small, between 2
to 390 times less than those of Comparative examples. Further,
it was found that solifenacin in any of the pharmaceutical
preparations is stable with time because the degree of the
change was small. On the other hand, it was found that there
is a tendency that the degradation products hardly increase
and solifenacin is stable in the case of performing the
humidification treatment to promote crystallization as shown
in Examples 2, 4, 6 and 8.
The values of Tg (if it does not have a Tg, mp) of the
binders used in this time are shown in Table 3, and a linear
regression for the relationship between the production amount
of a major degradation product (F1 (%)) at 2 months and the
Tg (°C) was examined. As a result, as shown in Fig. 3, the
squares of the correlation coefficient (R2) were 0.73 in the
case where humidification and drying were not performed, and
0.60 in the case where humidif ication and drying were performed,
which showed a favorable positive correlation.
As described above, it is obvious that the thermodynamic
53

parameters of an additive used in combination are predominant
factors for the stability of solifenacin in a pharmaceutical
preparation. This phenomenon arises from the fluidity, that
is, Tg of a binder as described above, and it was considered
that the higher the Tg is, the more easily the amorphous form
exists continuously in a pharmaceutical preparation in an
amorphous state, therefore the degradation products are easily
generated.
The results of the preliminary stability test for particulate
compositions containing solifenacin succinate
Storage conditions: 40°C, 75% RH, tightly sealed
Packaging form: HDPE bottle packaging with a metal cap
Testing item: Related substance (production amount of
a major degradation product, Fl (%))
54


The results of the preliminary stability test for particulate
compositions containing solifenacin succinate subjected to a
humidification treatment
Storage conditions: 40°C, 75% RH, tightly sealed
Packaging form: HDPE bottle packaging with a metal cap
Testing item: Related substance (production amount of
a major degradation product, Fl (%))
55


Industrial Applicability
Technical features of the present invention reside in
that a stable particulate pharmaceutical composition can be
produced by preparing it using a specific binder in the
particulate pharmaceutical composition containing
solifenacin or a salt thereof and that it becomes possible to
provide a more stable particulate pharmaceutical composition
with time by performing a crystallization- promoting treatment
56

such as humidification and drying as needed, which exerts a
significant influence on industry. Further, the use of the
particulate pharmaceutical composition of the present
invention is useful as a technique that can provide various
stable pharmaceutical preparations of solifenacin or a salt
thereof, for which development as an excellent pharmaceutical
product for frequent urination or urinary incontinence has been
demanded.
57

Claims
1. A stable particulate pharmaceutical composition,
comprising solifenacin or a salt thereof and a binder having
an action of stabilizing solifenacin or a salt thereof.
2. The pharmaceutical composition according to claim
1, wherein the binder having an action of stabilizing
solifenacin or a salt thereof is a binder having an action of
inhibiting retention of an amorphous form of solifenacin or
a salt thereof.
3. The pharmaceutical composition according to claim
1 or 2, characterized in that the binder is a binder having
a glass transition point or melting point is lower than 174°C.
4 . The pharmaceutical composition according to claim
3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, polyethylene
oxide, a polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl
cellulose, methacrylic acid copolymer L, methacrylic acid
copolymer LD, methacrylic acid copolymer S, cornstarch,
aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate
copolymer RS and maltose.
58

5. The pharmaceutical composition according to claim
3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose and maltose.
6. The pharmaceutical composition according to claim
3, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer and
hydroxypropyl cellulose.
7 . A stable particulate pharmaceutical composition
of solif enacin or a salt thereof, which can be obtained by using
a mixture in which solifenacin or a salt thereof and a binder
having an action of stabilizing solifenacin or a salt thereof
are codissolved and/or suspended.
8. The pharmaceutical composition according to claim
7, wherein the binder having an action of stabilizing
solifenacin or a salt thereof is a binder having an action of
inhibiting retention of amorphous form of solifenacin or a salt
thereof.
59

9. The pharmaceutical composition according to claim
7 or 8, characterized in that the binder is a binder having
a glass transition point or melting point is lower than 174°C.
10. The pharmaceutical composition according to claim
9, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, polyethylene
oxide, a polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl
cellulose, methacrylic acid copolymer L, methacrylic acid
copolymer LD, methacrylic acid copolymer S, cornstarch,
aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate
copolymer RS and maltose.
11. The pharmaceutical composition according to claim
9, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer,
hydroxypropyl cellulose, hydroxyethyl cellulose and maltose.
12. The pharmaceutical composition according to claim
9, wherein the binder is one or more substances selected from
the group consisting of polyethylene glycol, a
polyoxyethylene/polyoxypropylene block copolymer and
hydroxypropyl cellulose.
60

61
13. The pharmaceutical composition according to any
one of claims 1 to 12, the stability of which is enhanced by
further performing a crystallization-promoting treatment.
14. A disintegrating tablet in buccal cavity,
comprising a pharmaceutical composition according to any one
of claims 1 to 13.

The present invention relates to the provision of a
stable particulate pharmaceutical composition of solifenacin
or a salt thereof, which is in a spherical shape suitable for
coating and in which degradation with time can be inhibited
when a pharmaceutical preparation of solifenacin or a salt
thereof is supplied to clinical fields. More particularly,
it relates to a particulate pharmaceutical composition that
can be obtained by using a binder having a Tg or mp lower than
174°C upon formulating a particulate composition of
solifenacin into a pharmaceutical preparation. Further, by
performing a crystallization-promoting treatment after the
particulate pharmaceutical composition is produced, a more
stable particulate composition of solifenacin or a salt thereof
can be provided.
62