DESCRIPTION
PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
TECHNICAL FIELD
[0001] The present invention relates to a solid pharmaceutical composition, which
comprises a cocrystal of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-
D-glucitol and L-proline and which maintains good dissolution properties and dissolution
stability of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol.
[0002] The present invention also relates to a method for producing a solid pharmaceutical
composition, which comprises a cocrystal of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-
ylmethyl)-4-fluorophenyl]-D-glucitol and L-proline and which maintains good dissolution
properties and dissolution stability of (1S)-1,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-
fluorophenyl]-D-glucitol.
[0003] The present invention further relates to the use of crystalline cellulose for the
manufacture of a solid pharmaceutical composition, which comprises a cocrystal of (1S)-1,5-
anhydro-l-[3-(1 -benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol and L-proline and which
maintains good dissolution properties and dissolution stability of (1S)-l,5-anhydro-l-[3-(1-
benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol.
BACKGROUND ART
[0004] (1S)-1,5-Anhydro-1 -[3-(1 -benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol
(hereinafter referred to as "C-glycoside derivative A" or "known compound A") is a Na+-
glucose cotransporter inhibitor designed and developed by Astellas Pharma Inc. and
Kotobuki Pharmaceutical Co., Ltd. and is reported as a compound useful in treating and
preventing, for example, insulin-dependent diabetes (type I diabetes), non-insulin-dependent
diabetes (type II diabetes), as well as insulin resistance diseases and obesity (Patent Literature
1: see Example 138).
[0005] Moreover, there are disclosed inventions relating to a cocrystal of known compound
A and L-proline, i.e., an invention of a cocrystal with L-proline, which cocrystal has a
consistent quality and is excellent in storage stability as a crystal of a drug substance used for
medicament production, and an invention of a pharmaceutical composition comprising this
cocrystal as an active ingredient, which composition is particularly useful as a therapeutic
agent for diabetes (Patent Literature 2).
CITATION LIST
PATENT LITERATURE
[0006] PTL 1: WO2004/080990
PTL2:WO2007/114475
SUMMARY OF INVENTION
TECHNICAL PROBLEM
[0007] The crystal of known compound A disclosed in Patent Literature 1 forms a clathrate
hydrate and reversibly changes from an anhydride form to a non-stoichiometric hydrate on a
hygrothermal condition. Thus, known compound A has not been able to retain a consistent
quality as a drug substance for use in medicaments. For this reason, known compound A is
provided in the form of a cocrystal with L-proline, which cocrystal has a consistent quality
and is also excellent in storage stability as a crystal of a drug substance for use in
medicaments.
[0008] However, when capsule formulations containing a cocrystal of known compound A
and L-proline were produced, the cocrystal of known compound A and L-proline was found
to be problematic in that the cocrystal was subject to poor disintegration due to its strong
aggregation tendency, which caused a reduction in drug dissolution speed. Thus, there is a
concern that poor disintegration of the formulations and reduced drug dissolution speed will
give rise to further problems, such as reduced bioavailability (BA) and lack of any
pharmacologically sufficient therapeutic effect.
[0009] Thus, an object of the present invention is to provide a pharmaceutical composition
having good dissolution properties, which contains known compound A in the form of a
cocrystal with L-proline.
[0010] Another object of the present invention is to provide a method for producing a
pharmaceutical composition having good dissolution properties, which contains known
compound A in the form of a cocrystal with L-proline.
[0011] Yet another object of the present invention is to provide the use of crystalline
cellulose for the manufacture of a solid pharmaceutical composition, which contains a
cocrystal of known compound A and L-proline and which maintains good dissolution
properties and dissolution stability of known compound A.
SOLUTION TO PROBLEM
[0012] The inventors of the present invention prepared a granulated product containing a
cocrystal of known compound A and L-proline (1:1) by wet granulation process using a
stirring granulator known per se, and then produced tablets from this granulated product.
As a result, the inventors found that these tablets showed good drug dissolution properties
immediately after production, but were subject to problems such as a change in their
disintegration properties and a time-induced reduction in their dissolution properties.
[0013] The inventors of the present invention have conducted studies focusing on the state
of a drug during production of formulations, and have found the following: known compound
A is converted into a free form upon release of L-proline from the cocrystal structure by the
action of water used during production of formulations; drug dissolution properties are
temporarily improved based on the properties of the free form of known compound A; and as
time passes, the free form of known compound A associates again with L-proline remaining
in the composition through hydrogen bonding or other interactions to form an aggregate.
[0014] The inventors of the present invention conducted extensive and intensive studies of
solid pharmaceutical compositions having good dissolution properties while maintaining the
cocrystal structure between known compound A and L-proline. As a result of studies by
using D-mannitol, anhydrous dibasic calcium phosphate, lactose, crystalline cellulose and the
like as an excipient, the inventors found that a pharmaceutical composition containing
crystalline cellulose has good dissolution properties while maintaining the cocrystal structure
between known compound A and L-proline, and completed the present invention.
[0015] Namely, the present invention relates to
[1] A solid pharmaceutical composition comprising a cocrystal of (1S)-l,5-anhydro-l-
[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol and L-proline, in combination with
crystalline cellulose;
[2] The solid pharmaceutical composition according to [1], wherein the content of
crystalline cellulose in the pharmaceutical composition is 5% by weight or more to 90% by
weight or less;
[3] The solid pharmaceutical composition according to [1] or [2], which further
comprises a disintegrant;
[4] The solid pharmaceutical composition according to [3], wherein the disintegrant is
one or more members selected from the group consisting of sodium starch glycolate, and
hydroxypropylcellulose whose hydroxypropoxyl group content is 5% by weight or more to
less than 16% by weight;
[5] The solid pharmaceutical composition according to [3] or [4], wherein the content of
the disintegrant in the pharmaceutical composition is 5% by weight or more to 90% by
weight or less;
[6] The solid pharmaceutical composition according to any one of [1] to [5], wherein
65% or more of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol
is dissolved in 30 minutes, as analyzed by the dissolution test described in the 15th revised
Japanese Pharmacopoeia;
[7] A method for producing a solid pharmaceutical composition, which comprises the
steps of:
(1) mixing a cocrystal of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-
fluorophenyl]-D-glucitol and L-proline with crystalline cellulose; and
(2) granulating the resulting mixture by wet granulation while maintaining the cocrystal
structure between (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-
glucitol and L-proline;
[8] The method according to [7], which further comprises the step of (3) subjecting the
granulated product to compression molding;
[9] The method according to [7] or [8], wherein the content of crystalline cellulose in
the pharmaceutical composition is 5% by weight or more to 90% by weight or less;
[10] The method according to [7], which further comprises adding a disintegrant during
step (1), between steps (1) and (2), during step (2), or after step (2);
[11] The method according to [10], wherein the disintegrant is one or more members
selected from the group consisting of sodium starch glycolate, and hydroxypropylcellulose
whose hydroxypropoxyl group content is 5% by weight or more to less than 16% by weight;
[12] The method according to [10] or [11], wherein the content of the disintegrant in the
pharmaceutical composition is 5% by weight or more to 90% by weight or less;
[13] The method according to any one of [7] to [12], which is intended to produce a solid
pharmaceutical composition that allows 65% or more of (1S)-l,5-anhydro-l-[3-(1-
benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol to be dissolved in 30 minutes, as
analyzed by the dissolution test described in the 15th revised Japanese Pharmacopoeia;
[14] The method according to [7], wherein the wet granulation is performed such that the
solid pharmaceutical composition has a maximum moisture content value of 5% to 30% by
weight during granulation;
[15] Use of crystalline cellulose for the manufacture of a solid pharmaceutical
composition comprising a cocrystal of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-
fluorophenyl]-D-glucitol and L-proline.
ADVANTAGEOUS EFFECTS OF INVENTION
[0016] The present invention is characterized, for example, in that (1) pharmaceutical
formulations containing a cocrystal of known compound A and L-proline show good
dissolution properties, (2) it is possible to provide stable pharmaceutical formulations whose
dissolution speed remains unchanged over time, and (3) the pharmaceutical formulations
show improved bioavailability (BA) and exert a pharmacologically sufficient therapeutic
effect due to their good dissolution properties.
BRIEF DESCRIPTION OF DRAWINGS
[0017] Figure 1 shows the dissolution profile of the pharmaceutical compositions obtained
in Example 1.
Figure 2 shows the dissolution profile of the pharmaceutical compositions obtained
in Comparative Example 1.
Figure 3 shows the dissolution profile of the pharmaceutical compositions obtained
in Comparative Example 2.
Figure 4 shows the dissolution profile of the pharmaceutical compositions obtained
in Examples 3, 4, 5, 6, and 9.
DESCRIPTION OF EMBODIMENTS
[0018] The solid pharmaceutical composition of the present invention will be further
described in more detail below.
[0019] As used herein, the term "cocrystal of known compound A and L-proline" is
intended to mean a uniform cocrystal formed between known compound A and L-proline at a
molar ratio of 1:1. The cocrystal structure is identified from the results of differential
scanning calorimeter analysis (DSC analysis) and powder X-ray diffractometry, etc. For
example, in the case of powder X-ray diffractometry, a distinction can be made based on
diffraction angles (26 (°)) and relative intensity in the measured spectra (Table 1, Table 2).
It should be noted that crystal lattice spacings and overall pattern are important for
identification of crystal in powder X-ray diffractometry due to the characteristics of the data,
and the relative intensity should not be strictly interpreted because it may more or less vary
depending on the direction of crystal growth, particle sizes and measurement conditions.
Moreover, if the peaks unique to the structure of known compound A are as small as
negligible in X-ray diffractometry, such a case is defined to mean a cocrystal of known
compound A and L-proline.
[0020] [Table 1]

[0021] [Table 2]
Table 2: Diffraction angle (20 (°)) and relative intensity of cocrystal of known

[0022] Powder X-ray diffractometry was conducted under the following conditions.
(1) Standard measurement: "MAC Science MXP18TAHF22" was used in the measurement
under the following conditions: X-ray tube: Cu, tube current: 200 mA, tube voltage: 40 kV,
sampling width: 0.020°, scanning speed: 3°/min, wavelength: 1.54056 A, measured range of
diffraction angle (26): 3° to 40°.
(2) Humidity-controlled measurement: "MAC Science MXP18TAHF22 with a
multifunctional humidity and temperature converter (VAISALA MHP235)" was used in the
measurement under the following conditions: X-ray tube: Cu, tube current: 350 mA, tube
voltage: 50 kV, sampling width: 0.020°, scanning speed: 3°/min, wavelength: 1.54056 A,
measured range of diffraction angle (26): 5° to 40°.
[0023] As used herein, the term "good dissolution properties" is intended to mean having
dissolution properties equal or equivalent to those of standard formulations. For example,
this term is used herein in a definition stating that the dissolution rate after 30 minutes is 65%
or more, or alternatively, 75% or more, or alternatively, 80% or more, as analyzed by the
dissolution test described in the 15th revised Japanese Pharmacopoeia.
[0024] As used herein, the term "dissolution stability" is intended to mean that in drug
dissolution from a pharmaceutical composition, there is little time-induced change in the drug
dissolution rate as compared to before storage. For example, this term is used herein in a
definition stating that there is little time-induced change in the drug dissolution rate as
compared to before storage, as analyzed by the dissolution test described in the 15th revised
Japanese Pharmacopoeia. Alternatively, use is made of the term in a definition stating that
when tested after storage at 40°C and 75% for 6 months, the dissolution rate measured at
30 minutes after the start of the dissolution test was within ± 15% as compared to before
storage.
[0025] Known compound A used in the present invention is represented by the following
formula (I):
[0026] [Formula 1]

and has the chemical name of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-
fluorophenyl]-D-glucitol (hereinafter also referred to as "C-glycoside derivative A" or simply
"known compound A"). Known compound A forms a cocrystal structure with L-proline, as
represented by the following formula (II).
[0027] [Formula 2]

[0028] This cocrystal has an endothermic peak at 201°C to 213°C in DSC analysis, and/or
has peaks around 26 (°) = 4.44, 8.98, 12.4, 16.5, 17.5,18.7, 20.5 and 21.5 in powder X-ray
diffractometry.
[0029] Known compound A and a cocrystal of known compound A and L-proline can be
distinguished from each other based on diffraction angles (26 (°)) and relative intensity in
their powder X-ray diffraction spectra.
[0030] Although the clinical dosage (therapeutically effective dosage) of a cocrystal of
known compound A for humans is appropriately determined taking into account the
symptoms, weight, age, sex and the like of a patient to be administered, the daily dosage for
adults is usually 0.1 to 500 mg by the oral route, given as a single dose or in divided doses.
Since the dosage will vary according to various conditions, a dosage smaller than the above
range is sufficient in some cases.
[0031] Crystalline cellulose to be used in the present invention is purified, partially
depolymerized cellulose prepared by acid treatment of a-cellulose obtained as a pulp from
fibrous plants (15th revised Japanese Pharmacopoeia). Moreover, crystalline cellulose can
be used without any limitations on its bulk density and average polymerization degree, etc.,
as long as it is pharmaceutically acceptable and capable of maintaining good dissolution
properties and dissolution stability of known compound A. Specific examples include
Ceolus PH101, Ceolus PH102, Ceolus PH101D, Ceolus KG802, Ceolus UF711, Ceolus
UF702, Ceolus KG1000, Ceolus PH301, Ceolus PH301D, Ceolus PH301Z, Ceolus PH302,
Ceolus PH F20JP (all available from Asahi Kasei Corporation, Japan), Avicel PH101, Avicel
PHI 12, Avicel PHI 13, Avicel PH200, Avicel PH301, Avicel PH302, Avicel HFE-102,
Avicel (all available from FMC BioPolymer), Celex 101 (International Specialty Products),
Emcocel 90M (J.Rettenmaier & Sohne), Vivacel 12 (J.Rettenmaier & Sohne), Celphere (San-
Ei Gen F.F.I., Inc., Japan) and the like.
[0032] Crystalline cellulose may be of any shape, including granular or needle-like shape.
Crystalline cellulose of needle-like shape may further be ground before use. It is also
possible to use crystalline cellulose that is commercially available as a mixture associated
with another additive (e.g., carrageenan, sodium carboxymethylcellulose, guar gum). In a
case where crystalline cellulose is of granular shape, its average particle size is preferably 20
to 200 nm, as analyzed by the second method (analytical sieving) of powder particle size
determination described in the Japanese Pharmacopoeia. Crystalline celluloses of different
grades, shapes, average particle sizes or the like may be used alone or in combination as
appropriate for this purpose.
[0033] In general, the content of crystalline cellulose is not limited in any way as long as it
ensures good dissolution properties of known compound A. For example, it is 5% to 90%
by weight, or alternatively, 20% to 70% by weight, based on the pharmaceutical composition
of the present invention. Likewise, it is 20% to 1500% by weight, or alternatively, 50% to
1100% by weight or 40% to 350% by weight, relative to the amount of the cocrystal of
known compound A and L-proline.
[0034] In general, any type of disintegrant may be used in the present invention as long as
known compound A shows good dissolution properties. Examples include low-substituted
hydroxypropylcellulose, sodium starch glycolate, corn starch, potato starch, carmellose
calcium, carmellose sodium, partially pregelatinized starch, crospovidone, croscarmellose
sodium and the like. In other embodiments, low-substituted hydroxypropylcellulose and
sodium starch glycolate can be presented. These disintegrants may be used alone or in
combination as appropriate for this purpose.
[0035] In general, the content of disintegrant is not limited in any way as long as it ensures
good dissolution properties of known compound A. For example, it is 5% to 90% by weight,
or alternatively, 5% to 70% by weight or 5% to 55% by weight, based on the pharmaceutical
composition of the present invention. Likewise, it is 10% to 1500% by weight, or
alternatively, 10% to 1100% by weight or 25% to 300% by weight, relative to the amount of
the cocrystal of known compound A and L-proline.
[0036] Low-substituted hydroxypropylcellulose is not limited in any way as long as it is
pharmaceutically acceptable. An example is hydroxypropylcellulose whose
hydroxypropoxyl group content is 5% by weight or more to less than 16% by weight.
Specific examples include L-HPCs (1H-11, LH-21, LH-22, LH-B1, LH-31, LH-32, LH-B1;
all available from Shin-Etsu Chemical Co., Ltd., Japan) and the like. Low-substituted
hydroxypropylcellulose may be of any shape, including granular or fiber-like shape. Low-
substituted hydroxypropylcellulose of fiber-like shape may further be ground before use. In
a case where low-substituted hydroxypropylcellulose is of granular shape, its average particle
size is preferably 10 to 100 µm, as analyzed by the second method (analytical sieving) of
powder particle size determination described in the Japanese Pharmacopoeia. Such low-
substituted hydroxypropylcelluloses may be used alone or in combination as appropriate for
this purpose.
[0037] The content of low-substituted hydroxypropylcellulose is 5% to 90% by weight, or
alternatively, 5% to 70% by weight or 5% to 55% by weight, based on the pharmaceutical
composition of the present invention. Likewise, it is 10% to 1500% by weight, or
alternatively, 10% to 1100% by weight or 25% to 300% by weight, relative to the amount of
the cocrystal of known compound A and L-proline.
[0038] Sodium starch glycolate is not limited in any way as long as it is pharmaceutically
acceptable. Examples include Primojel (DMV), Explotab (Kimura Sangyo Co., Ltd., Japan)
and the like. Sodium starch glycolate may be of any shape, including granular, needle-like,
egg-like, or spherical shape. Sodium starch glycolate of needle-like shape may further be
ground before use. In a case where sodium starch glycolate is of granular shape, for
example, its average particle size is preferably 10 to 100 µm, as analyzed by the second
method (analytical sieving) of powder particle size determination described in the Japanese
Pharmacopoeia. Sodium starch glycolates of different grades or the like may be used alone
or in combination as appropriate for this purpose.
[0039] In general, the content of sodium starch glycolate is not limited in any way as long
as it ensures good dissolution properties of known compound A. For example, it is 5% to
90% by weight, or alternatively, 5% to 70% by weight, based on the pharmaceutical
composition of the present invention. Likewise, it is 10% to 1500% by weight, or
alternatively, 10% to 1100% by weight, relative to the amount of the cocrystal of known
compound A and L-proline.
[0040] The solid pharmaceutical composition of the present invention may optionally be
further supplemented, as appropriate, with various pharmaceutical additives before being
formulated. Such pharmaceutical additives are not limited in any way as long as they are
pharmaceutically acceptable and pharmacologically acceptable. Examples include
excipients, binders, disintegrants, acidulants, blowing agents, artificial sweeteners, flavorings,
lubricants, coloring agents, stabilizers, buffering agents, antioxidants, surfactants, coating
agents and the like.
[0041] Excipients include D-mannitol, lactose and the like.
[0042] Binders include, for example, hydroxypropylmethylcellulose,
hydroxypropylcellulose, gum arabic and the like.
[0043] Acidulants include, for example, citric acid, tartaric acid, malic acid and the like.
[0044] Blowing agents include, for example, sodium hydrogen carbonate and the like.
[0045] Artificial sweeteners include, for example, saccharin sodium, dipotassium
glycyrrhizinate, aspartame, stevia, thaumatin and the like.
[0046] Flavorings include, for example, lemon, lemon lime, orange, menthol and the like.
[0047] Lubricants include, for example, magnesium stearate, calcium stearate, sucrose fatty
acid ester, polyethylene glycol, talc, stearic acid and the like.
[0048] Coloring agents include, for example, yellow iron sesquioxide, red iron sesquioxide,
food yellow Nos. 4 and 5, food red Nos. 3 and 102, food blue No. 3 and the like.
[0049] Buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid,
ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine,
arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric
acid, boric acid or salts thereof and the like.
[0050] Antioxidants include, for example, ascorbic acid, dibutylhydroxytoluene, propyl
gallate and the like.
[0051] Surfactants include, for example, Polysorbate 80, sodium lauryl sulfate,
polyoxyethylene hydrogenated castor oil and the like.
[0052] Coating agents include talc, polyethylene glycol, hypromellose, titanium dioxide and
the like.
[0053] These pharmaceutical additives may be added alone or in combination as
appropriate in suitable amounts.
[0054] The content of pharmaceutical additive(s) is 0.1% to 70% by weight, based on the
pharmaceutical composition of the present invention.
[0055] The pharmaceutical composition of the present invention can be formulated into
various dosage forms, including tablets, capsules, powders, granules, dry syrups and the like.
In a certain embodiment, the solid pharmaceutical composition of the present invention is in
tablet form.
[0056] Formulations of various dosage forms may be produced in any known manner.
[0057] The pharmaceutical composition of the present invention can be produced, for
example, by any known process including the steps of grinding, wet granulation, drying,
tableting, film coating and the like.
[0058] For example, the solid pharmaceutical composition of the present invention in the
form of powders, granules or dry syrups can be produced by a process including the steps of
(1) mixing a cocrystal of known compound A and L-proline with crystalline cellulose, and
(2) granulating the resulting mixture by wet granulation. In a case where the above various
pharmaceutical additives are used as needed, these pharmaceutical additives may be added at
any stage, e.g., during step (1), between steps (1) and (2), or during step (2). In a certain
embodiment, a disintegrant is used as a pharmaceutical additive, and sodium starch glycolate
and L-HPC are presented as examples of the disintegrant.
[0059] For example, the solid pharmaceutical composition of the present invention in the
form of tablets can be produced by a process including the steps of (1) mixing a cocrystal of
known compound A and L-proline with crystalline cellulose, (2) granulating the resulting
mixture by wet granulation, and (3) subjecting the granulated product to compression
molding. In a case where the above various pharmaceutical additives are used as needed,
these pharmaceutical additives may be added at any stage, e.g., during step (1), between steps
(1) and (2), during step (2), or between steps (2) and (3). In a certain embodiment, a
disintegrate is used as a pharmaceutical additive, and sodium starch glycolate and L-HPC are
presented as examples of the disintegrant.
[0060] The cocrystal of known compound A and L-proline, crystalline cellulose, and the
pharmaceutical additive(s) may each be adjusted to any suitable size by being subjected to a
grinding step prior to the mixing step. In the grinding step, any apparatus or means may be
used as long as it generally allows pharmaceutical grinding of the drug and/or the
pharmaceutical additive(s). In the mixing step of the individual components, which is
subsequent to grinding, any apparatus or means may be used as long as it generally allows
pharmaceutical mixing of the individual components into a uniform state.
[0061] A granulator is used for wet granulation of the mixture to prepare a granulated
product. Examples of a granulator include a fluidized bed granulator, a tumbling fluidized
bed granulator, a stirring granulator and the like.
[0062] In wet granulation, a binder is used. The binder may be added as an aqueous
solution to a mixture containing a cocrystal of known compound A and L-proline as well as
crystalline cellulose. Although the speed of binder addition will vary depending on the type
of granulation method or the scale of production, for example, the binder solution may be
added at a speed of 1 to 30 g/minute, or alternatively, 5 to 20 g/minute in the case of 1 kg
scale production by fluidized bed granulation. Wet granulation may be accomplished, for
example, in a temperature range of 15°C to 35°C. During wet granulation, in addition to the
aqueous binder solution, another water-containing component may be added. In one
embodiment, a binder may be added to a mixture containing a cocrystal of known compound
A and L-proline as well as crystalline cellulose, followed by granulation while adding water.
The water may be added such that the maximum moisture content during granulation is 5%
to 40% by weight or 5% to 30% by weight. The maximum moisture content during
granulation refers to a maximum moisture content measured for a mixture during granulation,
mainly refers to a moisture content in a mixture at a time point when addition of the aqueous
binder solution (or water) is completed. The moisture content in such a mixture may be
measured with a halogen moisture analyzer (Mettler-Toledo Inc.) by allowing the mixture to
stand at 105°C for 5 minutes.
[0063] The solid pharmaceutical composition of the present invention comprises a cocrystal
structure between known compound A and L-proline, and the cocrystal structure should be
maintained even during preparation of the composition (i.e., L-proline should not be released
from the cocrystal to prevent known compound A from being left in free form). To
maintain the cocrystal structure, production conditions are preferably controlled such that a
strong shearing force and excess moisture are not applied to a mixture to be granulated.
Since a strong shearing force is excluded, the pharmaceutical composition of the present
invention is preferably granulated by use of fluidized bed granulation.
[0064] The granulated product thus prepared may be dried using any means. For example,
it is possible to use a fluidized bed granulator, a Multiplex, a shelf dryer, or other dryers.
The drying temperature is set to, for example, 40°C to 90°C.
[0065] The granulated product is then tableted to produce tablets. Any tableting technique
may be used for this purpose as long as it generally allows pharmaceutical production of
compression molded products. Examples include techniques in which a granulated product
is tableted in admixture with a disintegrant, a lubricant and the like. Any type of tablet
machine may be used for this purpose as long as it generally allows pharmaceutical
production of compression molded products. Examples include a rotary tablet machine, a
single-shot tablet machine and the like. The tablet hardness is set to, for example, 40 to 250
N, or alternatively, 50 to 200 N.
[0066] After tableting, the tablet surface may be coated with a film coating. Any
technique may be used for this purpose as long as it generally allows pharmaceutical tablet
coating. Examples include pan coating processes and the like. Any type of film coating
agent may be used for this purpose as long as it is generally used as a pharmaceutical additive
for pharmaceutical tablet coating. Film coating agents may be added alone or in
combination as appropriate in suitable amounts.
[0067] In general, the coating rate is not limited in any way as long as the tablet surface can
be coated. For example, it is 1.0% by weight or more to 5.0% by weight or less, relative to
uncoated tablets before coating.
[0068] Any method may be used to produce the pharmaceutical composition of the present
invention or a pharmaceutical formulation thereof, as long as it allows production of
pharmaceutical formulations having the desired effects of the present invention by the
method described above or an appropriate combination of methods known per se.
[0069] Use of crystalline cellulose in the present invention is intended for the manufacture
of a solid pharmaceutical composition that maintains good dissolution properties and
dissolution stability of known compound A.
EXAMPLE
[0070] The present invention will be further described in more detail below by way of the
following examples, comparative example and test examples, which are not intended to limit
the scope of the invention. A cocrystal of known compound A and L-proline (1:1) was
prepared as described in WO2007/114475 and used. The compositions of the examples and
the comparative example were prepared based on the formulations shown in Tables 3-5, 7,
and 8. It should be noted that each numeral in each table indicates the weight (g) of each
component used.

[0071] As an excipient, crystalline cellulose was used to prepare tablets based on the
formulation shown in Table 3.
[0072] After the cocrystal of known compound A and L-proline was mixed with crystalline
cellulose (product name: Ceolus PH101, Asahi Kasei Corporation, Japan, the same applies
hereinafter), an aqueous solution (10% by weight) of hydroxypropylcellulose (product name:
HPC-L, Nippon Soda Co., Ltd., Japan, the same applies hereinafter) was sprayed as a binder
solution (addition speed: 10 g/minute) to effect fluidized bed granulation (granulator (product
name: tumbling fluidized bed granulating, drying and coating apparatus, Powrex Corp.,
Japan), granulation temperature: 24°C to 25°C, granulation time: 48 minutes). The mixture
during granulation had a maximum moisture content value of 29.2%, and the resulting
granulated product had an average particle size of 292 jAm. The resulting granulated
product was dried (75°C, 40 minutes) and then mixed with sodium starch glycolate (product
name: Primojel, DMV, the same applies hereinafter) and magnesium stearate (product name:
Parteck LUB MST, Merck & Co., Inc., the same applies hereinafter), followed by tableting to
obtain tablets (A-l) (punch diameter: 9.5 mm x 11.4R, tableting pressure: 6 kN). The
moisture content value during granulation was measured as follows: the mixture was sampled
from the granulator at an interval of 12 minutes from the start until the completion of
spraying the binder solution, and allowed to stand at 105 °C for 5 minutes for measurement
with a halogen moisture analyzer (Mettler-Toledo Inc.). The maximum moisture content
value was measured after the completion of spraying.
[0073] Except that croscarmellose sodium (product name: Ac-Di-Sol, FMC BioPolymer,
the same applies hereinafter), low-substituted hydroxypropylcellulose whose
hydroxypropoxyl group content is 10% to 12.9% (product name: L-HPC, Shin-Etsu
Chemical Co., Ltd., Japan, the same applies hereinafter) or crospovidone (product name:
Kollidon CL, BASF, the same applies hereinafter) was used instead of sodium starch
glycolate, the same procedure as shown above was repeated to obtain tablets A-2 to A-4 (A-
2: maximum moisture content value: 29.2%, punch diameter: 9.5 mm x 11.4R, tableting
pressure: 5 kN; A-3: maximum moisture content value: 29.2%, punch diameter: 9.5 mm x
11.4R, tableting pressure: 5 kN; A-4: maximum moisture content value: 29.2%, punch
diameter: 9.5 mm x 11.4R, tableting pressure: 5 kN).

[0074] Except that D-mannitol (product name: PEARITOL 50C, Roquette, the same applies
hereinafter) was used as an excipient instead of crystalline cellulose, the same procedure as
shown in Example 1 was repeated to obtain a granulated product (average particle size: 144
\xm) and tablets B-l to B-4 (B-l: maximum moisture content value: 3.7%, punch diameter:
9.5 mm x 11.4R, tableting pressure: 10 kN; B-2: maximum moisture content value: 3.7%,
punch diameter: 9.5 mm x 11.4R, tableting pressure: 13 kN; B-3: maximum moisture content
value: 3.7%, punch diameter: 9.5 mm x 11.4R, tableting pressure: 11 kN; B-4: maximum
moisture content value: 3.7%, punch diameter: 9.5 mm x 11.4R, tableting pressure: 11 kN).

[0075] Except that anhydrous dibasic calcium phosphate (product name: GS CALICA,
Kyowa Chemical Industry Co., Ltd) was used as an excipient instead of crystalline cellulose,
the same procedure as shown in Example 1 was repeated to obtain a granulated product and
tablets C-l to C-4 (C-l: maximum moisture content value: 8.1%, punch diameter: 9.5 mm x
11.4R, tableting pressure: 15 kN; C-2: maximum moisture content value: 8.1%, punch
diameter: 9.5 mm x 11.4R, tableting pressure: 15 kN; C-3: maximum moisture content value:
8.1%, punch diameter: 9.5 mm x 11.4R, tableting pressure: 9 kN; C-4: maximum moisture
content value: 8.1%, punch diameter: 9.5 mm x 11.4R, tableting pressure: 13 kN).
[0076] [Table 3]

[0077]
< Test Example 1>
[0079] The individual tablets obtained in Example 1, Comparative Example 1, and
Comparative Example 2 were subjected to a dissolution test to study their dissolution
immediately after formulation (at the start of storage). The dissolution test was
accomplished by the paddle method described in the 15th revised Japanese Pharmacopoeia.
The test solution used was 900 mL of dissolution test solution 1 (0.1 N aqueous hydrochloric
acid). The rotation speed of paddles was set to 50 rotations/minute. The dissolution rate
of known compound A at 30 minutes after the start of the test is shown in Table 6.
Moreover, the dissolution profile is shown in Figures 1-3.
[0080] As can be seen from Table 6 and Figures 1-3, the tablets prepared using crystalline
cellulose showed good dissolution properties as compared to the tablets prepared using D-
mannitol or anhydrous dibasic calcium phosphate. Moreover, the dissolution properties of
the tablets prepared using crystalline cellulose were found to be good, regardless of the type
of disintegrant.
[0081] This suggests that when the cocrystal of known compound A and L-proline is
combined with crystalline cellulose, it is possible to provide a solid pharmaceutical
composition having good dissolution properties.
[0082] [Table 6]

[0083] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with crystalline cellulose, the aqueous hydroxypropylcellulose
solution was sprayed as a binder solution to effect fluidized bed granulation (maximum
moisture content value during granulation: 29.2%, average particle size: 144 µm). The
resulting granulated product was dried and then mixed with sodium starch glycolate and
magnesium stearate, followed by tableting to obtain the solid pharmaceutical composition of
the present invention (punch diameter: 9.5 mm x 11.4R, tableting pressure: 7 kN).

[0084] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol, crystalline cellulose and sodium starch
glycolate, the aqueous hydroxypropylcellulose solution was sprayed as a binder solution to
effect fluidized bed granulation (maximum moisture content value during granulation: 15.4%,
average particle size: 248 µm). The resulting granulated product was dried and then mixed
with magnesium stearate, followed by tableting to obtain the solid pharmaceutical
composition of the present invention (punch diameter: 9.5 mm x 11.4R, tableting pressure:
7kN).

[0085] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol, crystalline cellulose and sodium starch
glycolate, the aqueous hydroxypropylcellulose solution was sprayed as a binder solution to
effect fluidized bed granulation (maximum moisture content value during granulation: 20.1%,
average particle size: 164 µm). The resulting granulated product was dried and then mixed
with magnesium stearate, followed by tableting to obtain the solid pharmaceutical
composition of the present invention (punch diameter: 10.0 mm x 15.0R, tableting pressure:
8kN).

[0086] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol, crystalline cellulose and sodium starch
glycolate, the aqueous hydroxypropylcellulose solution was sprayed as a binder solution to
effect fluidized bed granulation (maximum moisture content value during granulation: 23.2%,
average particle size: 115 µm). The resulting granulated product was dried and then mixed
with magnesium stearate, followed by tableting to obtain the solid pharmaceutical
composition of the present invention (punch diameter: 9.5 mm x 11.4R, tableting pressure:
8kN).

[0087] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with crystalline cellulose, the aqueous hydroxypropylcellulose
solution was sprayed as a binder solution to effect fluidized bed granulation (maximum
moisture content value during granulation: 29.2%, average particle size: 292 µm). The
resulting granulated product was dried and then mixed with sodium starch glycolate and
magnesium stearate, followed by tableting to obtain the solid pharmaceutical composition of
the present invention (punch diameter: 9.5 mm x 11.4R, tableting pressure: 6 kN).

[0088] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with crystalline cellulose, the aqueous hydroxypropylcellulose
solution was sprayed as a binder solution to effect fluidized bed granulation (maximum
moisture content value during granulation: 29.2%, average particle size: 292 µm). The
resulting granulated product was dried and then mixed with magnesium stearate, followed by
tableting to obtain the solid pharmaceutical composition of the present invention (punch
diameter: 9.5 mm x 11.4R, tableting pressure: 5 kN).

[0089] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol, crystalline cellulose and low-substituted
hydroxypropylcellulose, the aqueous hydroxypropylcellulose solution was sprayed as a
binder solution to effect fluidized bed granulation (maximum moisture content value during
granulation: 10.4%, average particle size: 231 µm). The resulting granulated product was
dried and then mixed with magnesium stearate, followed by tableting to obtain the solid
pharmaceutical composition of the present invention (punch diameter: 9.5 mm x 11.4R,
tableting pressure: 5 kN).

[0090] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol and crystalline cellulose, the aqueous
hydroxypropylcellulose solution was sprayed as a binder solution to effect fluidized bed
granulation (maximum moisture content value during granulation: 16.6%, average particle
size: 197 µm). The resulting granulated product was dried and then mixed with low-
substituted hydroxypropylcellulose and magnesium stearate, followed by tableting to obtain
the solid pharmaceutical composition of the present invention (punch diameter: 9.5 mm x
11.4R, tableting pressure: 5 kN).

[0091] In the same manner as shown in Example 1, after the cocrystal of known compound
A and L-proline was mixed with D-mannitol and crystalline cellulose, the aqueous
hydroxypropylcellulose solution was sprayed as a binder solution to effect fluidized bed
granulation (maximum moisture content value during granulation: 16.6%, average particle
size: 197 µm). The resulting granulated product was dried and then mixed with low-
substituted hydroxypropylcellulose and magnesium stearate, followed by tableting to obtain
the solid pharmaceutical composition of the present invention (punch diameter: 9.5 mm x
11.4R, tableting pressure: 5 kN).
[0092]
: Crystalline analysis
[0094] The compositions obtained in Examples 2 to 10 were evaluated by powder X-ray
diffractometry for their crystal structure immediately after formulation. As a result, peaks
corresponding to the cocrystal of known compound A and L-proline were observed, whereas
there was no peak corresponding to free form of known compound A. This indicated that
the cocrystal structure between known compound A and L-proline was maintained even after
formulation (Table 9).
: Evaluation of dissolution properties and dissolution stability
[0095] The compositions obtained in Examples 2 to 10 were subjected to a dissolution test
to study their dissolution immediately after formulation (at the start of storage) and after
storage at 40°C and 75% relative humidity for 6 months. The dissolution test was
accomplished by the paddle method described in the 15th revised Japanese Pharmacopoeia.
The test solution used was 900 mL of dissolution test solution 1 (0.1 N aqueous hydrochloric
acid). The rotation speed of paddles was set to 50 rotations/minute. The dissolution rate
of known compound A at 30 minutes after the start of the test is shown in Table 9.
Moreover, the dissolution profile is shown in Figure 4.
[0096] [Table 9]

[0097] As shown in Examples 2 to 10, the dissolution rate after 30 minutes reached a high
value in each case. When crystalline cellulose was included in the formulation and wet
granulation was used, significant improvements were observed in dissolution properties.
[0098] Test Examples 1 and 2 demonstrated that the solid pharmaceutical compositions
containing the cocrystal of known compound A and L-proline in combination with crystalline
cellulose maintained the cocrystal structure between known compound A and L-proline and
also showed good dissolution properties. It is suggested that inclusion of crystalline
cellulose in the formulation allows a reduction in the strong aggregation tendency, which is
characteristic of the cocrystal of compound A and L-proline, and also allows an improvement
in dispersibility.
INDUSTRIAL APPLICABILITY
[0099] The present invention relates to a solid pharmaceutical composition, which
comprises a cocrystal of known compound A and L-proline and which maintains good
dissolution properties and dissolution stability of known compound A, a method for
producing the same, and the use of crystalline cellulose for the manufacture of the solid
pharmaceutical composition. The present invention ensures improved bioavailability (BA)
and a pharmacologically sufficient therapeutic effect, due to good dissolution properties of
the cocrystal of known compound A and L-proline.
We Claim:
1. A solid pharmaceutical composition comprising a cocrystal of (1S)-l,5-anhydro-l-
[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol and L-proline, in combination with
crystalline cellulose.
2. The solid pharmaceutical composition according to claim 1, wherein the content of
crystalline cellulose in the pharmaceutical composition is 5% by weight or more to 90% by
weight or less.
3. The solid pharmaceutical composition according to claim 1 or 2, which further
comprises a disintegrant.
4. The solid pharmaceutical composition according to claim 3, wherein the disintegrant
is one or more members selected from the group consisting of sodium starch glycolate, and
hydroxypropylcellulose whose hydroxypropoxyl group content is 5% by weight or more to
less than 16% by weight.
5. The solid pharmaceutical composition according to claim 3 or 4, wherein the content
of the disintegrant in the pharmaceutical composition is 5% by weight or more to 90% by
weight or less.
6. The solid pharmaceutical composition according to any one of claims 1 to 5,
wherein 65% or more of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-
D-glucitol is dissolved in 30 minutes, as analyzed by the dissolution test described in the 15th
revised Japanese Pharmacopoeia.
7. A method for producing a solid pharmaceutical composition, which comprises the
steps of:
(1) mixing a cocrystal of (1S)-l,5-anhydro-l-[3-(1-benzothien-2-yImethyl)-4-
fluorophenyl]-D-glucitol and L-proline with crystalline cellulose; and
(2) granulating the resulting mixture by wet granulation while maintaining the cocrystal
structure between (1S)-l,5-anhydro-l-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-
glucitol and L-proline.
8. The method according to claim 7, which further comprises the step of (3) subjecting
the granulated product to compression molding.
9. The method according to claim 7 or 8, wherein the content of crystalline cellulose in
the pharmaceutical composition is 5% by weight or more to 90% by weight or less.
10. The method according to claim 7, which further comprises adding a disintegrant
during step (1), between steps (1) and (2), during step (2), or after step (2).
11. The method according to claim 10, wherein the disintegrant is one or more members
selected from the group consisting of sodium starch glycolate, and hydroxypropylcellulose
whose hydroxypropoxyl group content is 5% by weight or more to less than 16% by weight.
12. The method according to claim 10 or 11, wherein the content of the disintegrant in
the pharmaceutical composition is 5% by weight or more to 90% by weight or less.
13. The method according to any one of claims 7 to 12, which is intended to produce a
solid pharmaceutical composition that allows 65% or more of (1S)-l,5-anhydro-l-[3-(1-
benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol to be dissolved in 30 minutes, as
analyzed by the dissolution test described in the 15th revised Japanese Pharmacopoeia.
14. The method according to claim 7, wherein the wet granulation is performed such
that the solid pharmaceutical composition has a maximum moisture content value of 5% to
30% by weight during granulation.
15. Use of crystalline cellulose for the manufacture of a solid pharmaceutical
composition comprising a cocrystal of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-
fluorophenyl]-D-glucitol and L-proline.

ABSTRACT

The present invention provides a solid pharmaceutical composition comprising a
cocrystal of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol
and L-proline, in combination with crystalline cellulose, and also provides a method for
producing the composition.