Title of Invention

POROUS CELLULOSE AGGREGATE AND MOLDING COMPOSITION THEREOF

Abstract A porous cellulose aggregate characterized in that the said aggregate is having a secondary aggregate structure formed by aggregation of primary cellulose particles, a pore volume within a particle of 0.265 cm3 / g-2.625 cm3 / g, containing type I crystals, and having an average particle size of more than 30 µm and 250 µm or less, a specific surface area of 0.1 m2 / g or more and less than 20 m2 / g, a repose angle of 25° or more and less than 44°, a swelling degree of 5% or more, and properties to disintegrate in water.
Full Text DESCRIPTION
POROUS CELLULOSE AGGREGATE AND MOLDING
COMPOSITION THEREOF
TECHNICAL FIELD
[0001]
The present invention relates to a porous
cellulose aggregate that is useful mainly as an
excipient in the field of chemical engineering, in
particular, of pharmaceuticals and of foods, and a
compacting (molding) composition thereof.
BACKGROUND ART
[0002]
In the fields of pharmaceuticals, foods and
other chemical engineering and the like, it has been a
general practice conventionally to prepare a molded
body containing an active ingredient using cellulose
particles such as crystalline cellulose, cellulose
powder and the like as an excipient, and for these
cellulose particles, good compactibility, fluidity and
disintegration property are required.
[0003]
Patent Document 1 describes a porous
cellulose aggregate (corresponding to Comparative
Example 15-17) having a secondary aggregate structure
formed by aggregation of primary cellulose particles,

the aggregate having a pore volume within a particle of
0.265 cm3/g to 2.625 cm3/g, containing type I crystals,
and having an average particle size of more than 30 µm
and 250 µm or less, a specific surface area of 1.3-20
m2/g, a repose angle of 25° or more and less than 44°
and properties to disintegrate in water, and a method
for producing the aforementioned porous cellulose
aggregate comprising a step of drying a dispersion
containing two or more groups of primary cellulose
particles having a different average particle size and
a liquid medium wherein the cellulose dispersion
particles have an average particle size of 1 to 110 µm.
Since the aforementioned porous cellulose aggregate of
the Patent Document requires two or more groups of
primary cellulose particles having a different average
particle size, different primary cellulose particles
prepared by two processes such as grinding dried acid
insoluble residue of commercially available pulp and
the like have to be mixed as described in Example of
the Patent Document. On the other hand the porous
cellulose particles of the present invention can be
obtained advantageously with a single process without
going through a process of grinding or the like. The
porous cellulose aggregates of the present invention
can be obtained by a single process by making the
primary cellulose particles to have a specified range
of average width and average thickness and by making
flexible, thereby promoting entanglement of primary

cellulose particles without being limited by the major
axis of the primary cellulose particles, in other words
by giving self aggregation ability thereto, and are
clearly different from that described in the Patent
Document in terms of the production method. In
addition, because the pore size of the secondary
aggregate structure of the porous cellulose particles
according to the Patent Document is smaller than that
of the porous cellulose aggregates of the present
invention, and the swelling degree is lower in water,
the disintegration property is sometimes not sufficient
for making tablets for a formulation that severely
requires disintegration property in the case of drugs
which is insoluble in water, and even in the case of
soluble drugs, when a water repellent additives such as
magnesium stearate and the like has to be added to
avoid problems in tablet pressing such as sticking and
the like. We have investigated in detail the particle
structure which controls disintegration property, and
as a result confirmed again that the cellulose
particles having a high swelling property have a high
disintegration property, and we realized that for
conventional cellulose powder, if the swelling property
is high, the compactibility is not sufficient, and
conversely if the compactibility is high, the swelling
property is low. That is, no cellulose powder having
both a high compactibility and high swelling property
has been known. We searched for a method to make the

particles porous while keeping the pore diameter of
porous cellulose particles as large as possible and
have managed to solve the aforementioned problem. That
is, we found that excess aggregation can be controlled,
and the inside of the particles can be made porous
while keeping the pore diameter large by using primary
cellulose particles having a specified range of average
width and average thickness and giving self-aggregation
ability thereto. For the porous cellulose aggregates
of Patent Document 1, it is described that when two or
more groups of cellulose particles having different
particle size are mixed, and the cellulose dispersion
is dried, the dispersed cellulose particles having a
small average particles size enter between the
dispersed cellulose particle components having a large
average particle size, and for this reason an excess
aggregation of the dispersed cellulose particles having
the larger average particle size is inhibited, and a
large pore volume is created in the secondary aggregate
structure. However, since tight aggregation is formed
among two or more groups of cellulose having different
average particle size, the pore diameter of the porous
cellulose aggregates obtained by the method
particularly disclosed in the Example was measured to
be small, about 1.5 µm. Since the porous cellulose
aggregate of the present invention uses the single
primary cellulose particles, they are not aggregated as
tightly as the porous cellulose aggregate of the Patent

Document and they are different in having a minimum 3
µm pore diameter. For the size of pore diameter, the
Patent Document describes that a clear peak can be
recognized in the range of 0.1-10 µm and the median
pore diameter, which is a peak top of the pore
distribution and closely related to water permeability
into the particles, is preferably 0.3 µm or larger, and
that although a larger median pore diameter is better,
it is at most 5 µm considering its distribution. It is
described that with a larger median pore diameter,
there is better disintegration property, but it is
speculated that in practice it is difficult to obtain a
large median pore diameter of 3 urn or larger by the
production method according to the Patent Document.
The porous cellulose aggregates of the present
invention has an advantage that porous cellulose
aggregates having a large median pore diameter of 3 µm
or above, which can not be obtained by the production
method of the Patent Document, can be prepared by a
single step without requiring mixing of the different
primary cellulose particles prepared through two steps.
Patent Document 2 describes porous cellulose
particles (corresponding to Comparative 6 of the
present application) having a crystal structure type I,
having pores of diameter of 0.1 µm or above and a
porous rate of 20% or above and containing 90% by
weight or above of a fraction with 350 mesh and above,
which is obtained by mixing cellulose particles with

the third component such as a crystalline compound or
the like that is insoluble or hard to be soluble in
water but soluble in an organic solvent, by granulating
and drying the mixture using water or a water soluble
organic solvent and then extracting/removing the third
component with an organic solvent. The porous
cellulose particles described in this document is
entirely different from the porous cellulose aggregates
of the present invention in the particle structure,
because the primary cellulose particles form such a
homogeneous continuous film-like tight strong cellulose
wall structure that the boundaries of the particles
become unclear. Although the cellulose particle in
Patent Document 2 is superior in its fluidity, the
tight continuous cellulose wall is impermeable to
water, so that the cellulose particle was not
disintegrated in water, and sometimes the rapid release
of an active ingredient was impeded. Further, the
cellulose particle of Patent Document 2 is poor in its
plastic deformation and has insufficient compactibility
while the cellulose is compressed, and furthermore
since an organic solvent and a third component, which
is a crystalline compound soluble in the organic
solvent, are used during the production process, not
only the production cost is high but also the active
ingredient can be inactivated. Thus it is insufficient
to be used stably as an excipient.
[0004]

Patent Document 3 describes porous micro-
cellulose particles (corresponding to Comparative
Example 7 of the present application) having a porous
structure with crystal structure type I, a specific
surface area of 20 m2/g of above and a pore volume of
0.3 cm3 or above for pores with diameter 0.01 µm or
larger, and having an average particle size of at most
100 µm, obtained by granulating and drying fine
particle natural cellulose dispersed in an organic
solvent using spray-dry method. These micro-cellulose
particles also have the aforementioned cellulose wall
structure and are entirely different from the porous
cellulose aggregates of the present invention in the
particle structure. Further, the pore volume itself of
the cellulose particles of Patent Document 3 is large,
but since the particle structure is different from that
of the porous cellulose aggregates of the present
invention, water permeation into the particles is
difficult, and there is a problem of the inferior
disintegration property. In addition, since an organic
solvent is used for these porous cellulose aggregate
particles during the production process, not only is
the production cost high but also the active ingredient
can be inactivated because the specific surface area is
too large and the interaction between the active
ingredient and water is promoted. Thus it is
insufficient to be used stably as an excipient.
[0005]

Patent Document 4 describes cellulose powder
(corresponding to Comparative Example 8 of the present
application) having an average degree of polymerization
of 150-375, apparent specific volume of 1.84-8.92 cm3/g,
a particle size of 300 µm or less as cellulose powder
having a good compactibility and disintegration
property .
[0006]
Patent Document 5 describes micro-crystalline
cellulose aggregates (corresponding to Comparative
Example 9 of the present application) having an average
degree of polymerization of 60-375, apparent specific
volume of 1.6-3.1 cm3/g, apparent tapping specific
volume of 1.4 cm3/g or above, a repose angle of 35-42°,
and containing 2-80% by weight of component of 200 mesh
or above. The cellulose powder obtained according to
Examples of these Patent Documents has a small
intraparticular pore volume according to the
measurement result of pore distribution using mercury
porosimetry and the pore structure is entirely
different from that of the present invention which is
formed intentionally. For that reason, these cellulose
powders have a small specific surface area of 0.6-1.2
cm3 and poor compactibility. These publications
disclose the control of the compactibility, fluidity
and disintegration property of cellulose particles by
adjusting the apparent specific volume, but there were
problems that in the range of relatively small apparent

specific volume of 2-0-2.9 cm3/g, the fluidity and
disintegration property were good but the
compactibility was unsatisfactory, while with larger
apparent specific volume of 3.0-3.2 cm3/g, the
compactibility was good but the fluidity and
disintegration property were poor.
[0007]
Patent Document 6 describes β-1, 4-glucan
powder (corresponding to Comparative Example 1 of the
present application) as cellulose powder having good
compactibility having an average particle size of at
most 30 µm and a specific surface area of 1.3 m2/g. The
(3-1, 4-glucan powder described in the document does not
have the secondary aggregate structure, and individual
primary particles exist singly. Although this glucan
powder has good compactibility, it has problems that
the disintegration property is poor and the fluidity is
inferior due to the small average particle size.
[0008]
Patent Document 7 describes a cellulose
powder (corresponding to Comparative Example 10 of the
present application) having an average degree of
polymerization of 100-375, an acetic acid retention
rate of 280% or above, Kawakita formula (P*V0/(V0-
V)=1/a*b + P/a) wherein a is 0.85-0.90, b is 0.05-0.10,
an apparent specific volume of 4.0-6.0 cm3/g,
substantially no particles of 355 µm or larger, and an
average particle size of 30-120 µm as a cellulose

powder having good compactibility and disintegration
property obtained by hydrolyzing a cellulose-like
substance. The cellulose powder obtained by the method
of Example described in that document has also a small
pore volume within a particle according to the
measurement result of pore distribution using the
mercury porosimetry and thus the pore structure is
entirely different from the intentionally formed pore
structure of the present invention. Although the
cellulose powder of Patent Document 7 is described to
have good compression compactibility and disintegration
property, the best balanced Example that is disclosed
specifically is measured to have a repose angle of over
55° and the fluidity is not satisfactory enough. There
was a problem that in formulations, in which an active
ingredient having poor fluidity was used in large
proportion, the variation coefficient of tablet weight
was larger thereby influencing uniformity of the drug
content. Further, when compacting (molding) was
performed under high pressure using the cellulose
powder according to the document, a high hardness can
be obtained but there was a problem of delayed
disintegration because there is no intentionally formed
intraparticular pore, and water permeability to inside
of the particle was low.
[0009]
Patent Document 8 describes a crystalline
cellulose (corresponding to Comparative Example of 11

of the present application) as the cellulose powder
having good compactibility, disintegration property and
fluidity, which has an average degree of polymerization
of 100-375, and in which the particles that pass
through a 75 µm sieve and are retained on a 38 µm sieve
occupy 70% or more of the total weight, and an average
major axis and minor axis ratio of the particles is 2.0
or higher.
[0010]
Patent Document 9 describes a cellulose
powder (corresponding to Comparative Example of 2-4 of
the present application) as the cellulose having good
compactibility, disintegration property and fluidity,
having an average degree of polymerization of 150-450,
an average L/D (ratio of major axis/minor axis) of 2.0-
4.5 for particles of 75 µm or less, an average particle
size of 20-250 µm, an apparent specific volume of 4.0-
7.0 cm3/g, and a repose angle of 54° or less and a
specific surface area of 0.5-4 m2/g. Since the pore
volume within a particle of the cellulose powders
described in these publications, similar to the cases
described above, measured by the mercury porosimetry is
small, the cellulose have entirely different pore
structure from the intentionally formed pore structure
of the present invention. The cellulose powders
described in these publications give a high hardness to
a molded body by elongating the shape of particles, but
because they have an elongated shape, the apparent

specific volume becomes larger, and the higher the
compactibility, the fluidity decreases. Among the
cellulose powders in Examples described in these
publications, the one having the best fluidity was
measured to have a repose angle of 44°. For example,
when continuous compression was performed at high speed
in a formulation in which an active ingredient having
poor fluidity was mixed in a large proportion, the
variation coefficient of tablet weight was getting
larger, thereby influencing uniformity of the drug
content, and thus satisfactory result was not obtained
in terms of fluidity. Further, when compacting
(molding) was performed under high pressure using the
cellulose powder according to these publications, high
hardness can be achieved but there was a problem of
delayed disintegration because there was no
intentionally formed intraparticular pore, and water
permeability to the inside of particle was low.
[0011]
Patent Document 10 describes a cellulose
powder (corresponding to Comparative Example 14 of the
present application) having an average degree of
polymerization of 150-450, an average particle size 30-
250 µm, an apparent specific volume of over 7 cm3/g and
a holding capacity of polyethylene glycol with a
molecular weight of 400 of 190% or more. The cellulose
powder of this document does not hold a secondary
aggregate structure, and primary cellulose particles

exist substantially as a singlet. Also, the
intraparticular pore volume measured by the mercury
porositometry is small and the cellulose powder has an
entirely different pore structure from the
intentionally formed pore structure of the present
invention. Further, when the apparent specific volume
is large, the fluidity is greatly impaired, and the
repose angle of the best cellulose powder in terms of
fluidity according to this document was measured to be
50°. For example, when continuous compacting (molding)
was performed at high speed in a formulation in which
an active ingredient having poor fluidity was mixed in
a large proportion, the variation coefficient of tablet
weight was increased, thereby influencing uniformity of
the drug content, and thus satisfactory result was not
obtained in terms of fluidity. Further, when
compacting (molding) was performed under high pressure
using the cellulose powder according to the document,
high hardness can be achieved but there was a problem
of delayed disintegration because there was no
intentionally formed intraparticular pores, and water
permeability to the inside of particle was low.
In addition, the average particle size of the
dispersed cellulose particles in the cellulose
dispersion must be 50 µm or larger to increase the
apparent specific volume, but the average particle size
of the dispersed cellulose particles of the present
invention is obtained at 10 µm or larger and less than

50 µm, which is, quite different in terms of the
production method.
[0012]
In the range of 2.3-6.4 cm3/g of the apparent
specific volume for the cellulose powders described in
these Patent Documents 6-9, and in the range of over 7
cm3/g of the apparent specific volume for the cellulose
powders described in Patent Document 10, sufficient
compactibility was obtained in each case but there was
a problem that the fluidity and disintegration property
were deteriorated.
[0013]
Patent Document 11 describes
pharmacologically inert round shaped seed core
containing 10-70% of a crystalline cellulose having an
average degree of polymerization of 60-375 and 10-90%
of a water soluble additive as cellulose particles
having good fluidity. Further, Patent Document 12
describes a pharmacologically inert round shaped seed
core (corresponding to Comparative Example 12 of the
present application) containing 50% or more of a
crystalline cellulose having a water absorbing capacity
of 0.5-1.5 ml/g, roundness of 0.7 or higher, an
apparent tapping specific volume of 0.65 g/ml or
higher, a friability of 1% or less and an average
degree of polymerization of 60-375, wherein distilled
water is added to powder containing crystalline
cellulose at 50% or more while mixing using a mixer

granulator and kneaded to prepare the round shaped seed
core. Patent Document 13 describes microcrystalline
cellulose particles having a loose bulk density of at
least 0.4 g/cm3 (2.5 cm3/g in apparent specific volume),
spherical shape, an average particle size of 2-35 µm
and a smooth surface, wherein the microcrystalline
cellulose particles is prepared by mechanically
reducing the particle size of hydrolyzed cellulose
particles and by spray-drying. Patent Document 14
describes cellulose system particles (corresponding to
Comparative Example 13 of the present application)
containing 10% or more of the crystalline cellulose
having an average degree of polymerization of 60-350,
and having an apparent tapping specific volume of 0.60-
0.95 g/ml, roundness of 0.7 or higher, a shape
coefficient of 1.10-1.50, and an average particle size
of 10-400 µm, wherein the crystalline cellulose is
obtained by hydrolyzing a cellulose material to an
average degree of polymerization of 60-350, then
grinding the result mechanically to the average
particle size of 15 urn, and then drying the dispersion
containing thus obtained crystalline cellulose in a
shape of liquid droplets.
[0014]
The cellulose particles described in these
documents do not form a secondary aggregate structure,
and the celluloses obtained by the method of Examples
described in Patent Documents have an apparent specific

volume of 2.5 cm3/g or lower, nearly spherical shape and
good fluidity but are poor in compression
compactibility, and under the commonly used compression
pressure of 10-20 MPa, a molded body which has
sufficient hardness for practical use can not be made.
As described above, for cellulose particles
of conventional arts, compactibility, fluidity and
disintegration property have been mutually
contradictory characteristics, and it has been hoped to
obtain cellulose particles having these characteristics
in good balance.
[0015]
On the other hand, since the cellulose
particles described in Patent Documents 4-9, and 11-14
do not have intraparticular pores that are
intentionally formed, and pore volume within a particle
is small, almost no active ingredient can be held in
the particles and therefore there have been problems of
liquid components bleeding out in compression
compacting (molding) and problems in tablet press
operation. Also, the cellulose particles described in
Patent Document 2 and 3 have intraparticular pores, but
the pore diameter is small, and therefore it is
difficult for water to permeate into the dense and
continuous cellulose wall, which imposes problems that
the cellulose particle does not disintegrate in water
and quick release of an active ingredient is hindered.
The cellulose particles described in Patent Document 10

has an apparent specific volume that is too big, and
especially in high speed compression compacting
(molding) they sometimes cannot be practically used
because of the their fluidity and disintegration
property.
[0016]
Furthermore, since these cellulose particles
do not have intraparticular pores that are
intentionally formed, and the pore volume within a
particle is small, almost no active ingredient can be
held in the particles, and thus they have a shortcoming
that in solid formulation of an active ingredient that
is hard to be soluble in water, the formulation can not
be practically used due to slow elution of the active
ingredient, unless complicated processes are performed
such as temporary granulation with water or an organic
solvent, drying and the like. They also have a
shortcoming that in solid formulation of an active
ingredient that tends to sublimate, the active
ingredient re-crystallizes during storage, ruining
their commercial value.
[0017]
The active ingredient in a solid formulation
for oral administration is eluted from the formulation
to the body fluid in the digestive tract, absorbed from
the digestive tract, enters into the blood circulation
and expresses the drug effect. Since the active
ingredient that is hard to be soluble in water is

poorly eluted, sometimes it is excreted out of the body
before all the administered active ingredient is eluted
and full effect is not expressed. The ratio of the
total amount of active ingredient entering into the
blood circulation to the administered amount of active
ingredient is generally known as bioavailability, and
to improve bioavailability and the rapid action of
active ingredient, various methods have been
investigated up until now for improving the elution of
hardly-soluble active ingredients.
[0018]
Patent Document 15 describes a method for
grinding an active ingredient that is hard to be
soluble in water and β-1,4-glucan powder together.
This method needs a long time for grinding treatment
until crystalline characteristics of β-1,4-glucan
powder are lost, and also powerful shear must be
applied continuously for a long time using a roll
mixer, thus creating a problem of poor efficiency in
the actual production process. Further, β-1,4-glucan
powder that has lost the crystalline characteristics
has a problem of poor compression compactibility.
[0019]
For a solid formulation for oral
administration prepared by the direct press method from
a main drug that is hard to be soluble in water, Patent
Document 16 describes a method for increasing the
disintegration of the tablet and the rate of elution of

the main drug by increasing the hardness of the tablet
and decreasing the variation of the main drug content
by adding β-1, 4-glucan, a disintegrator and a
surfactant. This document describes no intraparticular
pores, and it is not known at all to improve water
solubility of a drug by mixing an active ingredient
that is hard to be soluble in water and a porous
cellulose aggregate. Furthermore, since a surfactant
has to be added to facilitate the elution of the active
ingredient that is hard to be soluble in water, there
is a problem that when this solid formulation was
administered, the surfactant caused inflammation of the
mucus membrane of the digestive tract.
[0020]
Further, Patent Document 17 describes that
when tablets are produced by the wet press method using
a main drug that is hard to be soluble in water and β-
1,4-glucan through the steps of powder mixing,
kneading, granulation and drying, tablets having a high
tablet hardness, a short disintegration time and a fast
elution rate of the main drug can be produced by adding
a water soluble polymer solution. Also, this document
describes no porous cellulose particle having large
intraparticular pores, and it is not known at all to
improve water solubility of a drug by mixing an active
ingredient that is hard to be soluble in water and a
porous cellulose aggregate. Still further in such a
method, many steps are essential for drying and there

are problems of the cost related to the equipment, and
that the energy cost for drying is high. Also, there
are problems that this method cannot be applied to an
active ingredient inactivated by heat and the like
problems.
[0021]
Patent Document 18 describes a method for
improving the elution of a drug by mixing a hardly-
soluble drug with porous structured cellulose particles
having a particular specific surface area and a pore
volume, which is obtained by granulating and drying
fine particle like natural cellulose dispersed in an
organic solvent by the spray dry method, and absorbing
thereto by sublimation. Since the porous cellulose
particles described in that document have a high
specific surface area and a large pore volume within a
particle, the improvement of elution is sure to be
observed when the hardly-soluble active ingredient is
absorbed by sublimation. However, Example of this
Patent Document uses cellulose particles having
excessively high specific surface area and the active
ingredient absorbed on the surface by sublimation is
amorphous and therefore there is a problem of storage
stability because during the storage a part of the
active ingredient is crystallized and the elution rate
is changed, and in a tightly bound compacting
composition such as a tablet, there is a shortcoming
that the elution of the active ingredient is slow

because its disintegration is impeded due to the poor
disintegration property.
[0022]
A sublimatable active ingredient has a
problem of bleeding out of a solid formulation during
storage, and to prevent this from happening, many of
these solid formulations are film coated or sugar
coated. However, even with such treatments, there are
problems that the active ingredient bleeding out of the
formulation through the film layer causes low
uniformity of the active ingredient content in the
formulation, the active ingredient attached to the
surface of the formulation gives irritating smell when
taking the formulation or re-crystallizing in a
preserving container such as a vial greatly reduces the
commercial value. When the coating treatment is not
performed on the formulation, the sublimation-re-
crystallization is more pronounced than when the
coating treatment is performed.
[0023]
As already described above, in Patent
Document 18 cellulose particles having excessively high
specific surface area was used, and since the active
ingredient absorbed by sublimation on the surface was
amorphous, there was a problem of poor storage
stability of the active ingredient, and in a tightly
bound compacting composition such as a tablet, there
was a shortcoming that the elution of the active

ingredient was slow because its disintegration was
impeded due to the poor disintegration property.
[0024]
Also, as a method for preventing the re-
crystallization caused by sublimation of ibuprofen in
solid formulation, Patent Document 19 describes a
method for preserving ibuprofen containing solid
formulation together with 1 or plurality of stabilizers
selected from the group consisting of polyvinyl
pyrrolidone, magnesium oxide and sodium bicarbonate in
a closed container such as a vial. Using this method
the deposition of crystals to the original closed
container that has preserved the formulation and the
irritating smell of the formulation are surely
improved, but polyvinyl pyrrolidone, magnesium oxide,
sodium carbonate and the like have to be placed in the
container as separate formulations, making the process
more complicated, and thus this is entirely different
from a single formulation which is made sublimation-
proof by adding to the formulation a porous cellulose
such as the formulation of the present invention
containing a sublimatable active ingredient.
[0025]
In the past, a composition containing an
active ingredient that was oily, liquid or semi solid
at normal temperature had problems compared to a solid
active ingredient that it is especially prone to tablet
pressing problems due to the liquid component bleeding

out from the formulation, spots of the liquid component
are produced on the surface of the formulation, and in
the case of granular formulation, inferior fluidity
occurred. These problems not only markedly lower the
quality of the product but also cause the low
uniformity of the concentration and effect of the
active ingredient, and thus improving these problems is
a very important task.
[0026]
In the production of tablets, Patent Document
20-31 describe a method for retaining an active
ingredient that is liquid/semi solid at normal
temperature to an absorption carrier as it is, or
holding an active ingredient dissolved, emulsified or
suspended in water, organic solvent, oil, aqueous
polymer or surfactant to an absorption carrier, and
then compression compacting dried powder or granules
obtained after a drying step. However, by the methods
of these Patent Documents, the active ingredient that
is liquid or semisolid at normal temperature effuses
out at the time of compression, causing tablet pressing
troubles, and sometimes satisfactory compression molded
body may not be obtained. Also, for cellulose
particles these Patent Documents do not describe a pore
volume within a particle, and it is not known that when
the active ingredient that is liquid or semisolid at
room temperature is compressed, the addition of the
porous cellulose particles of the present invention

having a large pore volume within a particle prevents
bleeding out by the porous cellulose aggregate holding
the active ingredient that is liquid or semisolid
inside of the particles and makes preparation of solid
formulations such as powder, granules, tablets and the
like easier. Still further, in the method described in
Patent Document 20-31 many steps are essential for
drying and there are problems that the cost related to
the equipment, and the energy cost for drying is high.
[0027]
Patent Document 2
Patent Document 3
Patent Document 4
Patent Document 5
Patent Document 6
Patent Document 7
Patent Document 8
Patent Document 9
Patent Document 1: International Patent Application
No. 2005/073286 Pamphlet
JP-A-1-272643
JP-A-2-84401
JP-B-40-26274 (CA 699100 A)
JP-A-53-127553 (US4159345 A)
JP-A-63-267731
JP-A-6-316535 (US5574150)
JP-A-11-152233
International Patent Application
No. 02/02643 Pamphlet (US20040053887 Al)
Patent Document 10: International Patent Application
No. 2004/106416 Pamphlet (EP1634908)
Patent Document 11: JP-A-4-283520
Patent Document 12: JP-A-7-173050 (US5505983),
US5384130)
Patent Document 13: JP-A-7-507692 (US5976600 A)
Patent Document 14: International Patent Application


DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0028]
The problem of the present invention is to
provide an excipient having a good compactibility,
fluidity and disintegration property used for producing
a molded body containing various active ingredients by
making cellulose particles into a porous cellulose
aggregate having a specific pore volume.

it in a die, compressing it with a round flat punch
with a diameter of 1.1 cm until a pressure of 10 MPa is
attained, and holding at the target pressure for 10
seconds.
(3) The porous cellulose aggregate according to
(1), in which the cylinder-like molded body having a
hardness of 60-100 N and a repose angle of 25° or larger
and 36° or smaller is obtained by weighing 0.5 g of the
aforementioned porous cellulose aggregate and placing
in a die, compressing with a round flat punch with a
diameter of 1.1 cm until a pressure of 10 MPa is
attained, and holding at the target pressure for 10
seconds.
(4) The porous cellulose aggregate according to
any one of (1)-(3) that can be obtained by a production
method including: a step of obtaining a dispersion
(hereinafter may also be designated as a cellulose
dispersion) containing a natural cellulose material in
which primary cellulose particles have an average
particle size of 10 µm or larger and less than 50 µm,
average width of 2-30 µm and average thickness of 0.5-5
µm, and a step of drying thus obtained cellulose
dispersion.
(5) The porous cellulose aggregate according to
(4), in which the aforementioned cellulose dispersion
contains 10% by weight or less of particles that are
not sedimented at a centrifugal condition of
centrifugal force of 4900 m/s2.

(6) A method for producing the porous cellulose
aggregate according to any one of (1)-(3) including: a
step of obtaining a dispersion (hereinafter may also be
designated as a cellulose dispersion) containing a
natural cellulose material in which primary cellulose
particles have an average particle size of 10 µm or
larger and less than 50 µm, average width of 2-30 µm
and average thickness of 0.5-5 µm, and a step of drying
thus obtained cellulose dispersion.
(7) The method according to (6), in which the
aforementioned cellulose dispersion contains 10% by
weight or less of particles that is not sedimented at a
centrifugal condition of centrifugal force of 4900 m/s2.
(8) The method according to (6), in which
shearing and stirring are performed during a step of
subjecting the aforementioned natural cellulose
substance to a mechanical treatment such as crushing,
grinding or the like or a chemical treatment such as
hydrolysis or the like, or a combination of both
treatments, or stirring is performed during a step
after these treatments.
(9) The method according to (6), in which
shearing and stirring are performed during a step of
subjecting the aforementioned natural cellulose
substance to a mechanical treatment such as crushing,
grinding or the like and then during the step of
hydrolysis.
(10) The method according to (6), in which the

aforementioned natural cellulose substance is subjected
to stirring during the step of hydrolysis, or during
the step thereafter.
(11) The method according to (8), in which the
aforementioned cellulose dispersion contains 10% by
weight or less of particles that are not sedimented at
a centrifugal condition of centrifugal force of 4900
m/s2.
(12) The method according to (9), in which the
aforementioned cellulose dispersion contains 10% by
weight or less of particles that are not sedimented at
a centrifugal condition of centrifugal force of 4900
m/s2.
(13) The method according to (10), in which the
aforementioned cellulose dispersion contains 10% by
weight or less of particles that are not sedimented at
a centrifugal condition of centrifugal force of 4900
m/s2.
(14) The porous cellulose aggregate according to
(4), in which the aforementioned natural cellulose
substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-
99%, S10 of 5-20% and S18 of 1-10%.
(15) The porous cellulose aggregate according to
(5), in which the aforementioned natural cellulose
substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-
99%, S10 of 5-20% and S18 of 1-10%.

(16) The method for producing the porous cellulose
aggregate according to (6), in which the aforementioned
natural cellulose substance is a wood pulp having a
level-off polymerization degree of 130-250, a whiteness
of 90-99%, S10 of 5-20% and S18 of 1-10%.
(17) The method for producing the porous cellulose
aggregate according to (7), in which the aforementioned
natural cellulose substance is a wood pulp having a
level-off polymerization degree of 130-250, a whiteness
of 90-99%, S10 of 5-20% and S18 of 1-10%.
(18) The method for producing the porous cellulose
aggregate according to (8), in which the aforementioned
natural cellulose substance is a wood pulp having a
level-off polymerization degree of 130-250, a whiteness
of 90-99%, S10 of 5-20% and S18 of 1-10%.
(19) The method for producing the porous cellulose
aggregate according to (9), in which the aforementioned
natural cellulose substance is a wood pulp having a
level-off polymerization degree of 130-250, a whiteness
of 90-99%, S10 of 5-20% and S18 of 1-10%.
(20) The method for producing the porous cellulose
aggregate according to (10), in which the
aforementioned natural cellulose substance is a wood
pulp having a level-off polymerization degree of 130-
250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-
10%.
(21) The method for producing the porous cellulose
aggregate according to (11), in which the

aforementioned natural cellulose substance is a wood
pulp having a level-off polymerization degree of 130-
250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-
10%.
(22) The method for producing the porous cellulose
aggregate according to (12), in which the
aforementioned natural cellulose substance is a wood
pulp having a level-off polymerization degree of 130-
250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-
10%.
(23) The method for producing the porous cellulose
aggregate according to (13), in which the
aforementioned natural cellulose substance is a wood
pulp having a level-off polymerization degree of 130-
250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-
10%.
(24) A compacting (molding) composition containing
one or more groups of active ingredients and the porous
cellulose aggregate according to any one of (l)-(3).
(25) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
according to (4).
(26) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
according to (5).
(27) A compacting (molding) composition

characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to (6).
(28) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to (7).
(29) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to any one
of (8)-(10) .
(30) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to (11).
(31) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to (12).
(32) A compacting (molding) composition
characterized by containing one or more groups of
active ingredients and the porous cellulose aggregate
that can be obtained by the method according to (13).
(33) The compacting (molding) composition
according to (24) that is a tablet.
(34) The compacting (molding) composition
according to any one of (25)-(28) that is a tablet.

(35) The compacting (molding) composition
according to (29) that is a tablet.
(36) The compacting (molding) composition
according to any one of (30)-(32) that is a tablet.
Advantages of the Invention
[0031]
Since the porous cellulose aggregate of the
present invention is superior in compactibility,
fluidity and disintegration property, in using the
porous cellulose aggregate of the present invention as
an excipient in production of a molded body containing
various active ingredients, a molded body having a good
homogeneous miscibility with an active ingredient, no
variation of weight, a good uniformity in active
ingredient content, a sufficient hardness, no tablet
press problems, low friability loss and a good
disintegration property can be provided by a simple
method.
[0032]
Since the porous cellulose aggregate of the
present invention greatly enhances elution tablet
pressing and disintegration property of the active
ingredient in a solid formulation containing an active
ingredient which is hard to be soluble in water , it is
especially useful as an excipient for the solid
formulation. Further, since the porous cellulose
aggregate of the present invention prevents the

effusion of a liquid or semi-solid active ingredient
and improves disintegration property in a solid
formulation containing the liquid or semi-solid active
ingredient, it is especially useful as an excipient for
the solid formulation. In addition, in mixing of the
active ingredient and components other than the active
ingredient or in a solid formulation using thereof,
when an active ingredient exists in a minute amount,
and in particular when the average particle size of the
active ingredient is small and the attachment
aggregation characteristic is high, the porous
cellulose aggregate of the present invention can
contribute to a mixing rate of an active ingredient and
to a reduction of the variation of concentration, and
improves tablet pressing and disintegration property,
and thus it is especially useful as an excipient for
the solid formulation. Still further, the porous
cellulose aggregate of the present invention can
prevent recrystallization by a sublimation of a
sublimatable active ingredient in a solid formulation
of the sublimatable active ingredient and prevent a
reduction of the market value, and thus it is
especially useful as an excipient for the solid
formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0189]
Fig. 1 is the pore size distribution of the

porous cellulose aggregate (Example 1) of the present
invention measured by mercury porosimetry;
Fig. 2 is the pore size distribution of
cellulose powder H (Comparative Example 3) measured by
mercury porosimetry;
Fig. 3 is an electron micrograph of cellulose
particle K (Comparative Example 6) at a magnification
of x250;
Fig. 4 is an electron micrograph of cellulose
powder M (Comparative Example 8) at a magnification of
x250;
Fig. 5 is an electron micrograph of cellulose
particle K (Comparative Example 6) at a magnification
of xl500. From this photo it is seen that the septa
are film like and the boundaries of the primary
particles are unclear;
Fig. 6 is a particle cross section photograph
of the porous cellulose aggregate of the present
invention (Example 1) by an electron microscope; and
Fig. 7 is a particle cross section photograph
of cellulose powder M (Comparative Example 8)) by an
electron microscope.
BEST MODE FOR CARRYING OUT THE INVENTION
[0033]
The present invention will be described
particularly centered around the preferred mode as
follows.

The porous cellulose aggregate of the present
invention must have a secondary aggregate structure
composed of aggregated primary particles. This is the
secondary aggregate structure having clear boundaries
of the primary particles when the surface of the
particles is observed at a magnification of x250 or
xl500 by a scanning electron microscope (SEM). The
secondary aggregate structure formed by the aggregation
of the primary particles is closely related to
disintegration property, and the structure without this
particular structure is not preferable because the
disintegration property is deteriorated. When the
boundaries of the primary particles are not clear, for
example having the dense and continuous cellulose
septa, it is not preferable because the particles do
not disintegrate in water and the disintegration
property of a molded body becomes also poor due to the
densely continued and tightly bound primary cellulose
particles.
[0034]
Further, the secondary aggregate structure
formed by the aggregation of the primary particles is
also closely related to not only disintegration
property but also elution of an active ingredient.
Water permeability to the porous cellulose particles
having the secondary aggregate structure formed by the
aggregation of the primary particles is fast, and
disintegration of the primary particles are

accelerated, and when an active ingredient is retained,
the elution of the active ingredient which is hard to
be soluble in water is effectively improved because the
contact area between the active ingredient and water is
increased.
[0035]
In addition, this secondary aggregate
structure is homogeneously distributed whether in the
inside or on the surface of the particles, and is
preferred because, when the secondary aggregate
structure is mixed with an active ingredient, the
active ingredient can be retained between gaps of the
primary cellulose particles and in particular, effusion
of the liquid component can be prevented.
Still further, this secondary aggregate
structure is preferred because it allows retention of
the active ingredient not only on the surface but also
inside of the particles, and therefore it contributes
to the improvement of the mixing rate of the active
ingredient and mixing uniformity, and can greatly
reduce the variation of the concentration.
[0036]
In the porous cellulose aggregate of the
present invention the intraparticular pore volume must
be 0.265 cm3/g-2.625 cm3/g. Porous particles having a
large intraparticular pore volume are superior in
plastic deformability, and since the particles tend to
collapse on compression, they are superior in

compactibility. The porous cellulose aggregate of the
present invention is derived originally from cellulose
in which the pore volume of the aggregated particles is
intentionally enlarged, and thus the plastic
deformability is increased by changing the structure of
the particles themselves. For that reason the
particles express high compression compactibility
irrespective of the apparent specific volume of the
particles. When the intraparticular pore volume is
less than 0.265 cm3/g, the primary cellulose particles
have only the intraparticular pores that the primary
cellulose particles originally have or that are formed
naturally on aggregating cellulose, not intentionally
formed, and thus they are poor in plastic
deformability. To improve the compactibility, the
apparent specific volume of the particles must be
larger, resulting in poor fluidity. The porous
cellulose aggregate of the present invention can keep a
good compactibility with a relatively small apparent
specific volume, and as a result the aggregate having
also a superior fluidity can be obtained.
[0037]
When the intraparticular pore volume is 0.265
cm3 or larger, sufficient pore volume is present in the
particles, and an active ingredient, which is once
incorporated in the pores on the surface of the
particles during the mixing process and compression
process, is not released easily, and thus these

particles are preferred because sufficient amount of
the liquid component can be retained in the
intraparticular pores, and the effusion can be
prevented. When a solid active ingredient is used, the
finely ground active ingredient can be retained
homogeneously and in large amount to improve water
dispersion and elution, and the recrystallization of
sublimatable active ingredient is prevented, especially
the recrystallization during storage is prevented, and
thus these particles are preferred because they can
contribute to the stabilization and prevention of
degeneration of the commercial value, and further they
are preferred because they can contribute to the
improvement of a mixing rate and mixing uniformity of
the active ingredient and can reduce the variation of
the concentration greatly.
[0038]
When an active ingredient which is hard to be
soluble in water is used by dissolving temporally,
suspending or emulsifying, they are preferred because
they are superior in retaining a liquid component. A
drug concentration variation coefficient that is an
index of the variation of the concentration of an
active ingredient is preferably not over 3.0% during
the mixing period, more preferably 2.0% or less, and
especially preferably 1.5% or less. Especially when an
active ingredient that has an average particle size of
10 µm or less and has extremely high aggregatability is

mixed with cellulose particles having the
intraparticular pore volume of 0.265 cmVg or higher
such as the porous cellulose aggregate of the present
invention, it is preferred because the active
ingredient is retained not only on the surface of the
particles but also inside of the particles and thus the
drug concentration variable coefficient can be 2.0% or
less.
[0039]
When the intraparticular pore volume is less
than 0.2 65 cm3/g, the effect described above can not be
obtained because the dispersion uniformity and
retention capacity of a solid or liquid active
ingredient are impaired, causing variation of the
concentration of the active ingredient, aggregation of
solid formulation, poor compression compactibility,
recrystallization of sublimative active ingredients
during storage and lowering of the stability and
commercial value, and therefore it is not preferred.
The larger the intraparticular pore volume
is, the better, but the pore volume that a particle can
have is limited and is at most 2.625 cm3/g.
Furthermore, if the pore volume exceeds 2.625
cm3/g, it is not preferred because the apparent specific
volume is increased and the fluidity is decreased.
As described above, the larger the
intraparticular pore volume, the more it is preferred
because the compactibility is higher due to the

particle having plastic deformability, the active
ingredient is incorporated inside, improving the
elution, the ground active ingredient is retained in a
large quantity, recrystallization of the sublimative
component can be prevented, the mixing rate of the
active ingredient is increased, the mixing uniformity
is improved, the liquid component can be retained and
the like, but when the intraparticular pore volume is
too large, the apparent specific volume tends to be
increased and the fluidity is decreased and therefore
the preferred range of the intraparticular pore volume
where the compactibility and fluidity are in good
balance is 0.265 cm3/g-1.500 cmVg, and especially
preferred range is 0.265 cm3/g-l.000 cm3/g.
[0040]
The distribution of pore diameter of the
porous cellulose aggregate of the present invention is
measured, for example, by mercury porosimetry. It is
preferred that a clear peak is identified especially in
the range of 0.1-10 µm. Further, the median pore
diameter that is a peak top of the pore distribution is
closely related to water permeability into the
particle, and is preferably 0.3 µm or larger. Water
permeability becomes larger when the median pore
diameter is 0.3 µm or larger, and the disintegration
property is improved further. The larger the median
pore diameter the more preferable, but it is at most in
the range of 10-15 µm.

In the production method according to Patent
Document 1, two or more groups of primary cellulose
particles having different average particle size were
mixed and dried, and thus the packing among the
particles was too good and it was difficult to obtain
the pore diameter substantially of 3 µm or larger. The
present invention is especially superior in the balance
of the compactibility and disintegration property, and
the preferred median pore diameter is 3-15 µm and more
preferred is 3-10 µm.
[0041]
The crystalline structure of the porous
cellulose aggregate of the present invention must be
the type I. The crystalline structure of cellulose,
type I, II, III, IV and the like are known, and among
them type I and type II are called as "natural
cellulose" and "regenerated cellulose", respectively
and are used in general, but type III and IV are
obtained in laboratory scale only and not generally
used in industrial scale. Natural cellulose has been
consumed as a plant fiber foodstuff from ancient times
and is widely used at present as a dispersion
stabilizer for liquid foodstuffs and an excipient for
pharmaceutical products. On the other hand,
regenerated cellulose is a product of the altered
crystalline structure which is regenerated by removing
solvents and the cellulose solution of a chemical such
as carbon disulfide, sodium hydroxide or the like, and

some of them are used as a compacting agent for
foodstuffs in a wet processing. The regenerated
cellulose of type II crystalline structure is not
preferred, because with altered crystalline structure
from natural cellulose of type I crystalline structure,
the particles become stiff, have decreased plastic
deformability on compression and cannot give a
sufficient hardness to the molded bodies.
[0042]
In the porous cellulose aggregate of the
present invention, the average particle size must be
over 30 µm and 250 µm or less. When the average
particle size is 30 µm or less, cellulose particles
aggregate each other, the active ingredient is not
diffused homogeneously in mixing with the active
ingredient, the variation of the active ingredient
tends to be greater in the molded body obtained, and
the variation of the weight of the molded body in the
continuous production also tends to be greater.
Further, when the average particle size is over 250 µm,
separation and segregation tend to occur in continuous
compression of a powder formulation mixed with an
active ingredient having poor fluidity.
[0043]
The specific surface area of the porous
cellulose aggregate of the present invention must be
0.1 m2/g or larger and less than 20 m2/g. At the
specific surface area less than 0.1 m2/g, the

compression compactibility is lower, and it is
difficult to give a molded body high hardness and low
friability. Further, when the specific surface area is
over 20 m2/g, it is not preferable to mix an active
ingredient that tends to be inactivated by cellulose,
because the contact area between cellulose and the
active ingredient is excessively too large, and the
active ingredient tends to lose activity.
[0044]
The repose angle of the porous cellulose
aggregate of the present invention must be 25° or larger
and less than 44°. Normally, an active ingredient is
prepared so that when administered, it diffuses in
gastric juice and intestinal juice media and enhances
drug effect rapidly, and for that reason it is often
grounded or is fine powder from the beginning. Since
it is fine powder, the fluidity is poor, and at the
repose angle of 44° or larger, it is not preferred for
the fluidity of the mixed powder when a large amount of
an active ingredient having poor fluidity is mixed.
Especially, there is tendency of the variation of the
weight of the molded bodies at high speed tablet
pressing at a speed of several ten thousands-several
hundred thousands tablets/hour. The fluidity is better
with the smaller repose angle and the repose angle of
25°-42° is especially good. More preferable is a repose
angle of 25°-40°. The repose angle of less than 25° is
not preferable for separation and segregation of the

active ingredient.
The porous cellulose aggregate of the present
invention must have a swelling rate of 5% or larger,
preferably of 6-50%, especially preferably of 7-30%.
The swelling degree can be measured as follows. From
the volume (Vi) of about 10 g of a powder slowly poured
into a cylindrical container having a volume of 100 cm3,
and the volume (V2) after standing for 8 hours after
adding about 50 cm3 of pure water to the powder layer
and mixing so that the powder is completely wet, using
following formula the swelling degree is obtained.
Swelling degree (%) = (V2 - V1)/V1 x 100
Swelling degree is a gap between the primary
cellulose particles created when the primary cellulose
particles are aggregated by drying, and the larger is
the value, the easier to disintegrate due to elevated
water permeability into the particles. In the
conventional cellulose powder, the one having a high
compactibility has to reduce the swelling degree
resulting in sometimes insufficient disintegration
property, and for the other having a high fluidity,
although the swelling degree is high and the
disintegration property is good, it is difficult to
have a high level of compactibility. Among the
conventional cellulose powder, the one having the best
balance for compactibility and disintegration property

is the porous cellulose aggregate of Patent Document 1.
There is no description of the swelling degree in that
document, but the measurement of the porous cellulose
aggregate according to Example described in that Patent
Document revealed that the higher the compactibility,
the lower the value of the swelling degree, and it was
4% at most. So far it has not been achieved to
increase compactibility while maintaining
disintegration property by keeping swelling degree at
high level, and the present invention has achieved this
for the first time.
[0045]
The apparent specific volume of the porous
cellulose aggregate of the present invention is
preferably 2.0-6.0 cm3/g. The porous cellulose
aggregate of the present invention has hardness,
fluidity and disintegration property in a good balance
in almost whole part of the apparent specific volume
compared to the conventional one because of the porous
structure. To obtain a high compression
compactibility, the apparent specific volume is
preferably 2.0 cmVg or larger, and to obtain a higher
fluidity the apparent specific volume is preferable 6.0
cm3/g or less. Especially preferred apparent specific
volume is 2.5-5.0 cm /g.
[0046]
For the porous cellulose aggregate of the
present invention, cylindrical molded bodies, obtained

by weighing 0.5 g of the cellulose powder, placing it
in a die (KIKUSUI SEISAKUSHO LTD, Material SUS2, 3 were
used), compressing with a circular flat punch with a
diameter of 1.1 cm (KIKUSUI SEISAKUSHO LTD, Material
SUS2, 3 were used) until the pressure of 10 MPa and 20
MPa was attained (AIKOH ENGINEERING CO., LTD. PCM-1A
was used. The compression rate was 1 cm/minute), and
holding at the target pressure for 10 seconds, have
preferably the hardness of 60 N or higher and 165 N or
higher, respectively. If the hardness of 10 MPa is
less than 60 N and the hardness of 20 MPa is less than
165 N under each condition, the molded bodies
containing a large amount of an active ingredient
produced at the rate of several ten thousands - several
hundred thousands tablets/hour have a low hardness,
tablet pressing problem such as friability, capping
tend to occur. The tablet hardness shown here is
higher the better, but the hardness of 10 MPa and 20
MPa products are 160 N and 450 N, respectively, at
most.
[0047]
When the aforementioned cylindrical molded
body obtained by compressing to a pressure of 10 MPa
has hardness of 70-160 N, or the one obtained by
compressing to 20 MPa has hardness of 170-410 N and a
repose angle is over 36° and less than 44°, the porous
cellulose aggregate of the present invention is
especially superior because at a high drug content of

about 30% by weight or more, addition of a small amount
of 1-30% by weight of the porous cellulose aggregate of
the present invention gives physical property required
for a formulation such as sufficient compactibility,
friability, disintegration property, content uniformity
and the like. When a cylindrical molded body, obtained
by weighing 0.5 g of a drug having a tablet pressing
problems such as sticking, capping and the like,
placing it in a die (KIKUSUI SEISAKUSHO LTD, Material
SUS2, 3 were used), compressing with a circular flat
punch with a diameter of 1.1 cm (KIKUSUI SEISAKUSHO
LTD, Material SUS2, 3 were used) until the pressure of
50 MPa was attained (AIKOH ENGINEERING CO., LTD. PCM-1A
was used. The compression rate was 1 cm/minute), and
holding at the target pressure for 10 seconds, have
preferably the hardness of 50 N or lower, preferably 40
N or lower, more preferably 20 N or lower, or when both
of the characteristics are present, the porous
cellulose aggregate of the present invention is
especially effective. For conventional cellulose
powder, even if the tablet pressing problems such as
sticking and capping can be controlled at a high drug
content of about 30% by weight, the fluidity was not
sufficient, and the practical application was not
possible due to the tablet weight CV, content CV and
the like. The present invention has markedly improved
the fluidity of the conventional cellulose powder in
the usage described above, and is superior in

expressing both compactibility and fluidity at high
level, despite of the fact that compactibility and
fluidity have been contradictory characteristics until
now. Further, when the aforementioned cylindrical
molded body obtained by compressing to 10 MPa has
hardness of 60-100 N, or the one obtained by
compressing to 20 MPa has hardness of 165-410 N and a
repose angle is 25-36°, the porous cellulose aggregate
of the present invention is especially preferred
because the high drug content of 30% by weight or above
has become possible for the first time in a formulation
that can contain an excipient at about 30% by weight or
more. For the conventional cellulose, lowering the
repose angle causes lowering of the compactibility, and
thus even if the cellulose powder content is about 30%
by weight or more, in trying to increase drug content,
the cellulose powder having good fluidity shows
insufficient compactibility and the cellulose powder
having good compactibility shows insufficient fluidity
resulting in difficulty in formulating, but the present
invention has markedly improved the fluidity of the
conventional cellulose powder in the usage described
above, and is superior in expressing both
compactibility and fluidity at high level, despite of
the fact that compactibility and fluidity have been
contradictory characteristics until now. For the
porous cellulose aggregate of the present invention,
the disintegration time of the cylindrical molded body

obtained under the condition of compressing to a
pressure of 20 MPa and keeping the target pressure for
10 seconds by the aforementioned method is preferably
for 75 seconds or shorter for the sake of
disintegration property. Especially preferable if it
is 50 seconds or shorter. This disintegration time is
shorter the better. Normally, an active ingredient is
prepared so that when administered, it diffuses in
gastric juice and intestinal juice media and enhances
drug effect rapidly, but when the disintegration time
of the molded body is getting longer, and the drug is
eluted from the molded body slower and not absorbed at
the digestive tract quickly, and the rapid drug effect
tends to be decreased.
[0048]
Since compression compactibility and
disintegration property are contradictory
characteristics and the porous cellulose aggregate of
the present invention raised these characteristics to a
level not achieved before, preferably the hardness of
the cylindrical molded body obtained by compressing to
10 MPa is 60-160 N, or the hardness of the cylindrical
molded body obtained by compressing to 20 MPa is 165-
410 N and the disintegration time is 75 seconds or
shorter, and especially preferably the hardness of the
cylindrical molded body obtained by compressing to 10
MPa is 60-160 N, or the hardness of the cylindrical
molded body obtained by compressing to 20 MPa is 165-

410 N and the disintegration time is 50 seconds or
shorter. Since the porous cellulose aggregate of the
present invention can be made with a larger median pore
diameter compared to the porous cellulose aggregate of
the Patent Document 1, it has a higher swelling degree,
and when compared at the same hardness, it has an
advantage of having a shorter disintegration time.
[0049]
A formulated powder is obtained by placing 55
weight parts of acetaminophen (API Corporation, powder
type), 0.25 weight parts of light anhydrous silicic
acid (NIPPON AEROSIL CO., LTD., Commercial name:
Aerosil 200), 27 weight parts of cellulose powder, 2
weight parts of crospovidone (BASF, Commercial name:
Collidone CL) and 15 weight parts of granular lactose
(Lactose New Zealand, Commercial Name: Super-Tab) in a
100 L scale V Type Mixer (Dalton Co., Ltd.) and mixing
for 30 minutes, and then adding 0.5 weight parts of
magnesium stearate (TAIHEI CHEMICAL INDUSTRIAL CO.,
LTD., Plant origin) and mixing for further 5 minutes.
Thus obtained formulated powder is subjected to tablet
pressing using a rotary tablet press (KIKUSUI
SEISAKUSHO LTD, Commercial name: LIBRA-II, 36 lines,
Rotary table Φ410 mm) and a punch with 8 mm diameter and
12 R, at a turn table speed of 50 rpm, at a compression
force of 7.5 kN. For the porous cellulose aggregate of
the present invention it is preferable that thus
obtained 200 mg molded body has a hardness of 50 N or

higher and a friability of less than 1% and no tablet
pressing problem.
[0050]
An excipient having high compactibility is
required to give hardness and to reduce friability to a
formulation containing a large quantity of a drug
having poor compactibility, and at the same time an
excipient having fluidity is required to reduce the
variation of weight when a high speed and continuous
compacting is performed. Such a formulation containing
a large amount of a drug having low compactibility and
the production of the molded body at such a high speed
can only be realized by mixing the excipient having
good compactibility and good fluidity such as the
present invention. When the hardness of the molded
body is less than 50 N and the friability is 1% or
larger, it is not preferred because abrasion, dust
generation, cracking and chipping occur during
transportation. Occurrence of tablet pressing problems
is not preferred because inferior products are
produced. The hardness here is higher the better but
is at most 100 N, and the friability is lower the
better.
[0051]
For the porous cellulose aggregate of the
present invention the tablet hardness of the compacting
composition is preferably 50-100 N (tablet pressing
pressure range: 1-10 kN) and the variation of tablet

weight (CV value) is preferably 2.0 or less when the
repose angle of the final whole formulated powder which
composes the compacting composition of the present
invention is 25°-45° by adding 30-90% by weight of
cellulose particles to 0.001-50% by weight of a
formulated powder having poor fluidity consisting of an
active ingredient and components other than cellulose
particles and having a repose angle of 45°-55°, and
tablets are pressed at the high speed of 50,000 tablets
or more per hour. Preferably the whole formulated
powder has a repose angle of 45° or less, the tablet
hardness of the compacting composition is 50-100 N and
the variation of the tablet weight (CV value) is 1.5%
or less, and especially preferably the whole formulated
powder has a repose angle of 42° or less, the tablet
hardness of the compacting composition is 50-100 N and
the variation of the tablet weight (CV value) is 1.0%
or less (Example 17-19 and Comparative Example 80-91).
[0052]
In direct tablet pressing and the like, when
the fluidity of the active ingredient in the
composition and components other than the porous
cellulose aggregate of the present invention is bad
(repose angle of 45°-55°) and/or the compression
compactibility of such components are poor, it is one
of the characteristics that a remarkable effect can be
obtained by mixing the porous cellulose aggregate of
the present invention in a large quantity which could

not be obtained by conventional cellulose particles and
cellulose powder, because the porous cellulose
aggregate of the present invention has compactibility,
fluidity and disintegration property in a good balance.
That is, in conventional cellulose powder and cellulose
particles, the compactibility increases as the added
amount of cellulose is increased but the fluidity and
disintegration property are getting poorer due to the
fluidity being closer to that of cellulose powder and
cellulose particles themselves, and consequently there
were problems that the high speed tablet pressing at a
practical production speed was difficult and that the
disintegration of thus obtained tablets was delayed.
Against such problems, the porous cellulose aggregate
of the present invention has an advantage of the
fluidity being improved rather than getting worse when
the porous cellulose aggregate of the present invention
is mixed in a large quantity, because the porous
cellulose aggregate of the present invention has a
superior balance in the compactibility and fluidity,
disintegration property at such a high level which is
not attainable by the conventional cellulose powder and
cellulose particles. "Mixing in a large quantity" in
the present invention means that the composition
contains 30-90% of the porous cellulose aggregate of
the present invention. Preferably the content is 30-
80% and especially preferably 30-70%.
[0053]

Following is the description of the method
for producing the cellulose powder of the present
invention.
To produce the porous cellulose aggregate of
the present invention, for example, a dispersion
containing a natural cellulose material (hereinafter
also designated as cellulose dispersion) needs to be
obtained in which the average particle size of the
primary cellulose particles is 10 µm or larger and less
than 50 µm, the average width is 2-30 µm, and the
average thickness is 0.5-5 µm. It is preferable
because entanglement of the primary cellulose particles
to each other can be promoted during the drying process
by making the primary cellulose particles in such a
shape. In the past, it was difficult to keep the shape
of aggregated particles spherical because the longer
the major axis of the primary cellulose particles is,
the more difficult for entanglement of particles to
occur. However, the present invention has focused on
the shape of the primary cellulose particles and proven
for the first time that the entanglement of the
particles can be promoted by controlling it in a
specific range. By promoting the entanglement of the
primary cellulose particles each other, it became
possible for the first time to make the aggregated
particles in a spherical form in an easily controllable
manner and to enhance plastic deformability of the
particles thus giving compactibility more easily by

creating gaps inside of the aggregated particles. In
the past, to control the shape of aggregated particles
spherical, the major axis of the primary cellulose
particles need to be shortened. However, during the
process of treating the primary cellulose particles by
a mechanical treatment or hydrolysis, or a combination
of both, the shorter the major axis of the primary
cellulose particles becomes, the more of the fine
fragments of the primary cellulose particles are
generated, creating the problem that these fine
fragments occupy the gap between the aggregated
particles and a sufficient mold deformity can not be
obtained and the compactibility is decreased. Thus, it
was necessary to granulate particles without shortening
the major axis of the primary cellulose particles, but
such particles are difficult to aggregate and to
improve sphericity. Since the generation of the fine
fragments of the primary cellulose particles described
above in large quantity causes filling of the gaps
between the aggregated particles, it is preferable to
prepare a cellulose dispersion that contains 10% by
weight or less particles that are not sedimented under
a centrifuge condition with a centrifugal force of 4900
m/s2. The porous cellulose aggregate of the present
invention can be obtained by the method for production
including a step of drying that cellulose dispersion.
[0054]
The natural cellulose substance in the

Means for solving the Problem
[0029]
The present inventors, to solve the
aforementioned problem, controlled the particle
structure of a cellulose aggregate, expressed a
secondary aggregate structure, increased an
intraparticular pore volume of the cellulose aggregate
and controlled the powder properties of the cellulose
aggregate to a specific range to complete the present
invention.
That is, the present invention is as follows.
[0030]
(1) A porous cellulose aggregate having a
secondary aggregate structure formed by aggregation of
primary cellulose particles, a pore volume within a
particle of 0.265 cm3/g-2.625 cm3/g, containing type I
crystals, and having an average particle size of more
than 30 µm and 250 µm or less, a specific surface area
of 0.1 m2/g or more and less than 20 m2/g, a repose
angle of 25° or more and less than 44°, a swelling
degree of 5% or more, and properties to disintegrate in
water.
(2) The porous cellulose aggregate according to
(1), in which a cylinder-like molded body having a
hardness of 70-160 N and a repose angle of over 36° and
less than 44° is obtained by weighing 0.5 g of the
aforementioned porous cellulose aggregate and placing

present invention may be derived from plants or animals
and includes fibrous substances derived from natural
products containing cellulose, for example, wood,
bamboo, straw, cotton, ramie, bagasse, kenaf, beet,
ascidian and bacterial cellulose, and may have a
crystalline structure of type I cellulose. Among the
above natural cellulose substances, one group may be
used as a material or a mixture of two or more groups
can be used. It is preferable to be used in the form
of purified pulp but the purification of the pulp is
not particularly restricted, and any of the dissolved
pulp, kraft pulp, NBKP pulp and the like may be used.
The pulp derived from wood is preferable because of the
high purity of a-cellulose, easiness to obtain, the
supply being stable and the like.
It is preferably a wood pulp in which a level
off polymerization degree measured by the copper
ethylenediamine solution method is 130-250, and
whiteness 90-99%, S10 is 5-20% and S18 is 1-10%. The
level off polymerization degree of less than 130 is not
preferable because the compactibility is hard to be
expressed. The polymerization degree of over 250 is
not preferable because the average width and average
thickness of the primary cellulose particles are hard
to control in a specified range. The whiteness of less
than 90 is not preferable because the external
appearance of the porous cellulose aggregate is poor.
The whiteness is higher the better but is at most about

99%. S10 and S18 of outside the range described above
are not preferable in the compactibility and yield.
Here, in the natural cellulose substance, the material
such as pulp may be hydrolyzed or not hydrolyzed. If
hydrolyzed in particular, it may be acid hydrolysis,
alkali hydrolysis, thermal hydrolysis, steam explosion
or the like, and may be any one of the method or a
combination of two or more methods.
[0055]
In the method described above, a medium that
is used for dispersing a solid containing the natural
cellulose substance is preferably water but is not
particularly restricted as long as it can be used
industrially, for example, a mixture of water and an
organic solvent may be used. The organic solvent
includes, for example: alcohols such as methanol,
ethanol, isopropyl alcohol, butyl alcohol, 2-
methylbutyl alcohol and benzyl alcohol; hydrocarbons
such as pentane, hexane, heptane and cyclohexane;
ketones such as acetone and ethylmethyl ketone. In
particular, the organic solvent that can be used for
pharmaceutical use is preferred and includes those
classified as solvents in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.). Water and
organic solvents are freely used singly or in
combination of two or more, and after dispersing the
cellulose in one kind of medium, the medium is removed
and the cellulose may be dispersed in a different

medium.
[0056]
The porous cellulose aggregate of the present
invention needs to be produced by preparing a cellulose
dispersion, in which the primary cellulose particles
have an average particle size of 10 µm or above and
less than 50 µm, an average width of 2-30 µm, an
average thickness of 0.5-5 µm, and which contains 5-40%
by weight of the solid fraction, by subjecting the
natural cellulose substance to treatments that are not
particularly restricted as long as they are publicly
known, for example, mechanical treatment such as
milling and grinding, or chemical treatment such as
hydrolysis or an appropriate treatment of a combination
of both, and then by drying the dispersion.
[0057]
The primary cellulose particles in the
present invention mean particles having the size in the
range of 1-500 µm in which the fibers are split and
newly formed, in the case of fibers composing the
natural cellulose substance, or in the cases where the
natural cellulose substance is subjected to mechanical
treatments such as milling and grinding or the natural
cellulose substance is subjected to chemical treatment
such as hydrolysis. A method for making the average
particle size of the primary cellulose particles less
than 50 µm is achieved, for example, by a mechanical
treatment such as milling and grinding, or a publicly

known separation treatment such as cyclone,
centrifugation and sieving or an appropriate
combination of both by controlling appropriately
conditions generally known to influence the treatment
such as the amount to be treated, shearing force
(rotating rate, shape and size of rotating wings and
the like can influence), centrifugal force and the size
of the sieve mesh, or for example, by a chemical
treatment such as acid hydrolysis by changing
appropriately conditions such as acid concentration and
temperature, or in addition to these by changing
appropriately conditions that are already known to
influence the mechanical treatment and separation
treatment described above.
[0058]
Performing hydrolysis at higher acid or
alkali concentration and reaction temperature, in
general, the polymerization degree of cellulose tends
to be lower and the average dispersed particle size of
cellulose in the dispersion tends to be smaller. Also
stirring the solution with more force, the average
dispersed particle size of cellulose tends to be
smaller. Therefore, by controlling the stirring force
in the steps of hydrolysis and/or dispersion of the
natural cellulose substance, the polymerization degree
of the material cellulose can be controlled in the
desired range. Since the stirring force is dependent
on a width, height, volume of the stirring layer, a

kind of wing, a wind diameter, the stirring rotation
rate and the like, it is difficult to define in a
specific range, but it is preferable that the product
of the wing diameter (m) and the stirring rotation rate
(rpm) is in the range of 5-200, more preferably 10-150,
especially preferably 10-120.
[0059]
A method for making the primary cellulose
particles have an average width of 2-30 µm, an average
thickness 0.5-5 µm is not particularly restricted as
long as the method, for example, splits the primary
cellulose particles to a longitudinal direction, and
includes a method that subjects wood pulp to a
treatment such as a high pressure homogenizer treatment
and optionally to a mechanical treatment such as
grinding and a fraction treatment or an appropriate
combination of both. In the high pressure homogenizer
treatment a pressure may be appropriately controlled in
the range of 10-200 MPa but it may also be dependent on
the amount to be treated. Also, a pulp may be selected
and used in which the primary cellulose particles have
an average width of 2-30 µm and an average thickness of
0.5-5 µm. The cellulose dispersion is preferably
prepared containing particles that are not precipitated
by a centrifugal of condition centrifugal force of 4 900
m/s2 at 10% by weight or less, and such methods
includes, for example, in the case of acid hydrolysis,
a method for changing the hydrolysis conditions

appropriately so that the hydrolysis is difficult to
proceed, a method for removing fine particle components
that are hard to precipitate from the residue or the
dispersion by the separation treatment or the like, or
a combination of both methods.
[0060]
In the hydrolysis of a natural cellulose
substance there is a tendency that the higher the acid
concentration and the higher the temperature, the more
fine particle components that are hard to precipitate
are generated, but since the extent of hydrolysis is
different depending on the degree of polymerization of
the natural cellulose substance, origin of the
material, the extraction method for the cellulose
substance such as method for producing pulp and the
like, it is difficult to define the hydrolysis
conditions in a universal way. However, an appropriate
hydrolysis condition can be readily determined by
measuring the weight of particles which are not
precipitated at a centrifugal condition of centrifugal
force of 4900 m/s2 under which the% by weight of the
particles is 10% by weight or less.
[0061]
The centrifugal condition of centrifugal
force of 4900 m/s2 in the present invention means to
determine the rotating rate for each commercially
available centrifuge considering the rotating radius
(using the maximum radius) of the centrifuge using the

calculation method for a centrifugal force defined by
the following formula, and under the condition of such
rotating rate to perform a centrifugation at the range
of the temperature of 15-25°C for 10 minutes. As the
commercially available centrifuge, an inverter-multi
purpose high speed refrigerated centrifuge (Type 6930,
KUBOTA Corporation, Rapid was used as a mode for
acceleration and deceleration) and a RA-400 angle rotor
(volume: 50 cm3, material: polypropylene co-polymer,
tube angle: 35°, the maximum radius: 10.5 cm, the
minimum radius: 5.8 cm, rotation rate: 4100 rpm) are
preferably used.
Centrifugal force (m/s2) = 11.18 x (rotation
rate (rpm)/1000)2 x rotation radius (cm) x 9.8(m/s2)
[0062]
To prepare a cellulose dispersion, in which
the average particle size of the primary cellulose
particles is 10 µm or above and less than 50 µm, an
average width is 2-30 µm and an average thickness is
0.5-5 µm (preferably, in addition to these, particles
that are not precipitated at the centrifugal condition
of centrifugal force of 4900 m/s2 are 10% by weight or
less) , contributes to form gaps inside the aggregate
due to the entanglement each other between the
neighboring primary cellulose particles when aggregates
of the primary cellulose particles are formed, because
the primary cellulose particles having a specific
average width and average thickness are flexible when

the cellulose dispersion is dried, and further
preferably contributes for the gaps formed in the
aggregates, without being embedded by the particles, to
continue forming porous secondary aggregate structure
having a large intraparticular pore volume after drying
because among the primary cellulose particles in the
cellulose dispersion, 10% by weight or less of the
particles are not precipitated at the centrifugal
condition of centrifugal force of 4900 m/s2.
[0063]
When the average particle size of the primary
cellulose particles become 50 µm or larger, the
secondary aggregate structure is hard to form even if
the shape of the primary cellulose particles is in the
specific range, and the primary particles are dried
individually and this is not preferable in the aspect
of the intraparticular pore volume. Further the
apparent specific volume becomes too large and this is
not preferable in the aspect of the fluidity.
When the average particle size of the primary
cellulose particles is 10 µm or less, the inter-
particular bonding force is too strong when the
particles form the secondary aggregate structure and
this is not preferable in the aspect of disintegration
property. When the average width of the primary
cellulose particles exceeds 30 µm, the primary
cellulose particles become difficult to bend, and the
entanglement between neighboring primary cellulose

particles is decreased, and this is not preferrec in
the aspect of the intraparticular pore volume. When
the average width of the primary cellulose particles is
less than 2 µm, the particles aggregate densely and the
intraarticular pores are not formed. This is not
preferred because the compactibility and disintegration
property are worsened. When the average thickness of
the primary cellulose particles is over 5 µm, the
primary cellulose particles become difficult to bend,
and the entanglement between neighboring primary
cellulose particles is decreased, and this is not
preferred in the aspect of the intraparticular pore
volume. The lower limit of the average thickness of
the primary cellulose particles is the lower, the
easier it is for the particles to entangle, and this is
preferable in the aspect of the intraparticular pore
volume, but this is at most about 0.5 µm. When the
width of the primary cellulose particles is less than 2
µm and the thickness is less than 0.5 µm, such fine
particles are bound tightly, and the intraparticular
pore volume becomes small and thus this is not
preferred because of poor compactibility and
disintegration property.
[0064]
The primary cellulose particles are
preferably used which has a particle shape having the
ratio of the average values of the major axis and minor
axis (L/D) of 2.0 or above. The larger is the L/D, the

more effective it is in inhibiting excessive particle
aggregate in drying, and this contributes to give a
larger pore volume in the particles.
[0065]
The cellulose dispersion of the present
invention is not particularly restricted and may be
produced by any one of the methods selected from i) a
method for producing the cellulose dispersion using the
primary cellulose particles by treating one or
plurality of natural cellulose substances, ii) a method
for producing the cellulose dispersion by dividing the
cellulose dispersion of the aforementioned i), treating
separately and then mixing, iii) a method for producing
the cellulose dispersion by fractionating the cellulose
dispersion of the aforementioned i) or ii), treating
them separately and then mixing again or iv) a method
for producing the cellulose dispersion by mixing two or
more groups of the primary cellulose particles prepared
separately, and from the economical point of view i) is
especially preferable. The treatment method used here
may be a wet method or a dry method, or respective
products obtained by the wet method may be mixed before
drying, or respective products obtained by the dry
method may be mixed before drying or products obtained
by the wet method and dry method may be combined. The
treatment method may be a publicly known method and the
like, and not particularly restricted, including, for
example, a mechanical treatment such as milling and

grinding, and a separation treatment such as
centrifugal separation using a cyclone or a centrifuge
and sieving using a thieve. The method may be used
singly or in combination of both methods.
[0066]
The grinding method may be a grinding method
using the stirring blade of the one-way rotating,
multi-shaft rotary, reciprocating/reversing, vertically
moving, rotating+vertically moving, or duct type such
as a portable mixer, a spatial mixer, a side mixer, or
the like, a jet-type stirring/grinding method such as a
line mixer, a grinding method using a high-shear
homogenizer, a high-pressure homogenizer, an ultrasonic
homogenizer, or the like; or a grinding method using a
rotating axis extrusion kneader. The milling method to
be used may be any one of: a screen milling method such
as a screen mill and hammer mill; a rotating blade
shear screen milling method such as a flush mill; a jet
milling method such as a jet mill; a ball milling
method such as a ball mill, vibration ball milling; a
screw type stirring milling method; and the like.
[0067]
The cellulose dispersion particle mixture
obtained by the aforementioned procedure is preferably
made into a dispersion of a concentration of 5-40% by
weight before drying. If the concentration is less
than 5% by weight, the average particle size of the
cellulose particles to be obtained decreases and the

water soluble macromolecules described in
"Pharmaceutical additives" (published by Yakuji Nippo
Limited.) such as hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyacrylic acid,
carboxyvinyl polymer, polyethylene glycol, polyvinyl
alcohol, polyvinyl pyrrolidone, methylcellulose, gum
Arabic and starch glue, and one kind may be used alone
or a combination of two kinds or more may be used.
[0070]
The surfactant includes surfactants
classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.), for example,
phospholipids, glycerin fatty acid ester, polyethylene
glycol fatty acid ester, sorbitan fatty acid ester,
polyoxyethylene hardened caster oil,
polyoxyethylenecetyl ether, polyoxyethylene stearyl
ether, polyoxyethylenenonylphenyl ether,
polyoxyethylenepolyoxypropylene glycol,
polyoxyethylenesorbitan monolaurate, polysorbate,
sorbitan monooleate, glyceride monostearate,
monooxyethylenesorbitan monoparmitate,
monooxyethylenesorbitan monostearate,
polyoxyethylenesorbitan monooleate, sorbitan
monopalmitate, sodium laurylsulfate, and these are used
alone or a combination of two kinds or more may be used
freely.
[0071]
The foaming agent includes foaming agents

described in "Pharmaceutical additives" (published by
Yakuji Nippo Limited.), for example, tartaric acid,
sodium bicarbonate, potato starch, anhydrous citric
acid, medicinal soap, sodium laurylsulfate, lauric
diethanolamide, macrogoaliaurate, and one kind may be
used alone or a combination of two kinds or more may be
used. Also, other than the pharmaceutical additives,
bicarbonate such as sodium bicarbonate and ammonium
bicarbonate that generate gas by pyrolysis, and
carbonates such as sodium carbonate and ammonium
carbonate that generate gas by reacting with acids may
be used. However, when carbonates described above are
to be used, an acid must be used together. The acid
includes: organic acids such as citric acid, acetic
acid, ascorbic acid, adipic acid; protonic acids such
as hydrochloric acid, sulfuric acid, phosphoric acid
and nitric acid; Lewis acids such as boron fluoride,
and the one used for pharmaceuticals/foods is preferred
but others have the similar effect. In place of the
foaming agent, gases such as nitrogen, carbon dioxide,
liquefied petroleum gas and dimethyl ether may
impregnate the dispersion.
These water soluble macromolecules,
surfactants and gas generating substances may be added
before drying and the timing of addition is not
particularly restricted.
[0072]
The compacting composition in the present

invention may contain one kind or more of the active
ingredients and the porous cellulose aggregate of the
present invention, and the amount is not particularly
restricted, but normal range of the usage is 0.001-99%
for the active ingredient and 1-99% for the cellulose
powder of the present invention. Further, it can be
processed by publicly known methods such as mixing,
stirring, granulating, regulating particle size and
pressing tablet. When the active ingredient is less
than 0.001%, the effective dosage for treatment cannot
be obtained, and at over 99%, the porous cellulose
aggregate of the present invention is less than 1% and
the molded body having practical hardness, friability
and disintegration property is difficult to obtain.
The compacting composition of the present invention can
freely contain not only an active ingredient and
cellulose particles but also optionally an excipient,
disintegrator, binder, fluidizer, lubricant, tasting
agent, flavoring agent, coloring agent, sweetener.
Examples of the compacting composition of the
present invention for pharmaceutical use include
tablets, powder, fine granules, granules, extracts and
pills. The present invention includes the compacting
compositions used for not only pharmaceuticals but also
foods such as sweets, health foods, taste improvers,
dietary fiber supplements and cosmetic solid

foundations, bathing agents, veterinary drugs,
diagnostic agents, agricultural chemicals, fertilizers,

ceramic catalysts.
[0073]
The active ingredient in the present
invention means pharmaceutical drug components,
agricultural chemical components, fertilizer
components, animal feeds components, food components,
cosmetic components, dyes, flavoring agents, metals,
ceramics, catalysts and surfactants, and may take any
form such as solid (powder, crystalline and the like),
oil, liquid or semi solid. Also a coating may be
applied to control elution, reduce bitter taste and the
like. The active ingredients may be used alone or in
combination of a plurality of them. The active
ingredient may be used by dissolving, suspending or
emulsifying in a medium.
For example, a pharmaceutical drug component
that is administered orally such as an antipyretic
analgesic antiphlogistic, hypnotic, antisleepiness
drug, antidizziness drug, pediatric analgesic,
stomachic, antacid, digestive drug, cardiotonic,
antiarrhythmic drug, antihypertensive, vasodilator,
diuretic, antiulcer drug, intestinal regulator,
antiosteoporosis drug, antitussive expectorant,
antiasthmatic drug, antibacterial drug, anti-
pollakiuria drug, analeptic and vitamin can be the
active ingredient. The drug component can be used
alone or in combination of two kinds or more freely.
[0074]

The pharmaceutical active ingredient of the
present invention includes pharmaceutical drug
components described in "Pharmacopeia of Japan", "Rule
for Unofficial Drugs", "USP", "NF", "EP", such as
aspirin, aspirin aluminum, acetaminophen, ethenzamide,
salicylosalicylic acid, salicylamide, lactyl
phenetidine, isothibenzyl hydrochloride,
diphenylpyraline hydrochloride, diphenhydramine
hydrochloride, difeterol hydrochloride, triprolidine
hydrochloride, tripelennamine hydrochloride,
thonzylamine hydrochloride, fenethazine hydrochloride,
methdilazine hydrochloride, diphenhydramine salicylate,
carbinoxamine diphenyldisulfonate, alimemazine
tartarate, diphenehydramine tannate, diphenylpyraline
theoclate, mebhydrolin napadisilate,
promethazinemethylene disalicylate, carbinoxamine
maleate, dl-chlorpheniramine maleate, dl-
chlorpheniramine maleate, difeterol phosphate,
alloclamide hydrochloride, cloperastine hydrochloride,
petoxyverine citrate (carbetapentane citrate),
tipepidine citrate, sodium dibunate, dextromethorphan
hydrobromide, dextromethorphan phenolphthalinate,
tipepidine hibenzate, cloperastine fendizoate, codeine
phosphate, dihydrocodeine phosphate, noscapine
hydrochloride, noscapine, dl-methylephedrine
hydrochloride, dl-methylephedrine saccharin salt,
guaiacol potassium sulfonate, guaifenesin, caffeine
sodium benzoate, caffeine, anhydrous caffeine, vitamin

Bl and derivatives and salts thereof, vitamin B2 and
derivatives and salts thereof, vitamin C and
derivatives and salts thereof, hesperidine and
derivatives and salts thereof, vitamin B6 and
derivatives and salts thereof, nicotinamide, calcium
pantothenate, aminoacetic acid, magnesium silicate,
synthetic aluminum silicate, synthetic hydrotalcite,
magnesium oxide, dihydroxy aluminum aminoacetate
(aluminum glycinate), aluminum hydroxide gel (as dried
aluminum hydroxide gel) , dried aluminum hydroxide gel,
dried mixed gel of aluminum hydroxide/magnesium
carbonate, co-precipitates of aluminum hydroxide/sodium
bicarbonate, co-precipitates of aluminum
hydroxide/calcium carbonate/magnesium carbonate, co-
precipitates of magnesium hydroxide/aluminum potassium
sulfate, magnesium carbonate, magnesium aluminometa
silicate, ranitidine hydrochloride, cimetidine,
famotidine, naproxen, dichlophenac sodium, piroxicam,
azulene, indomethacin, ketoprofen, ibuprofen, difenidol
hydrochloride, diphenylpyraline hydrochloride,
diphenhydramine hydrochloride, promethazine
hydrochloride, meclizine hydrochloride, dimenhydrinate,
diphenhydramine tannate, phenetazine tannate,
diphenylpyraline theoclate, diphenhydramine fumarate,
promethazinemethylene disalicylate, spocolamine
hydrobromide, oxyphencyclimine hydrochloride,
dicyclomine hydrochloride, methixene hydrochloride,
atropine methylbromide, anisotropine methylbromide,

spocolamine methylbromide, methyl bromide-1-
hyoscyamine, benactizium methylbromide, belladonna
extract, isopropamide iodide,
diphenylpiperidinomethyldioxolan iodide, papaverine
hydrochloride, aminobenzoic acid, cesium oxalate, ethyl
piperidylacetylaminobenzoate, aminophylline,
diprophylline, theophylline, sodium bicarbonate,
fursultiamine, isosorbide nitrate, ephedrine,
cephalexin, ampicillin, sulfixazole, sucralfate,
allylisopropylacetylurea, bromovalerylurea or the like,
and ephedra herb, nandia fruit, cherry bark, polygala
root, glycyrrhiza, platycodon root, plantago seed,
plantago herb, senega, fritillaria, fennel,
phellodendron bark, coptis rhizome, zedoary, german
camomile, cinnamon bark, gentiana, oriental bezoar,
animal bile, ladybells, ginger, atractylodes lancea
rhizome, citrus unshiu peel, atractylodes rhizome,
earthworm, panax rhizome, ginseng, kanokoso, moutan
bark, zanthoxylum fruit, and extracts thereof, and
insulin, vasopressin, interferon, urokinase,
serratiopeptidase and somatostatin. One kind selected
from the above group may be used alone or in a
combination of two or more.
[0075]
The active ingredient hard to be soluble in
water in the present invention means, for example, a
pharmaceutical active ingredient, one gram of which
requires 30 ml or more water to dissolve according to

the 14th edition Japanese Pharmacopeia. If it is hard
to be soluble in water, the effect can be obtained by
compounding as an active ingredient to the composition
of the present invention regardless of the extent of
its sublimatablity or surface polarity.
[0076]
The solid active ingredient hard to be
soluble in water includes pharmaceutical drug
components described in "Pharmacopeia of Japan", "Rule
for Unofficial Drugs", "USP", "NF", "EP", such as:
antipyretic analgesics, drugs for nervous system,
sedative hypnotic drugs, muscle relaxant,
antihypertensive drugs, anti-histamine drugs, such as
acetaminophen, ibuprofen, benzoic acid, ethenzamide,
caffeine, camphor, quinine, calcium gluconate, dimethyl
caprol, sulfamin, theophylline, theopromine,
riboflavin, mephenesin, phenobarbital, aminophyllin,
thioacetazone, quercetin, rutin, salicylic acid, sodium
theophyllinate, pyrapital, quinine HC1, irgapirin,
digitoxin, griseofulvin and phenacetin; antibiotics
such as acetylspiramycin, ampicillin, erythromycin,
xatamycin, chloramphenicol, triacetyloleandomycin,
nystatin and colistin sulfate; steroid hormones such as
methyltestesterone, methyl-androsterone-diol,
progesterone, esteradiol benzoate, ethinyl esteradiol,
deoxycorticosterone acetate, cortisone acetate,
hydrocortisone, hydrocortisone acetate and
prednisolone; non-steroid progestogen such as

dienestrol, hexastrol, diethylstillbesterol,
diethylstillbesterol propionate, chlorotrianisene; and
other lipid soluble vitamins, and one kind selected
from the above group may be used alone, or a
combination of two kinds or more may be used freely.
[0077]
The oily or liguid active ingredient hard to
be soluble in water used in the present invention
includes pharmaceutical drug components described in
"Pharmacopeia of Japan", "Rule for Unofficial Drugs",
"USP", "NF", "EP", for example: vitamins such as
teprenone, indomethacin-farnesyl, menatetrenone,
phytonadione, vitamin A oil, fenipentol, vitamin D and
vitamin E; highly unsaturated fatty acids such as DHA
(docosahexaenoic acid), EPA (Eicosapentaenoic acid) and
cod liver oil; coenzyme Qs; lipid soluble flavoring
agents such as orange oil, lemon oil and peppermint
oil. Vitamin E has various isomers and derivatives,
but is not particularly restricted as long as they are
liquid at normal temperature. For example, dl-a-
tocopherol, dl-a-tocopherol acetate, d-a-tocopherol and
d-a-tocopherol acetate are included, and one kind
selected from the above group may be used alone or in a
combination of two or more kinds may be used freely.
[0078]
The semisolid active ingredient hard to be
soluble in water include for example: Chinese medicines
or herbal extracts such as earthworm, glycyrrhiza,

cinnamon bark, peony root, moutan bark, Japanese
valerian, zanthoxylum fruit, ginter, citrus unshiu
peel, ephedra herb, nandia fruit, cherry bark, polygala
root, platycodon root, plantago seed, plantago herb,
red spider lily, senega, fritillaria, fennel,
phellodendron bark, coptis rhizome, zedoary, german
camomile, gentiana, oriental bezoar, animal bile,
ladybells, ginger, atractylodes lancea rhizome, clove,
chlnh.i , atractylodes rhizome, panax rhizome, ginseng,
kakkonto, keishito, kososan, saikeishito, shosaikoto,
shoseiryuto, bakumondoto, hangekobokuto and Maoto;
oyster extract, propolis and propolis extract and
coenzyme Qs, and one kind selected from the above group
may be used alone or in a combination of two or more
kinds may be used freely. The solid formulation
composition of the present invention may further
contain other physiologically active components in
addition to the water insoluble active ingredients
described above.
[0079]
The finely ground active ingredient used in
the present invention means the one finely ground to 1-
40 urn or below for targeting to improve the
dispersibility of the solid active ingredient hard to
be soluble in water, the mixing uniformity of an active
ingredient with pharmaceutical effect even in a small
amount and the like. The smaller is the average
particle size, the greater is the effect of the present

invention. More preferable average particle size of
the active ingredient is 1-20 µm and still more
preferable diameter is 1-10 µm.
[0080]
The sublimatable active ingredient of the
present invention is not particularly restricted as
long as it is sublimatable, and may be solid, liquid or
semi solid at normal temperature.
The sublimatable active ingredient includes
sublimatable pharmaceutical drug components described
in "Pharmacopeia of Japan", "Rule for Unofficial
Drugs", "USP", "NF", "EP", for example, benzoic acid,
ethenzamide, caffeine, camphor, salicylic acid,
phenacetin and ibuprofen. One kind selected from the
above group may be used alone or combination of two or
more may be used freely. The solid formulation
composition of the present invention may further
contain other physiologically active components in
addition to the sublimative active ingredients
described above.
[0081]
The liquid active ingredient at normal
temperature used in the present invention includes
pharmaceutical drug components described in
"Pharmacopeia of Japan", "Rule for Unofficial Drugs",
"USP", "NF", "EP", for example: vitamins such as
teprenone, indomethacin-farnesyl, menatetrenone,
phytonadione, vitamin A oil, fenipentol, vitamin D and

from the above group may be used alone or a combination
of two or more kinds may be used freely.
[0083]
The excipient includes excipients classified
as such in "Pharmaceutical additives" (published by
Yakuji Nippo Limited.) such as, starch acrylate, L-
aspartic acid, aminoethylsulfonic acid, aminoacetic
acid, molasses (powder), gum Arabic, gum Arabic powder,
alginic acid, sodium alginate, gelatinized starch,
pumice particles, inositol, ethylcellulose, ethylene-
vinylacetate copolymer, sodium chloride, olive oil,
kaolin, cacao butter, casein, fructose, pumice
particles, carmellose, carmellose sodium, hydrated
silicone dioxide, dried yeast, dried aluminum hydroxide
gel, dried sodium sulfate, dried magnesium sulfate,
agar, agar powder, xylitol, citric acid, sodium
citrate, disodium citrate, glycerin, calcium
glycerophosphate, sodium gluconate, L-glutamine, clay,
clay 3, clay particles, croscarmellose sodium,
crospovidone, magnesium aluminosilicate, calcium
silicate, magnesium silicate, light anhydrous silicate,
light liquid paraffin, cinnamon powder, crystalline
cellulose, crystalline cellulose carmellose sodium,
crystalline cellulose (particles), genmaikoji,
synthetic aluminum silicate, synthetic hydrotalcite,
sesame oil, wheat flour, wheat starch, wheat germ
flour, rice flour, rice starch, potassium acetate,
calcium acetate, cellulose acetate phthalate, safflower

vitamin E; highly unsaturated fatty acids such as DHA
(docosahexaenoic acid), EPA (Eicosapentaenoic acid) and
cod liver oil; coenzyme Qs; lipid soluble flavoring
agents such as orange oil, lemon oil and peppermint
oil. Vitamin E has various isomers and derivatives,
but is not particularly restricted as long as they are
liquid at normal temperature. For example, dl-a-
tocopherol, dl-a-tocopherol acetate, d-a-tocopherol and
d-a-tocopherol acetate are included, and one kind
selected from the above group may be used alone or a
combination of two or more kinds may be used freely.
[0082]
The semisolid active ingredient at normal
temperature used in the present invention include for
example: Chinese medicines or herbal extracts such as
earthworm, glycyrrhiza, cinnamon bark, peony root,
moutan bark, Japanese valerian, zanthoxylum fruit,
ginter, citrus unshiu peel, ephedra herb, nandia fruit,
cherry bark, polygala root, platycodon root, plantago
seed, plantago herb, red spider lily, senega,
fritillaria, fennel, phellodendron bark, coptis
rhizome, zedoary, german camomile, gentiana, oriental
bezoar, animal bile, ladybells, ginger, atractylodes
lancea rhizome, clove, chinhi, atractylodes rhizome,
panax rhizome, ginseng, kakkonto, keishito, kososan,
saikeishito, shosaikoto, shoseiryuto, bakumondoto,
hangekobokuto and Maoto; oyster extract, propolis and
propolis extract and coenzyme Qs, and one kind selected

oil, bleached beeswax, zinc oxide, titanium oxide,
magnesium oxide, β-cyclodextrin, dihydroxyaluminum
aminoacetate, 2,6-di-butyl-4-methylphenol,
dimethylpolysiloxane, tartaric acid, potassium hydrogen
tartrate, burnt gypsum, sucrose fatty acid ester,
magnesium-aluminum hydroxide, aluminum hydroxide gel,
co-precipitates of aluminum hydroxide/sodium
bicarbonate, magnesium hydroxide, squalane, stearyl
alcohol, stearic acid, calcium stearate, polyoxyl
stearate, magnesium stearate, hardened soybean oil,
purified gelatin, purified shelac, purified white
sugar, purified granule sugar, cetostearyl alcohol,
polyethylene glycol 1000 mono cetyl ether, gelatin,
sorbitan fatty acid ester, D-sorbitol, tricalcium
phosphate, soybean oil, unsaponified soybean product,
soybean lecithin, defatted powdered milk, talc,
ammonium carbonate, calcium carbonate, magnesium
carbonate, neutral anhydrous sodium sulfate, low
substitution hydroxypropyl cellulose, dextran, dextrin,
natural aluminum silicate, corn starch, tragacanth
powder, silicon dioxide, calcium lactate, lactose,
granular lactose, Perfiller 101, white shellac, white
vaseline, white clay, white sugar, white sugar/starch
granule, powder of green leaf extract of rye, dried
powder of green juice of bud leaf of rye, honey,
paraffin, potato starch, half digested starch, human
serum albumin, hydroxypropylstarch,
hydroxypropylcellulose, hydroxypropylcellulose,

self-fluidity tends to be impaired. Also, if this
concentration is over 40% by weight, the apparent
specific volume of the cellulose particles becomes
smaller and the compression compactibility tends to be
impaired. The preferable concentration is 10-40% by
weight and the more preferable concentration is 15-40%
by weight.
[0068]
The drying method is not particularly
restricted and any method such as freeze drying, spray
drying, drum drying, shelf drying, air stream drying
and vacuum drying may be used, and a single method or a
combination of two or more methods may be used. The
spray method in performing spray drying may be any of
the method selected from the disc spray, pressurized
nozzle, pressurized two fluid nozzle and pressurized
four fluid nozzle, and a single method or a combination
of two or more methods may be used. From the
economical point of view, the spray drying is
preferable.
On performing the aforementioned spray
drying, a minute amount of a water soluble
macromolecule or surfactant may be added to the
dispersion to reduce the surface tension, and a foaming
agent or a gas may be added to the dispersion to
accelerate the vaporization rate of the medium.
[0069]
The water soluble macromolecule includes

hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose phthalate, phytic acid,
glucose, glucose hydrate, partially gelatinized starch,
pullulan, propylene glycol, reduced maltose molasses
powder, powdered cellulose, pectin, bentonite, sodium
polyacrylate, polyoxyethylenealkyl ether,
polyoxyethylene hardened caster oil, polyoxyethylene
(105) polyoxypropylene (5) glycol, polyoxyethylene
(160) polyoxypropylene (30) glycol, sodium
polystyrenesulfonate, polysorbate 80, polyvinyl acetal
diethylamino acetate, polyvinyl pyrrolidone,
polyethyleneglycol, maltitol, maltose, D-mannitol,
molasses, isopropyl myristate, anhydrous lactose,
anhydrous calcium hydrogen phosphate, granular
anhydrous calcium hydrogen phosphate, magnesium
aluminometa silicate, methylcellulose, cotton seed
powder, cotton seed oil, wood wax, aluminum
monostearate, glycerin monostearate, sorbitan
monostearate, medical charcoal, peanut oil, aluminum
sulfate, calcium sulfate, granular corn starch, liquid
paraffin, dl-malic acid, calcium monohydrogen
phosphate, calcium hydrogen phosphate, granular calcium
hydrogen phosphate, sodium hydrogen phosphate,
potassium dihydrogen phosphate, calcium dihydrogen
phosphate and sodium dihydrogen phosphate, and one kind
selected from the above group may be used alone or a
combination of two or more kinds may be used freely.
[0084]

The disintegrator includes integrators
classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.) for example:
celluloses such as, croscarmellose sodium, carmellose,
carmellose calcium, carmellose sodium and low
substitution hydroxypropylcellulose; starches such as
carboxymethylstarch sodium, hydroxypropylstarch, rice
starch, wheat starch, corn starch, potato starch and
partially gelatinized starch; and synthetic polymers
such as crospovidone and crospovidone co-polymer. One
kind selected from the above group may be used alone or
a combination of two or more kinds may be used freely.
[0085]
The binder includes binders classified as
such in "Pharmaceutical additives" (published by Yakuji
Nippo Limited.) for example: sugars such as white
sugar, glucose, lactose and fructose; sugar alcohols
such as mannitol, xylitol, maltitol, erythritol and
sorbitol; water soluble polysaccharides such as
gelatin, pullulan, carrageenan, locust bean gum, agar,
glucomannan, xanthan gum, tamarindo gum, pectin, sodium
alginate and gum Arabic; celluloses such as crystalline
cellulose, powdered cellulose, hydroxypropylcellulose
and methylcellulose; starches such as gelatinized
starch and starch glue; synthetic polymers such as
polyvinyl pyrrolidone, carboxyvinyl polymer and
polyvinyl alcohol; and inorganic compounds such as
calcium hydrogen phosphate, calcium carbonate,

synthetic hydrotalcite and magnesium aluminosilicate.
One kind selected from the above group may be used
alone or a combination of two or more kinds may be used
freely.
[0086]
The fluidizing agent includes fluidizing
agents classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.) for example
silicon compounds such as hydrated silicon dioxide and
light anhydrous silicate. One kind selected from the
above group may be used alone or a combination of two
or more kinds may be used freely.
[0087]
The lubricant includes lubricants classified
as such in "Pharmaceutical additives" (published by
Yakuji Nippo Limited.) for example magnesium stearate,
calcium stearate, stearic acid, sucrose fatty acid
ester and talc. One kind selected from the above group
may be used alone or a combination of two or more kinds
may be used freely.
[0088]
The tasting agent includes tasting agents
classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.) for example
glutamic acid, fumaric acid, succinic acid, citric
acid, sodium citrate, tartaric acid, malic acid,
ascorbic acid, sodium chloride and 1-menthol. One kind
selected from the above group may be used alone or a

combination of two or more kinds may be used freely.
[0089]
The flavoring agent includes flavoring agents
classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.) for example oils
such as orange, vanilla, strawberry, yogurt, menthol,
fennel oil, cinnamon oil, picea oil and peppermint oil,
green tea powder. One kind selected from the above
group may be used alone or a combination of two or more
kinds may be used freely.
[0090]
The dye includes dyes classified as such in
"Pharmaceutical additives" (published by Yakuji Nippo
Limited.), for example, food dyes such as food dye red
No. 3, Food dye yellow No. 5, food dye blue No. 1,
copper chlorophyn sodium, titanium oxide and
riboflavin. One kind selected from the above group may
be used alone or a combination of two or more kinds may
be used freely.
[0091]
The sweetener includes sweeteners classified
as such in "Pharmaceutical additives" (published by
Yakuji Nippo Limited.) for example aspartame,
saccharin, dipotassium glycyrrhizinate, stebia,
maltose, maltitol, morasses and powder of Hydrangea
macrophylla var. thunbergii. One kind selected from
the above group may be used alone or a combination of
two or more kinds may be used freely.

[0092]
Following is the description of the method
for production of the tablets, the main components of
which are one or plurality of active ingredients and
the porous cellulose aggregates of the present
invention, but this is an example and the effect of the
invention is not limited by the following method. The
method can be used including a step of mixing an active
ingredient and the porous cellulose aggregates of the
present invention and then a step of compression
compacting. During these steps additives other than
the active ingredient can be mixed optionally, and one
or more kind of the components for example selected
from the group shown above such as excipients,
disintegrators, binders, fluidizers, lubricants,
tasting agents, flavors, dyes, sweeteners and
solubilizers may be added.
[0093]
The order of the addition of the respective
components is not particularly restricted, and any of
the method may be used, i) by which the active
ingredient, the porous cellulose aggregates of the
present invention and optionally other additives are
mixed altogether and subjected to compression
compacting or ii) by which the active ingredient, and
the additives such as the fluidizer and/or lubricant
are pre-mixed and then mixed with the porous cellulose
aggregates of the present invention and, optionally,

with other additives, and subsequently the mixture is
subjected to compression compacting. The lubricant may
be added to the powder mixture for compression
compacting obtained in i) or ii), mixing is continued
and then the mixture may be subjected to compression
compacting.
[0094]
When an active ingredient hard to be soluble
in water is especially used, the following production
method can be used. The production methods, for
example, may be any of, the methods: i) by which the
active ingredient is ground or used as it is, mixed
with the porous cellulose aggregates of the present
invention and optionally with the other additives, and
then the mixture is subjected to compression
compacting, or ii) by which, after dissolving or
dispersing the active ingredient in water and/or an
organic solvent and/or a solubilizer, the solution or
dispersion is absorbed to the porous cellulose
aggregate of the present invention and/or optionally to
the other additives, and mixed with the porous
cellulose aggregate and/or optionally with the other
additives, and after distilling off water and/or the
organic solvent optionally, the mixture is subjected to
compression compacting.
[0095]
Among i), in particular, it is preferable
from the view point of compactibility and fluidity that

after mixing an active ingredient with additives such
as a fluidizer in advance , the active ingredient is
mixed with the porous cellulose aggregates of the
present invention and optionally with other components
and subjected to compression compacting. The
crystalline form of the active ingredient before
compression compacting may be the same or different
from that before the formulation, it is preferable to
be the same from the view point of the stability. When
using a water insoluble active ingredient, it is
effective to use a water soluble polymer or surfactant
in combination especially as a solubilizer to disperse
the active ingredient into the medium. Here, the other
additive means an additive other than the porous
cellulose aggregates of the present invention,
including, for example, the aforementioned excipients,
disintegrators, binders, fluidizers, lubricants,
tasting agents, flavors, sweeteners and solubilizers.
These additives may be used alone or in a combination
of two or more kinds.
[0096]
In the cases of ii) in particular, since the
active ingredient that is hard to be soluble or
insoluble in water goes through a step of
solubilization or dispersion once, an improving effect
for the elution of the active ingredient can be
expected. When a liquid dispersion medium such as
polyethylene glycol is used in combination as a

dispersion medium for a pharmaceutical active
ingredient, the dispersed becomes liquid or semi-solid
even if the active ingredient is originally a
crystalline powder, and thus tablet formulation
therefrom is impossible unless a substance such as the
porous cellulose aggregate of the present invention
having superior compression compactibility and fluidity
is used. Further, when polyethylene glycol or the like
is used as a dispersing agent for a pharmaceutical
active ingredient, it is said that the active
ingredient absorbed in the body takes a structure
covered by polyethylene glycol in the blood stream, and
thus it is expected that the effect of the active
ingredient that is easily metabolized in the liver
lasts longer.
[0097]
A method for adding each component is not
particularly restricted if it is commonly practiced
method, and either the continuous addition or one time
addition may be performed using a small suction
transport device, air transport device, bucket
conveyer, pressure transport device, vacuum conveyer,
quantitative vibration feeder, spray, funnel and the
like.
[0098]
When the active ingredient is a solution,
suspension or emulsion, it is preferable to adopt a
method of spraying that to the porous cellulose

aggregates of the present invention or to the other
additive because it reduces the variation of the
concentration of the active ingredient in the final
products. The spray method may be any methods for
spraying the solution/dispersion of the active
ingredient using a pressure nozzle, 2-fluid nozzle, 4-
fluid nozzle, rotating disc, ultrasonic nozzle or the
like, or methods for instilling the solution/dispersion
of the active ingredient from a tube like nozzle. When
the solution/dispersion of the active ingredient is
added, the active ingredient may be layered on the
surface of the porous cellulose aggregate particles by
layering or coating treatment, may be held inside of
the porous cellulose aggregate particles, or the
solution/dispersion of the active ingredient may be
used as a binding agent for granulating the porous
cellulose aggregate particles or a mixture of the
porous cellulose and the other additives in a matrix-
like structure. The layering and coating treatment may
be performed by a wet method or a dry method.
[0099]
A method for mixing is not particularly
restricted if it is a commonly practiced method, and it
may use a vessel rotation type mixer such as a V type,
W type, double corn type, or container tack type mixer,
a stirring mixer such as a high-speed agitation type,
universal agitation type, ribbon type, pug type, or
nautor type mixer, a super mixer, a drum type mixer, or

a fluidized bed type mixer. In addition, a vessel
shaking type mixer such as a shaker may be also used.
[0100]
A method for the compression compacting of
the composition is not particularly restricted if it is
a commonly practiced method; a method which includes
using a die and a punch for making the composition into
a desired form by means of the compression compacting
or a method which includes preliminarily making the
composition into sheet form by means of the compression
compacting, and cutting into a desired form may be
used. A compression compacting machine may use, for
example, a roller type press such as a hydrostatic
press, a briquetting roller type press, or a smoothing
roller type press, or a compressor such as a single-
punch tableting machine or a rotary tableting machine.
[0101]
A method for dissolving or dispersing an
active ingredient in a medium is not particularly
restricted if it is carried out by the usual
dissolution or dispersion method; a stirring/mixing
method such as a portable mixer, a spatial mixer, a
side mixer, or the like using the stirring blade of the
one-way rotating, multi-shaft rotary,
reciprocating/reversing, vertically moving,
rotating+vertically moving, or duct type, a jer-type
stirring/mixing method such as a line mixer, a gas-
blowing stirring/mixing method, a mixing method using a

high-shear homogenizer, a high-pressure homogenizer, an
ultrasonic homogenizer, or the like, or a mixing method
of vessel shaking type using a shaker, or the like may
be used.
[0102]
A solvent used in the production method
described above is not particularly restricted if it is
used for pharmaceuticals and includes solvents
classified as such in "Pharmaceutical additives"
(published by Yakuji Nippo Limited.), for example,
alcohols such as methanol, ethanol, isopropyl alcohol,
butyl alcohol, 2-methylbutyl alcohol and benzyl
alcohol, hydrocarbons such as pentane, hexane, heptane
and cyclohexane, ketones such as acetone and
ethylmethylketone, and one kind selected from the above
group may be used alone or a combination of two or more
kinds may be used freely, or after dispersing with one
kind of solvent, the solvent may be removed and another
solvent may be used for dispersion.
[0103]
A water soluble polymer as a solubilizer
includes water soluble polymers described in
"Pharmaceutical additives" (published by Yakuji Nippc
Limited.), for example, hydroxypropylcellulose,
hydroxypropylmehylcellulose, polyacrylic acid,
carboxyvinylpolymer, polyethylene glycol, polyvinyl
alcohol, polyvinyl pyrrolidone, methylcellulose,
ethylcellulose, gum Arabic and starch glue, and these

may be used alone or in a combination of two or more
freely.
[0104]
Fat and oils as a solubilizer include fat and
oils described in "Pharmaceutical additives" (published
by Yakuji Nippo Limited.), for example, monoglyceride
stearate, triglyceride stearate, sucrose stearate
ester, paraffins such as liquid paraffin, carnauba wax,
hardened oils such as hardened castor oil, castor oil,
stearic acid, stearyl alcohol and polyethyleneglycol;
these may be used alone or in a combination of two or
more kinds freely.
[0105]
A surfactant as a solubilizer may be, for
example, those classified as a surfactant in
"Pharmaceutical additives" (published by Yakuji Nippo
Limited.), including phospholipid, glycerin fatty acid
ester, polyethylene glycol fatty acid ester, sorbitan
fatty acid ester, polyoxyethylene hardened castor oil,
polyoxyethylene cetyl ether, polyoxyethylene stearyl
ether, polyoxyethylene nonylphenyl ether,
polyoxyethylene polyoxypropylene glycol,
polyoxyethylene sorbitan monolaurate, polysorbate,
sorbitan monooleate, glyceride monostearate,
monooxyethylene sorbitan monopalmitate, monooxyethylene
sorbitan monostearate, polyoxyethylene sorbitan
monooleate, sorbitan monopalmitate, and sodium lauryl
sulfate; these may be used alone or in a combination of

two or more kinds.
[0106]
As used herein, "tablet" refers to a molded
body obtained by compression compacting that includes
the porous cellulose aggregates of the present
invention, one or more active ingredients, and
optionally other additives. A composition for a
tablet, formulated with the porous cellulose aggregates
of the present invention has practical hardness
obtained by a simple and easy method such as direct
tablet pressing without going through a complex
process; however, any preparation method including a
dry granule compression method, a wet granule
compression method, wet granulation compression
(extragranular addition of microcrystalline cellulose),
or a method for preparing a multicore tablet using, as
inner core, a tablet preliminarily subjected to
compression compacting a method for preparing a multi-
layer tablet by stacking molded bodies preliminarily
subjected to compression compacting and compressing
them again may be also used.
[0107]
Since the porous cellulose aggregates of the
present invention is superior in various physical
properties required for an excipient such as
compression compactibility, self fluidity and
disintegration property, it is effectively used for:
tablets containing many kinds and a large quantity of

drugs, which tend to cause tablet pressing troubles
such as lowering of tablet hardness, fractures on the
surface of the tablet, chipping, peeling off from
inside and cracking, for example, the tablets for over-
the-counter drugs and tablets containing extract powder
such as Chinese herb medicine; small tablets; non-
cylinder type odd shaped tablets having a part where
compression pressure is difficult to be applied
homogeneously such as a constricted edge; tablets
containing drugs like enzymes/proteins that are easily
inactivated by tabletting pressure or friction with the
excipient; and tablets containing coated granules. In
addition, since the cellulose powder of the present
invention is superior in compression compactibility and
disintegration property, tablets having a practical
friability can be obtained at a relatively low
compression pressure. For that reason, gaps (watering
capillary) can be maintained in the tablet, it is
effectively used for tablets that disintegrate quickly
in the oral cavity.
[0108]
Further, for multi-layer and multi-core
tablets in which several components of the composition
are compression molded in one or multi-steps, the
porous cellulose aggregates of the present invention is
effective, in addition to preventing the general tablet
pressing troubles described above, in preventing
peeling between the layers and cracks. Having a

secondary aggregate structure that is formed by the
aggregation of the primary particles, the porous
cellulose aggregates of the present invention has a
good cleavability of the particle itself, and when used
in a scored tablet, it is easy to cleave the tablet
evenly. Still further, having a well developed porous
structure, the porous cellulose aggregates of the
present invention has a good retention of drugs in a
fine particulate condition, in a suspension liquid and
in solubilized solution, and thus the tablets utilizing
these have also a good retention of drugs in a fine
particulate condition, in a suspension liquid and in
solubilized solution. Therefore it is effectively used
for preventing the peeling off and strengthening of
layering the coating layer and sugar coat layer of
layering and coating tablets which are treated with
components in suspended liquid or solution, and also
sugar coated tablets on which components such as sugar
and calcium carbonate are layered.
[0109]
Next, the usage of a composition containing
one kind or more of the active ingredients and the
porous cellulose aggregate particles will be described.
The compositions that are obtained by the method
described above containing solid, liquid and semisolid
active ingredients and the porous cellulose aggregate
particles may be used as a solid formulation in powder
or granular conditions, or as coated powder or granular

solid formulation by treating the powder or granular
composition with a coating agent. The powder or
granular composition with or without coating may be
used by filling in a capsule or may be used as a tablet
type solid formulation by treating by the compression
compacting procedure. Still further capsules or
tablets may be used after coating.
[0110]
Here, a coating agent for applying a coating
includes coating agents described in "Pharmaceutical
additives" (published by Yakuji Nippo Limited.), for
example, a dispersion of ethyl acrylate/methyl
methacrylate copolymer, acetyl glycerin fatty acid
ester, aminoalkyl methacrylate copolymer, gum Arabic
powder, ethylcellulose, aqueous dispersion of
ethylcellulose, octyl-decyl triglyceride, olive oil,
kaolin, coca butter, kagoso, castor wax, caramel,
carnauba wax, carboxyvinyl polymer,
carboxymethylethylcellulose, carboxymethylstarch
sodium, calcium carmellose, sodium carmellose, hydrated
silicon dioxide, dried aluminum hydroxide gel, dried
milky white lac, dried methacrylate copolymer, Kanbai
powder (rice granules), fish scale powder, gold foil,
silver foil, triethyl citrate, glycerin, glycerin fatty
acid ester, magnesium silicate, light anhydrous silicic
acid, light anhydrous silicic acid containing
hydroxypropylcellulose, light liquid paraffin, whale
wax, crystalline cellulose, hardened oil, synthetic

aluminum silicate, synthetic wax, high glucose
molasses, hard wax, succinylated gelatin, wheat flour,
wheat starch, rice starch, cellulose acetate, vinyl
acetate resin, cellulose acetate phthalate, bleached
beeswax, titanium oxide, magnesium oxide,
dimethylaminoethylmethacrylate/methylmetharylate
copolymer, dimethylpolysiloxane,
dimethylpolysiloxane/silicon dioxide mixture, silicon
oxide mixture, burnt gypsum, sucrose fatty acid ester,
jinko powder, aluminum hydroxide gel, hydrogenated
rosin glycerin ester, stearyl alcohol, stearic acid,
aluminum stearate, calcium stearate, polyoxyl stearate,
magnesium stearate, purified gelatin, purified shellac,
purified white sugar, zeine, sorbitan sesquioleate,
cetanol, gypsum, gelatin, shellac, sorbitan fatty acid
ester, D-sorbitol, D-sorbitol solution, tricalcium
phosphate, talc, calcium carbonate, magnesium
carbonate, simple syrup, burnt silver foil,
precipitated calcium carbonate, low substituted
hydroxypropylcellulose, turpentine resin, starch
(soluble), corn syrup, corn oil, triacetin, calcium
lactate, white shellac, white sugar, honey, hard fat,
paraffin, pearl powder, potato starch,
hydroxypropylcellulose, hydroxypropylcellulose,
hydroxypropylcellulose acetate succinate,
hydroxypropylcellulose/titanium oxide/polyethylene
glycol mixture, hydroxypropylmethylcellulose phthalate,
piperonyl butoxide, castor oil, diethyl phthalate,

dibutyl phthalate, butylphthalylbutyl glycolate,
glucose, partially gelatinized starch, fumaric
acid/stearic acid/ polyvinyl acetal diethylamino
acetate/hydroxypropylcellulose mixture, pullulan,
propylene glycose, powder sugar, bentonite, povidone,
polyoxyethylene, hardened caster oil, polyoxyethylene
(105) polyoxypropylene (5) glycol, polyoxyethylene
(160) polyoxypropylene (30) glycol,
polyoxyethylenesorbitan monostearate, polyvinyl acetal
diethylaminoacetate, polyvinyl alcohol (partially
saponified), polyethylene glycol, terminal hydroxyl
group substituted methylpolysiloxan silicone resin
copolymer, D-mannitol, molasses, beeswax, myristyl
alcohol, anhydrous silicic acid hydrate, anhydrous
phthalic acid, anhydrous calcium hydrogen phosphate,
methacrylate copolymer, magnesium aluminometa silicate,
methylcellulose, 2-methyl-5-
vinylpyridinemethylacrylate/methacrylic acid copolymer,
wood wax, glycerin monostearate, sorbitan monostearate,
sorbitan monolaurylate, montanic acid ester wax,
medical charcoal, lauromacrogol, calcium sulfate,
liquid coumarone resin, liquid paraffin, dl-malic acid,
calcium monohydrogen phosphate, calcium hydrogen
phosphate, sodium hydrogen phosphate, calcium
dihydrogen phosphate and rosin and these may be used
alone or a combination of two kinds or more may be used
freely.
[0111]

Since the porous cellulose aggregates of the
present invention have a well developed porous
structure, and the particle itself has a superior
retention capability, the particles that retain a drug
in the pores may be used as it is as fine particles, as
granules after granulation, or these may be compression
molded. These fine particles, granules and tablets may
be further coated thereon. The method of retention is
not particularly restricted if it is a publicly known
method, and may include i) a method which includes
mixing with a drug in a fine particle condition and
retaining in the pores, ii) a method which includes
mixing the porous cellulose aggregates with a drug in a
powder condition under a high shearing and forcefully
retaining them in the pores, iii) a method which
includes mixing the porous cellulose aggregates with a
drug preliminary dissolved or dispersed, retaining them
in the pores and then optionally drying for retention,
iv) a method which includes mixing the porous cellulose
aggregates with a sublimatable drug, and sublimating
and absorbing in the pores by heating and/or reducing
pressure, v) a method include mixing and fusing the
porous cellulose aggregates with a drug before or
during heating and retaining fused materials in the
pores, and any of the above methods may be used alone
or a combination of two kinds or more may be used.
[0112]
Since the porous cellulose aggregates of the

present invention have a well developed porous
structure and have a suitable water holding capacity
and oil holding capacity, they can be used not only as
an excipient but also as an core particle for layering
and coating, and in this usage they have an effect for
preventing aggregation among the particles during the
process of layering and coating. The layering and
coating may be a dry method or a wet method.
[0113]
Further, when an active ingredient is a
solution, suspension or emulsion, a method like a
dipping method, which uses the porous cellulose
aggregate particles or a mixture of the porous
cellulose aggregate particles and other additives as a
carrier, may be used which includes immersing in the
solution, suspension or emulsion of the active
ingredient and retaining the active ingredient.
Although it depends on the conditions such as the kind
of the active ingredient and the concentration, even in
the liquid immersion method such as the dipping method,
the uniformity of the active ingredient can be
maintained and it is superior compared to the spray
method described above from the view point of the
simplicity of the process.
Still further, when the active ingredient is
in a solution, suspension or emulsion, a method may be
adopted in which the porous cellulose aggregate
particles or a mixture of the porous cellulose

aggregate particles and the other additives is immersed
as a carrier in the solution, suspension or emulsion of
the active ingredient, and then the dispersion is spray
dried to make a complex.
[0114]
In the porous cellulose aggregate particles
or a mixture of the porous cellulose aggregate
particles and the other additives before or after the
addition of an active ingredient solution/dispersion,
the respective unit particles may be dispersed
individually or may take a form of aggregated granules.
[0115]
When the production process includes
granulation, the method for granulation includes a dry
granulation, wet granulation, heating granulation,
spray granulation and microcapsulation. More
specifically, among the wet granulation methods,
fluidized bed granulation, stirring granulation,
extrusion granulation, disintegration granulation and
tumbling granulation are effective. In the fluidized
bed granulation method, the granulation is performed in
a fluidized bed granulation device by spraying the
binder solution to fluidized powder. In the stirring
granulation method, mixing, kneading and granulation of
the powder are performed in a closed structure at the
same time by rotating a stirring blade in a mixing
trough while the binding solution is added. In the
extrusion granulation, granulation is performed by

forcefully extruding a wet lump that is kneaded by
adding a binder solution through a screen of a suitable
size by means of the screw method or basket method. In
disintegration granulation, granulation is performed by
shearing and disintegrating a wet lump that is kneaded
by adding a binder solution by a rotating blade of a
granulator, and spring granules out of a surrounding
screen by centrifugal force. In tumbling granulation,
spherical granules are tumbled by centrifugal force of
a rotating rotor, and at the same time a binder
solution is sprayed from a spray gun to grow the
particles having a homogeneous particle size like snow
balls.
[0116]
Any of the methods for drying granules such
as a hot air heating type (shelf drying, vacuum drying
and fluidized bed drying), conduction heat type (flat
pan type, shelf box type, drum type) or freeze drying
type may be used. In the hot air heating type, a
material is directly in contact with hot air, and at
the same time evaporated water is removed. In the
conduction heat type, the material is heated indirectly
through a conduction wall. In freeze drying type, the
material is frozen at -10 to -40°C and then water is
removed by sublimation by heating under a high vacuum
(1.3 x 10-5-2.6 x 10-4 MPa) .
[0117]
The methods for compression compacting

include, i) a method in which a mixture of an active
ingredient and the porous cellulose aggregate
particles, or a mixture of one or more groups of active
ingredients and the porous cellulose aggregate
particles, and optionally other additives is
compression molded by a normal method (direct tablet
pressing method), ii) a method in which after mixing an
active ingredient and the porous cellulose aggregate
particles, and optionally other additives, the mixture
was granulated and the granules are compression molded
by a normal method (wet/dry type granule compression
method), or iii) a method in which an active ingredient
and porous cellulose aggregate particles, and
optionally other additives are mixed, granulated and
further the porous cellulose aggregate particles, and
optionally other additives are added and compression
molded by a normal method (compression compacting after
wet/dry type granulation).
[0118]
A method for adding one or more of active
ingredients, the porous cellulose aggregates, other
additives or granules is not particularly restricted if
it is commonly practiced method, and either the
continuous addition or one time addition may be
performed using a small suction transport device, air
transport device, bucket conveyer, pressure transport
device, vacuum conveyer, quantitative vibration feeder,
spray, funnel and the like.

Other than using as tablets after compression
compacting, the composition for tablets of the present
invention may be used as a granular formulation or
powder formulation to improve especially the fluidity,
anti-blocking and anti-coagulation characteristics
because the composition for tablet of the present
invention is superior in retention of solid and liquid
components. Any of the methods for producing granular
formulation and powder formulation, for example, a dry
granulation, wet granulation, heat granulation, spray
drying and microcapsulation may be used.
EXAMPLES
[0119]
The present invention will be described based
on Examples. However, the embodiment of the present
invention is not limited by this description of
Examples. In addition, the methods for measurement and
evaluation of each physical property in Examples and
Comparative Examples are as follows.
[0120]
(1) Average width (|om) of primary cellulose
particles
Primary cellulose particles consisting of a
natural cellulose substance was optionally dried,
placed on a sample platform covered with a carbon tape,
vacuum coated with platinum/palladium (thickness of
vapor deposited film is 20 nm or less), and observed

using JSM-5510V (Commercial Name) made by JASCO
Corporation, at an acceleration voltage of 6 kV at a
magnification of x250. The average of three
representative primary cellulose particles was
calculated.
[0121]
(2) Average thickness (|im) of primary cellulose
particles
Primary cellulose particles consisting of a
natural cellulose substance was optionally dried,
placed on a sample platform covered with a carbon tape,
vacuum coated with gold, and then a cross section of a
primary cellulose particle was excised by Ga ion beam
using a converging ion beam manufacturing apparatus
(Hitachi, Ltd. FB-2100 (Commercial Name)) and observed
at an acceleration voltage of 6 kV at a magnification
of xl500. The average of three representative primary
cellulose particles was calculated.
[0122]
(3) Amount (% by weight) of particles that are
not precipitated under centrifugal condition of
centrifugal force of 4900 m/s2
A cellulose dispersion before drying was
accurately weighed (A(g)) in a centrifuge tube (50 ml
capacity) and adjusted to about 1% cellulose
concentration by adding pure water. The cellulose
dispersion before drying was weighed so that the weight
after the adjustment was about 30 g. The centrifuge

tube containing the cellulose dispersion of about 1%
concentration was placed in an inverter-multi purpose
high speed refrigerated centrifuge (Type 6930, KUBOTA
Corporation, Rapid was used as a mode for acceleration
and deceleration) and a RA-400 angle rotor (volume: 50
cm3, material: polypropylene co-polymer, tube angle:
35°, the maximum radius: 10.5 cm, the minimum radius:
5.8 cm, rotation rate: 4100 rpm) and centrifuged at a
centrifugal force of 4900 m/s2, in the temperature range
of 15-25°C for 10 minutes. After the centrifugation,
the supernatant was transferred to a weighing vial,
dried at 110°C for 5 hours, and the weight of the solid
cellulose after drying was measured (B(g)). In
addition, the cellulose dispersion was weighed
separately in the range of 2-5 g, dried at 110°C for 5
hours and the weight of the solid after drying was
measured (C (%)) .
The amount of particles that are not
precipitated under centrifugal condition of centrifugal
force of 4900 m/s2, D (% by weight), was calculated from
the following formula.
D (% by weight) = {B(g)/[A(g) x (C(%)/100)]} x 100
[0123]
(4) Average particle size (µm) of cellulose
dispersion
The average particle size was expressed as a

cumulative volume 50% particle by measuring the
cellulose dispersed in water using a laser diffraction
particle size distribution analyzer (HORIBA, LA-910
(Commercial Name)) after ultrasonic treatment of one
minute, at refractive index of 1.20. However, this
measurement does not necessarily correlate to the
particle size distribution of dried particles obtained
by the Ro-tap method described below because of
entirely different principle of measurement. The
average particle size measured by the laser diffraction
is obtained from the volume frequency that is dependent
on the major axis of the fibrous particle, while the
average particle size obtained by the Ro-tap method is
dependent on the minor axis of the fibrous particle
because the fractionation is performed by shaking the
obtained powder on a sieve. Therefore, the laser
diffraction method that depends on the major axis of
the fibrous particle sometimes produces larger figures
than that of the Ro-tap method that depends on the
minor axis of the fibrous particle.
[0124]
(5) Crystalline form
An X ray diffraction analysis was conducted
by an X ray diffract meter and the crystalline form was
determined from the X ray pattern.
(6) Average particle size (µm) of dried
particles.
The average particle size of powder sample

was measured using a Ro-tap sieve shake (Taira
Kosakusho Ltd., Sieve Shaker A type (Commercial Name)),
and JIS standard sieve (Z8801-1987) by sieving 10 g of
the sample for 10 minutes and expressed as the
accumulated weight 50% particle size.
(7) Specific surface area (m2/g)
The measurement was made by the BET method
using a TriSTAR (Micrometrics Co., Commercial Name) and
nitrogen as an absorbing gas. About one gram of each
sample was placed in a cell and measured. Each sample
powder used for the measurement had been dried at 110°C
for 3 hours under reduced pressure.
[0125]
(8) Intraparticular pore volume (cm3/g) and median
pore diameter (µm)
Pore size distribution was obtained by the
mercury porosimetry using an autopore type 9520
(Commercial Name, made by Shimadzu Corporation). Each
sample powder used for the measurement had been dried
at room temperature for 15 hours under reduced
pressure. From the pore size distribution obtained by
the measurement at the initial pressure of 20 kPa, "the
clear peak area" in the range of pore diameter of 0.1-
15 µm was calculated as the intraparticular pore
volume. Further the peak top of "the clear peak"
observed in the range of pore diameter of 0.1-15 µm was
regarded as the median pore diameter from the obtained
pore size distribution and the value was recorded.

[0126]
(9) Apparent specific volume (cm3/g)
The powder sample was poured into a 100 cm3
measuring cylinder using a quantitative feeder or the
like in 2-3 minutes and the top layer of the powder
sample was made flat using a soft brush and the volume
was read. The apparent specific volume was obtained by
dividing this volume with the weight of the powder
sample. The weight of the powder sample was suitably
set so that the volume was 70-100 cm3.
[0127]
(10) Observation of the particle surface and pores
by SEM
Each cellulose sample was placed on a sample
platform covered with a carbon tape and vacuum coated
with platinum/palladium (thickness of vapor deposited
film is 20 nm or less), and observed using JSM-5510V
(Commercial Name) made by JASCO Corporation, at an
acceleration voltage of 6 kV at a magnification of
x250-xl500. A sample was regarded O when it has a
secondary aggregated particle structure consisting of
continuously aggregated primary particles, in which the
boundary between the primary particles were clear and
the confirmable median pore diameter was 0.1 urn or
above. A sample having a structure other than that was
regarded X.
[0128]
(11) Disintegration of cellulose particles in

water
Each cellulose sample of 0.1 g was placed in
a glass test tube, mixed with 10 g of pure water and
treated with ultrasonic for 1 minute. Observations
were made using a microscope (Made by Keyence
Corporation, VH-7000 (Commercial name)) with or with
our ultrasonic treatment, and the presence or absence
of particle disintegration was monitored. The sample
in which disintegration was observed was O and not
observed was x.
[0129]
(12) Reactivity to a drug
Aspirin (Japanese Pharmacopeia crystalline
aspirin was treated with a small grinder Φ0.5 mm, with 1
pass treatment) and each cellulose sample was mixed at
5/5 (total 0.5 g) in dry conditions and then placed in
a glass sample vial and mixed. The vial was stored in
an oven (Made by Tabai Espec Corp. Perfect Oven
(Commercial Name)) with the cap tightly closed (at 60°C)
for two weeks and then the decomposition rate was
measured. Ferric (III) sodium sulfate 12 hydrate 8 g
was placed in a 100 ml measuring flask, mixed with pure
water to bring the volume up to 100 ml to make a
coloring test solution. 0.25 g of stored aspirin
(total 0.5 g of the blended powder) was introduced to a
50 ml measuring flask, mixed with ethanol to bring the
volume up to 50 ml and the mixture was shaken for 5
minutes. Thus obtained ethanol solution was filtered,

the filtrate was transferred to a 100 ml measuring
flask and ethanol was added to bring the volume up to
100 ml. One milliliter of this ethanol solution and 1
ml of the coloring test solution described above were
introduced to a 50 ml measuring flask, mixed with pure
water to bring the volume up to 50 ml and the
absorption was measured at the wavelength of 532 nm
using a UV absorption meter (made by JASCO
Corporation). The decomposition rate was calculated
from the following formula.
Decomposition rate (%) = (1-(absorption after
the storage/absorption before the storage)) x 100
The sample showing a decomposition rate over
15%, which is the decomposition rate of aspirin alone
was judged to be reactive.
[0130]
(13) Repose angle (°)
Using a Sugihara type repose angle measuring
device (slit size: depth 10 mm x width 50 mm x height
140 mm, a protractor was placed at the position of 50
mm width), the dynamic self-fluidity was measured when
cellulose powder was dropped to the slit at 3 g/minute
using a quantitative feeder. The angle between the
bottom of the device and the top layer of the cellulose
powder is the repose angle.
(14) Swelling degree

The swelling degree was obtained from the
volume (V1) of about 10 g of powder which was slowly
poured into a cylindrical container having 100 cm3
capacity and the volume (V2) of the same powder when
about 50 cm3 of pure water was added to the powder and
the result is mixed so that the powder was thoroughly
wetted and then left standing for 8 hours, by the
following formula.
Swelling degree (%) = (V2-V1) /V1 x 100
[0131]
(14) Compression compacting of a cellulose sample
alone
0.5 g of each cellulose powder was weighed,
placed in a die (KIKUSUI SEISAKUSHO LTD, Material SUS2,
3 were used), compressed with a circular flat punch
with a diameter of 1.1 cm (KIKUSUI SEISAKUSHO LTD,
Material SUS2, 3 were used) until the pressure of 10
MPa and 20 MPa was attained (AIKOH ENGINEERING CO.,
LTD. PCM-1A was used. The compression rate was 1
cm/minute), and held at the target pressure for 10
seconds, and then a cylindrical molded body was taken
out.
[0132]
(15) Rotary tablet pressing of the formulated
powder
55 weight parts of acetaminophen (API

Corporation, powder type), 0.25 weight parts of light
anhydrous silicic acid (Nippon NIPPON AEROSIL CO.,
LTD., Commercial name: Aerosil 200), 27 weight parts of
cellulose particles of powder obtained in Examples and
Comparative Examples, two weight parts of crospovidone
(BASF, Commercial name: Collidone CL) and 15 weight
parts of granular lactose (Lactose New Zealand,
Commercial Name: Super-Tab) were placed in a 100 L
scale V Type Mixer (Dalton Co., Ltd.) and mixed for 30
minutes, and then 0.5 weight parts of magnesium
stearate (TAIHEI CHEMICAL INDUSTRIAL CO., LTD., Plant
origin) was added and mixed for further 5 minutes to
obtain the formulated powder. Here the total amount of
input powders was 25 kg. Thus obtained formulated
powder was subjected to tablet pressing using a rotary
tablet press (KIKUSUI SEISAKUSHO LTD, Commercial name:
LIBRA-II, 36 lines, Rotary table Φ410 mm) and the
formulated powder was supplied by a stirring feeder.
Tablet pressing was performed using a punch with 8 mm
diameter and 12 R, at a turn table speed of 50 rpm, at
a compression force of 7.5 kN to obtain tablets
weighing 200 mg each.
[0133]
(16) Variation of tablet mass (%)
Twenty tablets obtained by the rotary tablet
pressing were weighed, and the average weight and the
standard deviation of the weight were calculated, and
the variation of the mass was evaluated from the

variation coefficient defined by the formula (standard
deviation/average weight) x 100. The smaller is the
variation coefficient, the smaller is the variation.
[0134]
(17) Tablet hardness (N)
Using a Schleuniger hardness tester (Freund
Corporation 6D type (Commercial Name)), a cylindrical
molded body or a tablet was subjected to a load from
the direction of the diameter until destroyed and the
load at this time was measured. The hardness was
expressed as an average of 10 samples.
[0135]
(18) Disintegration time (second)
The disintegration test was conducted
according to the tablet disintegration test method, in
the general test method of the 14th edition of the
Japanese Pharmacopeia. For a cylindrical molded body
or a tablet the disintegration time was obtained in
pure water at 37°C using a disintegration tester (Toyama
Sangyo Co., Ltd., NT-40HS type (Commercial Name), in
the case of cellulose alone: with disc; in the case of
the formulation: without disc). The disintegration
time was expressed as the average of 6 samples.
[0136]
(19) Tablet friability (% by weight)
Twenty tablets were weighed (Wa), placed in a
friability tester (Japan Machinery Company, PTF-3RA
type (Commercial Name)), rotated at 25 rpm for 4

minutes, and then fine powder attached to the tablets
was removed. The weight (Wb) of the tablets was
measured again and the friability was calculated from
the following formula.
Friability = 100 x (Wa-Wb)/Wa
[0137]
(20) Incidence of tablet pressing problems (%)
One hundred tablets obtained by a rotary
tablet press were randomly selected and subjected to
visual inspection. The number of tablets with
splitting (lamination), breaking off (chipping) and
peeling off (capping) was counted, and the total number
of these tablets was divided by the number of the
inspected tablets to obtain the%.
(21) Level-off polymerization degree of wood pulp
Ten grams of wood pulp was shredded,
hydrolyzed under the condition of 2.5 N hydrochloric
acid, at a boiling temperature for 15 minutes and then
purified. The dried powder thus obtained was subjected
to measurement according to the viscosity method
(copper ethylenediamine method) described in the
crystalline cellulose confirmation test (13) of the 13th
edition of the Japanese Pharmacopeia to obtain the
polymerization degree.
(22) Whiteness of wood pulp
This value is measured according to ISO

(filter R4 57). The measurement was made by a color
difference meter using a blue filter regarding the
perfect white as 100%. The degree of whiteness was
defined as a reflection rate at a transmission central
wavelength of 457 µm.
(22) S10, S18 of wood pulp
A value measured according to Tappi T253m-60.
S10:
100 cm3 of 10% NaOH was placed in a glass
container, cooled to 20°C for 30 minutes, and 1.6 g of
shredded pulp (dry weight is G) was added and immersed
well in alkali. The mixture was then stirred at 2300-
2800 rpm to dissolve the pulp completely. After
cooling the glass container with water, 10 cm3 of 0.4 N
potassium dichromate and 30 cm3 of concentrated sulfuric
acid were added to 10 cm3 of the filtered solution, and
then 100 cm3 of pure water was added and the mixture
cooled in water for 30 minutes. After adding 10 cm3 of
10% KI and standing, the mixture was titrated with 0.1
N sodium thiosulfate. The volume of sodium thiosulfate
at the endpoint was A (cm3) . For 10 cm3 of 10% NaOH
before adding pulp, the titration described above was
performed. The volume of sodium thiosulfate at the
endpoint was B (cm3) . S10 is calculated from the
following formula.
S10 (%) = (B-A) x 0.685/G
G = weight of pulp x (100-water content of pulp)/100

The water content of pulp is calculated by drying the
pulp at 125°C for 1.5 hours.
S10:
Was measured according to the same method as
S10 except that 18% NaOH was used.
[0138]
(Example 1)
Two kg of shredded commercially available
pulp (natural cellulose dissolved pulp derived from
wood, average polymerization degree: 1030, average
fiber width of the primary cellulose particles: about
39 µm, average thickness: about 8 µm) was immersed in
water and, under the condition of containing about 70%
water, passed through a cutter mill (URSCHEL
LABORATORIES, INC. "Comitrol" (Commercial Name), Model
1700, Microhead/blade gap: 2.029 mm, Immpeler rotation
rate: 9000 rpm) and mixed with pure water to prepare a
cellulose dispersion of about 2% concentration, which
was treated twice with a high pressure homogenizer
(MFIC Corp. Commercial Name "Microfluidizer" M-140K
type, Process pressure: 200 MPa) and then centrifuged
at a centrifugal force of 19600 m/s2 to obtain the
precipitates after discarding the supernatant. The
precipitates were dried at 40°C for 16 hours, and about
2 kg of the dried precipitates and 30 L of 4 N
hydrochloric acid solution were placed in a low speed
stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGL Reactor

(Commercial Name)). Hydrolysis was performed at 40°C
for 48 hours while stirring to obtain an acid insoluble
residue. After sufficient washing with pure water, the
acid insoluble residue thus obtained was filtered,
introduced to a 90 L polyethylene bucket, mixed with
pure water to bring the concentration of the total
solid fraction to 20% by weight and neutralized with
ammonia water while stirring with a 3-1 motor (pH after
neutralization was 7.5-8.0). The average fiber width
of the primary cellulose particles in this cellulose
dispersion containing 20% by weight of the solid
fraction was about 19 µm, average thickness was about
3µm and average particle size was 38 µm. This
cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220°C, outlet
temperature: 50-70°C) to obtain the cellulose particle A
that is the cellulose aggregate. The physical
properties of the cellulose particle A are shown in
Table 1.
[0139]
Fig. 1 shows the results of the measurement
of the pore size distribution of the cellulose particle
A by the mercury porosimetry, and Fig. 6 shows an
electron micrograph of the cross section of the
cellulose particle A. As shown in Fig. 1, in the
cellulose particle A, a "clear peak" that was derived
from the intraparticular pores was confirmed in the
range of 0.1-15 µm. This is about the same size as the

pore size shown in the electron micrograph by SEM. In
addition, the peak shown in the range of 10-50 µm in
Fig. 1 is derived from the gap between particles. As
shown in Fig. 6, the development of the intraparticular
pores having the pore diameter that corresponded to the
"clear peak" shown in Fig. 1 was also observed.
(Example 2)
By subjecting broadleaf trees to a known
pulping treatment and bleaching treatment, a pulp was
obtained having an average fiber width of the primary
cellulose particle of about 19 µm, average thickness of
about 3 µm, level off polymerization degree of 140-220,
water content of 5-10%, whiteness of 92-97%, viscosity
of 5-40 cps, S10 5-15%, S18 1-8%, copper value of 0.5-1.5
and dichloromethane extracts of 0.03 ppm or less. Two
kilograms of this pulp and 30 L of 4 N hydrochloric
acid solution were placed in a low speed stirrer
(Ikebukuro Horo Kogyo Co., Ltd., 50LGL Reactor
(Commercial Name)). Hydrolysis was performed at 40°C
for 48 hours while stirring to obtain an acid insoluble
residue. After sufficient washing with pure water, the
acid insoluble residue thus obtained was filtered,
introduced to a 90 L polyethylene bucket, mixed with
pure water to bring the concentration of the total
solid fraction to 15% by weight and neutralized with
ammonia water while stirring with a 3-1 motor (pH after
neutralization was 7.5-8.0). The average fiber width
of the primary cellulose particles in this cellulose

dispersion containing 15% by weight of the solid
fraction was about 22 µm, average thickness was about
2.5 µm and average particle size was 38 µm. This
cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220°C, outlet
temperature: 50-70°C) to obtain the cellulose particle B
that is the cellulose aggregate. The physical
properties of the cellulose particle B are shown in
Table 1.
(Example 3)
By subjecting broadleaf trees to a known
pulping treatment and bleaching treatment, a pulp was
obtained having an average fiber width of the primary
cellulose particle of about 19 µm, average thickness of
about 3 µm, level off polymerization degree of 140-220,
water content of 5-10%, whiteness of 92-97%, viscosity
of 5-40 cps, S10 5-15%, S18 1-8%, copper value of 0.5-1.5
and dichloromethane extracts of 0.03 ppm or less. Two
kilograms of this pulp and 30 L of 5 N hydrochloric
acid solution were placed in a low speed stirrer
(Ikebukuro Horo Kogyo Co., Ltd., 50LGL Reactor
(Commercial Name)). Hydrolysis was performed at 40°C
for 20 hours while stirring to obtain an acid insoluble
residue. After sufficient washing with pure water, the
acid insoluble residue thus obtained was filtered,
introduced to a 90 L polyethylene bucket, mixed with
pure water to bring the concentration of the total
solid fraction to 15% by weight and neutralized with

ammonia water while stirring with a 3-1 motor (pH after
neutralization was 7.5-8.0). The average fiber width
of the primary cellulose particles in this cellulose
dispersion containing 18% by weight of the solid
fraction was about 22 µm, average thickness was about
2.5 µm and average particle size was 35 µm. This
cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220°C, outlet
temperature: 50-70°C) to obtain the cellulose particle C
that is the cellulose aggregate. The physical
properties of the cellulose particle C are shown in
Table 1.
(Example 4)
Two kilograms of shredded commercially
available pulp (natural cellulose dissolved pulp
derived from wood, average polymerization degree: 1030,
average fiber width of the primary cellulose particles:
about 39 µm, average thickness: about 8 µm) was
immersed in water and, under the condition of
containing about 70% water, passed through a cutter
mill (URSCHEL LABORATORIES, INC. "Comitrol" (Commercial
Name), Model 1700, Microcuthead/blade gap: 2.029 mm,
Immpeler rotation rate: 9000 rpm) and mixed with pure
water to prepare a cellulose dispersion of about 2%
concentration, which was treated 4 times with a high
pressure homogenizer (MFIC Corp. Commercial Name
"Microfluidizer" M-140K type, Process pressure: 200
MPa) and then centrifuged at a centrifugal force of

19600 m/s2 to obtain the precipitates after discarding
the supernatant. The precipitates were dried at 40°C
for 16 hours, and about 2 kg of the dried precipitates
and 30 L of 5 N hydrochloric acid solution were placed
in a low speed stirrer (Ikebukuro Horo Kogyo Co., Ltd.,
50LGL Reactor (Commercial Name)). Hydrolysis was
performed at 40°C for 20 hours while stirring to obtain
an acid insoluble residue. After sufficient washing
with pure water, the acid insoluble residue thus
obtained was filtered, introduced to a 90 L
polyethylene bucket, mixed with pure water to bring the
concentration of the total solid fraction to 20% by
weight and neutralized with ammonia water while
stirring with a 3-1 motor (pH after neutralization was
7.5-8.0). The average fiber width of the primary
cellulose particles in this cellulose dispersion
containing 20% by weight of the solid fraction was
about 15 µm, average thickness was about 1.5 µm and
average particle size was 31 µm. This cellulose
dispersion was spray dried (dispersion supply rate: 6
kg/hr, inlet temperature: 180-220°C, outlet temperature:
50-70°C) to obtain the cellulose particle D that is the
cellulose aggregate. The physical properties of the
cellulose particle D are shown in Table 1.
(Example 5)
Two kilograms of shredded commercially
available pulp (natural cellulose dissolved pulp
derived from wood, average polymerization degree: 1030,

containing 15% by weight of the solid fraction was
about 8 µm, average thickness was about 0.6 µm and
average particle size was 18 µm. This cellulose
dispersion was spray dried (dispersion supply rate: 6
kg/hr, inlet temperature: 180-220°C, outlet temperature:
50-70°C) to obtain the cellulose particle E that is the
cellulose aggregate. The physical properties of the
cellulose particle E are shown in Table 1.
[0140]
(Comparative Example 1)
Two kilograms of shredded commercially
available pulp (natural cellulose dissolved pulp
derived from wood, average polymerization degree: 1030,
average fiber width of the primary cellulose particles:
about 39 µm, average thickness: about 8 µm) and 30 L of
0.14 N hydrochloric acid solution were placed in a low
speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGL
Reactor (Commercial Name)). Hydrolysis was performed
at 121°C for 1 hour while stirring to obtain an acid
insoluble residue. After sufficient washing with pure
water, the acid insoluble residue thus obtained was
filtered, introduced to a 90 L polyethylene bucket,
mixed with pure water to bring the concentration of the
total solid fraction to 17% by weight and neutralized
with ammonia water while stirring with a 3-1 motor (pH
after neutralization was 7.5-8.0). The average fiber
width of the primary cellulose particles in this
cellulose dispersion containing 17% by weight of the

solid fraction was about 39 µm, average thickness was
about 8 µm and average particle size was 36 µm. This
cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220°C, outlet
temperature: 50-70°C) to obtain the cellulose
aggregates. These cellulose aggregates were milled
using a jet mill (SEISHIN ENTERPRISE CO., LTD., Single
Track Jet Mill STJ-200 (Commercial Name)) to obtain
cellulose powder F (corresponding to Example 1 of
Patent Document 6). The physical properties of the
cellulose particle F thus obtained are shown in Table
1.
Results of the SEM observation of cellulose
powder B indicated that the particles did not have
intraparticular pores, the primary particles existed
alone without having the secondary aggregate structure
and that no disintegration of the particles in water
was observed.
[0141]
(Comparative Example 2)
The similar operations were performed as
Comparative Example 1 except that the hydrolysis
condition was 3N hydrochloric acid solution, at 40°C,
for 40 hours and drying at the concentration of the
solid 8% to obtain cellulose powder G (corresponding to
Example 5 of Patent document 9). The physical
properties of the cellulose powder G thus obtained are
shown in Table 1. The average fiber width of the

primary cellulose particles in the cellulose dispersion
before drying was 39 µm, the average thickness was 8 µm
and the average particle size was 47 µm.
[01421
(Comparative Example 3)
The similar operations were performed as
Comparative Example 1 except that the hydrolysis
condition was 3 N hydrochloric acid solution, at 40°C,
for 20 hours and drying at the concentration of the
solid fraction of 6% to obtain cellulose powder H
(corresponding to Example 7 of Patent Document 9). The
physical properties of the cellulose powder H thus
obtained are shown in Table 1. The average fiber width
of the primary cellulose particles in the cellulose
dispersion before drying was 39 µm, the average
thickness was 8 µm and the average particle size was 49
µm.
Further, Fig. 2 shows a pore size
distribution pattern of the cellulose powder H measured
by the mercury porosimtry. For the cellulose powder H
no "clear peak" like the one seen in the porous
cellulose aggregates of Example 1 was confirmed. Such
pores having no "clear peak" are intrinsic to the
original primary cellulose particles. Still further,
considering the distribution of the particle size of
the powder, the peak seen in the range of 10-50 µm was
derived from the gap between particles.
[0143]

average fiber width of the primary cellulose particles:
about 39 µm, average thickness: about 8 µm) was
immersed in water and, under the condition of
containing about 70% water, passed through a cutter
mill (URSCHEL LABORATORIES, INC. "Comitrol" (Commercial
Name), Model 1700, Microcuthead/blade gap: 2.029 mm,
Immpeler rotation rate: 900C rpm) and mixed with pure
water to prepare a cellulose dispersion of about 2%
concentration, which was treated 6 times with a high
pressure homogenizer (MFIC Corp. Commercial Name
"Microfluidizer" M-140K type, Process pressure: 200
MPa) and then centrifuged at a centrifugal force of
19600 m/s2 to obtain the precipitates after discarding
the supernatant. The precipitates were dried at 40°C
for 16 hours, and about 2 kg of the dried precipitates
and 30 L of 4 N hydrochloric acid solution were placed
in a low speed stirrer (Ikebukuro Horo Kogyo Co., Ltd.,
50LGL Reactor (Commercial Name)). Hydrolysis was
performed at 40°C for 48 hours while stirring to obtain
an acid insoluble residue. After sufficient washing
with pure water, the acid insoluble residue thus
obtained was filtered, introduced to a 90 L
polyethylene bucket, mixed with pure water to bring the
concentration of the total solid fraction to 15% by
weight and neutralized with ammonia water while
stirring with a 3-1 motor (pH after neutralization was
7.5-8.0). The average fiber width of the primary
cellulose particles in this cellulose dispersion

(Comparative Example 4)
The similar operations were performed as
Comparative Example 1 except that the hydrolysis
condition was 4 N hydrochloric acid solution, at 40°C,
for 48 hours and drying at the concentration of the
solid fraction of 16% to obtain cellulose powder I
(corresponding to Example 4 of Patent Document 9). The
physical properties of the cellulose powder I thus
obtained are shown in Table 1. The average fiber width
of the primary cellulose particles in the cellulose
dispersion before drying was 39 µm, the average
thickness was 8 µm and the average particle size was 44
µm.
[0144]
(Comparative Example 5)
FMC Co., Ltd., product "Abicel" PH-200 was
assigned to be the cellulose powder J. The physical
properties of the cellulose powder J are shown in Table
1.
[0145]
(Comparative Example 6)
The cellulose aggregates obtained in
Comparative Example 1 and acetaminophen, Japanese
Pharmacopeia (MERCK HOEI CO., LTD.) milled using a
bantam mill (Made by Hosokawa Tekkosho, screen size: 2
mm) were introduced to a high speed stirring granulator
(made by GOKYO SEISAKUSHO CO., LTD., NSK250 (Commercial
Name)) in a composition of cellulose 50% by weight and

acetaminophen 50% by weight, total 500 g of the powder
mixture, mixed well by rotating a stirring blade at 500
rpm for 1 minute, further mixed for 2 minutes while
adding 245-255 g of 50% by weight ethanol solution to
obtain spherical granules. The granules thus obtained
were dried at 50°C for 12 hours, and then after 12 mesh
or larger fractions were discarded as coarse large
particles, acetaminophen was extracted with acetone for
20 hours using a Soxhlet extraction apparatus. This
was again dried at 50°C for 12 hours to obtain the
cellulose powder K (corresponding to Example 2 of
Patent Document 2). The physical properties of the
cellulose powder K thus obtained are shown in Table 1.
[0146]
Fig. 3 shows an electron micrograph of the
cellulose particle K at a magnification of x250 and
Fig. 5 shows an electron micrograph at a magnification
of xl500.
In the cellulose powder K, a "clear peak" was
confirmed in the range of 0.1-10 µm of the pore size
distribution from the results of the measurement of the
pore size distribution by the mercury porosimetry.
However, the electron microgram (Figs. 3 and 5) by SEM
confirmed that the particle structure was not the
"secondary aggregate structure of the aggregation of
the primary particles" but the "dense homogeneously
continuous film like septum structure". From Figs. 3
and 5, it is seen that the primary cellulose particles

became microfine particles which bound tightly each
other in drying process forming the "dense
homogeneously continuous film like septum structure"
resulting in that boundaries between the primary
particles became unclear. In addition, the particles
did not disintegrate in water. Furthermore, the
cylindrical molded body (compression pressure 10 MPa)
obtained from the cellulose particle K was very much
fragile and friable.
[0147]
(Comparative Example 7)
A commercially available dissolved pulp was
shredded and hydrolyzed in 7% hydrochloric acid
solution at 105°C for 20 minutes, and a wet cake was
obtained by neutralizing, washing, filtering and
dehydrating thus obtained acid insoluble residue. The
wet cake (water content: 50% by weight) was dispersed
in isopropyl alcohol and subjected to two cycles of
filtration, dehydration and re-dispersion, and further
subjected to the dispersion treatment three times using
a Manton-Goring homogenizer (made by NIHONSEIKI K7AISHA
LTD. Type 15M (Commercial Name)) at a treatment
pressure of 400 kg/cm2 to obtain a cellulose dispersion
having the solid fraction concentration of 9.8% by
weight, water content of 2.5 weigh%, isopropyl alcohol
of 87.7% by weight. The average particle size of the
primary cellulose particles of the cellulose dispersion
having the solid fraction concentration of 9.8% by

weight was 1 µm. This cellulose dispersion was spray
dried using a nitrogen circulating type spray dryer.
The sample thus obtained was sieved through a JIS
standard sieve to cut off the coarse fraction of 250 µm
or above to obtain the cellulose powder L
(corresponding to Example 2 of Patent Document 3). The
physical properties of the cellulose powder L thus
obtained are shown in Table 1.
In the cellulose particle L, a "clear peak"
was confirmed at 0.1 µm or below from the results of
the measurement of the pore size distribution by the
mercury porosimetry. Also, the electron microgram by
SEM confirmed that the particle structure was not the
"secondary aggregate structure of the aggregation of
the primary particles" but the "dense homogeneously
continuous film like septum structure". The boundaries
between the primary particles were unclear in the
septa. The particles did not disintegrate in water,
and the aspirin decomposition rate was higher than that
of the drug alone.
[0148]
(Comparative Example 8)
Two kilograms of shredded commercially
available pulp (natural cellulose dissolved pulp
derived from wood, average polymerization degree: 1030,
average fiber width of the primary cellulose particles:
about 39 µm, average thickness: about 8 µm) and 30 L of
0.14 N hydrochloric acid solution were placed in a low

speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 50LGL
Reactor (Commercial Name)). Hydrolysis was performed
at 121°C for 1 hour while stirring to obtain an acid
insoluble residue. After sufficient washing with pure
water, the acid insoluble residue thus obtained was
filtered, introduced to a 90 L polyethylene bucket,
mixed with pure water to bring the concentration of the
total solid fraction to 17% by weight and neutralized
with ammonia water while stirring with a 3-1 motor (pH
after neutralization was 7.5-8.0). The average fiber
width of the primary cellulose particles in this
cellulose dispersion containing 17% by weight of the
solid fraction was about 39 µm, average thickness was
about 8 µm and average particle size was 36 µm. This
cellulose dispersion was spray dried (dispersion supply-
rate: 6 kg/hr, inlet temperature: 180-220°C, outlet
temperature: 50-70°C) to obtain the cellulose powder M
(corresponding to Example of Patent Document 4).
[0149]
The physical properties of the cellulose
powder M are shown in Table 1. Also an electron
micrograph of the cellulose powder M at a magnification
x250 is shown in Fig. 4.
From Fig. 4, it is seen that the particle
structure of the cellulose powder M is the "secondary
aggregate structure of the aggregation of the primary
particles". However, since this is the product of
drying the dispersion of the cellulose particles having

a single average particle size, the intracellular pore
volume is small, and no clear peak was observed in the
range of 0.1-10 µm in the pore size distribution from
the results of the measurement of the pore size
distribution by the mercury porosimetry.
Further, Fig. 7 is a cross section view of
the particle of the cellulose powder M by an electron
microscope, and a tightly bound structure can be
confirmed that was formed by the stiff binding of the
cellulose particles. The intraparticular pores were
sparse and not well developed and the pore volume
measured by the mercury porosimetry is also small.
[0150]
(Comparative Example 9)
Two kilograms of a commercially available
kraft pulp was shredded and hydrolyzed in 0.7% by
weight hydrochloric acid aqueous solution at 125°C for
150 minutes, and the acid insoluble residue thus
obtained was filtered and neutralized. The wet flock
thus obtained was sufficiently pulverized in a kneader,
mixed with an equal volume of ethanol, pressed and
filtered and air dried.
The average fiber width of the primary
cellulose particle in cellulose water/ethanol
dispersion before drying was 31 µm, the average
thickness was 8 µm and average particle size was 28 µm.
After air drying, it was milled by a normal hammer
mill, and the coarse fraction was removed by sieving

through a 40 mesh sieve to obtain the cellulose powder
N (corresponding to Example 1 of Patent Document 5).
The various physical properties of the cellulose powder
N thus obtained are shown in Table 1.
[0151]
(Comparative Example 10)
A commercially available dissolved pulp was
shredded and hydrolized in 10% by weight hydrochloric
acid aqueous solution at 105°C for 30 minutes. The
obtained acid insoluble residue was filtered, washed,
and neutralized to obtain a dispersion with a solid
fraction concentration of 17% by weight. The primary
cellulose particles in the cellulose dispersion had an
average fiber width of 39 µm, an average thickness of 8
µm, and an average particle size of 33 µm. The
obtained cellulose dispersion was dried with a drum
drier (product name KDD-1 from Kusunoki Kikai
Seisakusho Co., Ltd. at a steam pressure of 0.35 MPa, a
drum temperature of 136°C, a drum speed of 2 rprr., and
reservoir dispersion temperature of 100°C). This was
then crushed with a hammer mill and bulk particles were
removed with a sieve having a mesh size of 425 µm,
providing a Cellulose Powder 0 (corresponds to Example
1 in Patent Document 7). Various properties of the
obtained Cellulose Powder 0 are shown in Table 1.
[0152]
(Comparative Example 11)
An airjet sieve was used on the Cellulose

Powder K obtained from Comparative Example 10 and large
particles were removed with a 75 µm sieve and fine
particles were removed with a 38 µm sieve. This
provided the Cellulose Powder P (corresponds to the
Example of Patent Document 8). Various physical
properties of the obtained Cellulose Powder P are shown
in Table 1.
[0153]
(Comparative Example 12)
A high-speed stirrer and granulator (model
FS-10 (Commercial Name) from Fukae Industries Co.,
Ltd.) was used with 1.5 kg of Cellulose Powder M
obtained from Comparative Example 8 and 1.5 kg of
distilled water was added. Kneading was performed for
5 minutes. The Marumerizer Q-230 (Commercial Name,
Fuji Paudal Co., Ltd.) was used on 1.0 kg of the wet
powder to form spheres by rolling for 10 minutes at 500
rpm. At the same time, 200 g of distilled water was
added at a rate of 20 g/min. Then, the powder was left
out overnight at 40°C to dry, after which a 16 mesh (1
mm mesh size) was used to obtain spherical particles Q
(corresponds to Example 1 of Patent Document 12). The
various physical properties of the obtained spherical
particles are shown in Table 1.
The cellulose spherical particles Q are
extremely heavy and provide superior fluidity, but
there was almost no specific surface area or
intraparticular pore volume. A molded body could not

be formed under standard compression pressures of 10,
20 MPa.
[0154]
(Comparative Example 13)
As in Example 1, a commercially available
kraft pulp was shredded and hydrolized in a 10% by
weight of hydrochloric acid aqueous solution at 105°C
for 30 minutes. The obtained acid insoluble residue
was filtered to obtain a crystal cellulose cake with a
solid concentration of 40% (the degree of
polymerization of the cake was 153). The cake was
ground for 1 hour with an all-purpose mixer/stirrer
(model number 5DM-03-R (Commercial Name) from San-Ei
Seisakusho, Ltd.). Water was added to the ground cake
and a homogenizing mixer (model number TK Homomixer
Mark II from Tokushu kika Kogyo) was used to form a
12.5% by weight of solid content cellulose dispersion
with adjustments made for particle size, pH, and IC.
The primary cellulose particles in the resulting
cellulose dispersion had an average particle size of 7
µm. The dispersion was spray dried using a turntable
of approximately 8 cm at a rotation speed of 5000 rpm,
a flow rate of 6 L/hr, an intake temperature of 170°C,
and an outlet temperature of 85°C. Large particles were
removed with a sieve having a mesh size of 177 µm to
obtain a cellulose powder R. The various physical
properties of the obtained cellulose particle R
(corresponds to Example 1 of Patent Document 14) are

shown in Table 1.
The cellulose particles R are also heavy and
have superior fluidity but specific surface area and
intraparticular pore volume are low. While a molded
body could be formed under standard compression
pressures of 10, 20 MPa, the molded body was fragile,
with friability taking place upon release. The molded
body could be easily destroyed by hand.
[0155]
(Comparative Example 14)
A low-speed stirrer (30LGL reactor from
Ikebukuro Horo Kogyo Co., Ltd., approximately 30 cm
blade diameter) was used with 2 kg of shredded
commercially available pulp (with a degree of
polymerization of 790) and 30 L of 4 N aqueous
hydrochloric acid. Hydrolization was performed for 48
hours at 40°C while stirring at a stirring speed of 5
rpm, resulting in acid insoluble residue with an
average polymerization degree of 270. The obtained
acid insoluble residue was filtered to a solid
concentration of 40% using a suction funnel. The
filtered residue was then washed with pure water and
neutralized with ammonia water. This was placed in a
90 L polyethylene bucket. Pure water was added and the
result was stirred at a stirring speed of 5 rpm using a
3-1 motor (type 1200G from Heidon, 8 M/M, average blade
diameter 5 cm). This provided a cellulose dispersion
with a solid concentration of 22%. The primary

cellulose particles in the cellulose dispersion had an
average fiber width of 39 µm, an average thickness of 8
µm, and an average particle size of 54 µm. This was
spray dried (dispersion supply rate: 6 L/hr, inlet
temperature: 180-220°C, outlet temperature: 50-70°C),
resulting in a cellulose powder S. The various
physical properties of the obtained cellulose particles
S (corresponds to Example 2 of Patent Document 10) are
shown in Table 1. While the cellulose particles S
provided a high degree of hardness in the molded body
at 10, 20 MPa, the apparent specific volume was too
high, resulting in inferior fluidity (repose angle) and
disintegration property.
(Comparative Example 15)
A low-speed stirrer (30LGL reactor
(Commercial Name) from Ikebukuro Horo Kogyo Co., Ltd.)
was used with 2 kg of shredded commercial by available
pulp (a natural cellulose dissolved pulp derived from
wood) and 30 L of 4 N aqueous hydrochloric acid.
Hydrolization was performed for 48 hours at 40°C while
stirring, resulting in acid insoluble residue. After
thoroughly washing the obtained acid insoluble residue
in pure water, the residue was filtered, resulting in a
wet flock (the average particle size of the dispersed
cellulose particles in the acid insoluble residue was
55 µm. ) Of the obtained wet flock, 60% by weight was
further washed thoroughly with pure water, neutralized,
refiltered, and air dried to produce a dried flock.

This dried flock was shredded with a home mixer and
then further crushed with a jet mill (single-track jet
mill STJ-200 from SEISHIN ENTERPRISE CO., LTD.) to
obtain a crushed product (the cellulose particle size
was 3 µm. The obtained crushed product and the wet
acid insoluble residue described above were placed in a
90 L polyethylene bucket at a composition of 60 parts
by weight to 40 parts by weight (dry base). Pure water
was added for a total solid fraction concentration of
25% by weight. While stirring with a 3-1 motor, the
mixture was neutralized with ammonia water (the pH
after neutralization was 7.5-8.0). This was then spray
dried (dispersion supply rate: 6 kg/hr, inlet
temperature: 180-220°C, outlet temperature: 50-70°C),
resulting in a cellulose powder T (corresponds to
Example 2 of Patent Document 1). The various physical
properties of the cellulose powder T are shown in Table
1.
(Comparative Example 16)
A low-speed stirrer (30LGL reactor
(Commercial Name) from Ikebukuro Horo Kogyo Co., Ltd.)
was used with 2 kg of shredded commercially available
pulp (a natural cellulose dissolved pulp derived from
wood) and 30 L of 3 N aqueous hydrochloric acid.
Hydrolization was performed for 24 hours at 40°C while
stirring, resulting in acid insoluble residue. After
thoroughly washing the obtained acid insoluble residue
with pure water, the residue was filtered, resulting in

a wet flock (the average particle size of the dispersed
cellulose particles in the acid insoluble residue was
55 µm. Of the obtained wet flock, 10% by weight was
further washed thoroughly with pure water, neutralized,
refiltered, and air dried to produce a dried flock.
This dried flock was shredded with a home mixer and
then further crushed with a jet mill (single-track jet
mill STJ-200 from SEISHIN ENTERPRISE CO., LTD.) to
obtain a crushed product (the cellulose particle size
was 3 µm. ) The obtained crushed product and the wet
acid insoluble residue described above were placed in a
90 L polyethylene bucket at a composition of 10 parts
by weight to 90 parts by weight (dry base). Pure water
was added for a total solid fraction concentration of
35% by weight. While stirring with a 3-1 motor, the
mixture was neutralized with ammonia water (the pH
after neutralization was 7.5-8.0). This was then spray
dried (dispersion supply rate: 6 kg/hr, inlet
temperature: 180-220°C, outlet temperature: 50-70°C),
resulting in a cellulose powder U (corresponds to
Example 5 of Patent Document 1). The various physical
properties of the cellulose powder U are shown in Table
1.
(Comparative Example 17)
A low-speed stirrer (30LGL reactor
(Commercial Name) from Ikebukuro Horo Kogyo Co., Ltd.)
was used with 2 kg of shredded commercially available
pulp (a natural cellulose kraft pulp derived from

cotton linter) and 30 L of 0.14 N aqueous hydrochloric
acid. Hydrolization was performed for 1 hour at 121°C
while stirring, resulting in acid insoluble residue.
After thoroughly washing the obtained acid insoluble
residue with pure water, the residue was filtered,
resulting in a wet flock (the average particle size of
the dispersed cellulose particles in the acid insoluble
residue was 36 µm. Of the obtained wet flock, 90% by
weight was further washed thoroughly with pure water,
and then friability with a planetary mixer (the
dispersed cellulose particles in the friated wet flock
had an average particle size of 1 µm. The friated wet
flock and the unfriated wet flock were placed in a 90 L
polyethylene bucket at a composition of 90 parts by
weight to 10 parts by weight (dry base). Pure water
was added for a total solid fraction concentration of
30% by weight. While stirring with a 3-1 motor, the
mixture was neutralized with ammonia water (the pH
after neutralization was 7.5-8.0). This was then spray
dried (dispersion supply rate: 6 kg/hr, inlet
temperature: 180-220°C, outlet temperature: 50-70°C),
resulting in a cellulose powder V (corresponds to
Example 7 of Patent Document 1). The various physical
properties of the cellulose powder V are shown in Table
1-1 and Table 1-2.
Among conventional cellulose powders, only
Comparative Examples 15-17 corresponding to the
Examples of Patent Document 1 meet the ranges of the

porous cellulose aggregates of the present application:
the repose angle range; the hardness range of a
cylindrical molded body molded at 10 MPa; and the
hardness range of a cylindrical molded body molded at
20 MPa the disintegration time range of a cylindrical
molded body molded at 20 Mpa. The advantage of the
porous cellulose aggregates of the present application
is that the disintegration time is shorter for similar
hardnesses (Example 5 and Comparative Example 15,
Example 2 and Comparative Example 16, and Example 3 and
Comparative Example 17), thus allowing cylindrical
molded bodies to be disintegrated in roughly half the
time. This is due to the fact that, with the porous
cellulose aggregates from Patent Document 1, even the
larger central pore diameters were approximately 1.5
µm, while the central pore diameters of the porous
cellulose aggregates of the present application are at
least approximately 3.0 µm. Thus, the larger central
pore diameters provide a faster water permeation rate.





[0157]
(Example 6 and Comparative Examples 18-28)
The following were placed in a 100 L scale V-
type mixer (Dalton Co., Ltd.) and mixed for 30 minutes:
55 parts of acetaminophen (powder type, API
Corporation); 0.25 parts by weight of light anhydrous
silicic acid (Aerosil 200 (Commercial Name) of NIPPON
AEROSIL CO., LTD.); 27 parts by weight of the cellulose
powder A obtained from Example 1 or the cellulose
powder B, C, E-L, and 0 obtained from the Comparative
Examples 1, 2, and 4-11, 14; 2 parts by weight of
crospovidone (Kollidon CL (Commercial Name) from BASF);
and 15 parts of granular lactose (Super-Tab (Commercial
Name) from Lactose New Zealand). Then, 0.5 parts by
weight of magnesium stearate (plant-based, made by
TAIHEI CHEMICAL INDUSTRIAL CO., LTD.) are added and
mixed for 5 minutes to obtain a formulated powder. The
total intake for the powders was 25 kg. The formulated
powder was used in a rotary tablet press (LIBRA-II
(Commercial Name) from KIKUSUI SEISAKUSHO LTD, 36
stations, 410 mm turn table diameter). Pressing was
performed with an 8 mm diameter, 12R punch with a turn
table speed of 50 rpm and a compression force of 7.5
kN, resulting in tablets weighing 200 mg. Tablets were
sampled 60 minutes after initiation of tablet pressing,
and tablet weight, hardness, friability, and tablet
pressing trouble rates were measured. The physical
properties of the obtained tablet are shown in Table 2.

Since this formula contains a large amount of
drugs with inferior compactibility, obtaining a
hardness of 50 N or higher, the hardness considered
practical for tablets, is difficult. Obtaining
practical tablets is also made difficult because of the
tendency for tablet pressing troubles to occur, i.e.,
sticking at low pressures and capping at high
pressures. Out of the Comparative Examples, the
Comparative Examples 18, 19, 26, 27, 28 provided a
practical tablet hardness of 50 N or higher, but the
variation of 1.8-3.5% in tablet weight was much higher
than the 0.8% of the Examples, making practical
implementation difficult.

(Embodiments 7, 8 and Comparative Examples 29-39)
The following were placed in a 100 L scale V-
type mixer (Dalton Co., Ltd) and mixed for 30 minutes:
40 parts of acetaminophen (powder type from API

Corporation crushed, 6 µm average particle size); 0.5
parts by weight of light anhydrous silicic acid
(Aerosil 200 (Commercial Name) of NIPPON AEROSIL CO.,
LTD.); 30 parts by weight of the cellulose powder C and
D obtained from Example 3 and Example 4 and the
cellulose powder G, I-P, S, and V obtained from the
Comparative Examples 2, 4-11, 14 and 17; 2 parts by
weight of sodium croscarmellose (Kiccolate ND-2HS
(Commercial Name) produced by NICHIRIN CHEMICAL
INDUSTRIES, LTD. and distributed by Asahi Kasei
Chemicals Corporation); and 27.5 parts of granular
lactose (Super-Tab (Commercial Name) from Lactose New
Zealand). Then, 0.5 parts by weight external ratio of
magnesium stearate (plant-based, made by TAIHEI
CHEMICAL INDUSTRIAL CO., LTD.) were added and mixed for
5 minutes to obtain a formulated powder. The total
intake for the powders was 2 kg. The formulated powder
was used in a rotary tablet press (Clean Press - 12HUK
(Commercial Name) from KIKUSUI SEISAKUSHO LTD, 12
stations). Pressing was performed with an 8 mm
diameter, 12R punch with a turntable speed of 54 rpm
and a compression force of 5 kN, resulting in tablets
weighing 180 mg. Tablets were sampled 10 minutes after
initiation of tablet pressing, and tablet weight,
hardness, friability, tablet pressing trouble rates,
and disintegration times (no disk) were measured. The
properties of the obtained tablet are shown in Table 3.
The type of drug in this formula was the same

as the previous section, but the fluidity of this
formula is inferior since the drug is crushed. Thus,
the drug content is lower, making reduction of tablet
weight variations difficult while obtaining a practical
tablet hardness of 50 N or higher is difficult.
Obtaining practical tablets is also made difficult
because of the tendency for tablet pressing troubles to
occur, i.e., sticking at low pressures and capping at
high pressures. Out of the Comparative Examples, the
Comparative Examples 29, 30, 33, 36, 37, 38, 39
provided a practical tablet hardness of 50 N or higher,
but besides the Comparative Example 39 the variation of
1.6-3.5% in tablet weight was much higher than the 0.2-
0.5% of the Examples, making practical implementation
difficult. With the Comparative Example 39, tablet
hardness and tablet weight variations were similar to
those of the porous cellulose aggregates of the present
invention, but the disintegration time at similar
hardnesses was inferior. In direct tablet pressing,
stable production can be difficult because of a
tendency for there to be differences between drug lots,
especially in granularity. Thus, in terms of drug
granularity it would be preferable to crush the drugs,
but in such cases the fluidity of the crushed drug is
inadequate, preventing the drug content from being
increased. Of the porous cellulose aggregates of the
present invention, those with good fluidity, i.e., with
repose angles in a low range of 25-36°, are especially

useful in overcoming this problem. Also, for drugs
providing inferior tablet compactibility, excipient
must be added to provide practical hardness. Thus, the
excipient itself must have good fluidity and, in order
to increase the drug content as much as possible, the
excipient must have a degree of compactibility high
enough that a limited amount can provide practical
hardness. The porous cellulose aggregates of the
present invention provides advantages not available in
the conventional cellulose powders in that fluidity and
compactibility are both high enough to overcome the
above problem.



(Embodiment 9, 10, and Comparative Examples 40-51)
The following were placed in a 5 L scale V-
type mixer (Dalton Co., Ltd) and mixed for 30 minutes:
60 parts of ethenzamide (API Corporation, powder grade
crushed with a compact crusher); 0.5 part by weight of
light anhydrous silicic acid (Aerosil 200 (Commercial
Name) of NIPPON AEROSIL CO., LTD.); 10 parts by weight
of the cellulose powder B and E obtained from Examples
2 and 5 and the cellulose powder G, I-P, and S-U
obtained from the Comparative Examples 2, 4-11, and 14-
16; 1.5 parts by weight of sodium croscarmellose
(Kiccolate ND-2HS (Commercial Name) produced by
NICHIRIN CHEMICAL INDUSTRIES, LTD. and distributed by
Asahi Kasei Chemicals Corporation); and 28 parts of
granular lactose (Super-Tab (Commercial Name) from
Lactose New Zealand). Then, 0.5 part by weight
external ratio of magnesium stearate (plant-based, made
by TAIHEI CHEMICAL INDUSTRIAL CO., LTD.) are added and
mixed for 5 minutes to obtain a formulated powder. The
total intake for the powders was 2 kg. The formulated
powder was used in a rotary tablet press (Clean Press -
12HUK (Commercial Name) from KIKUSUI SEISAKUSHO LTD, 12
stations). Pressing was performed with an 8 mm
diameter, 12R punch with a turn table speed of 54 rpm
and a compression force of 8 kN, resulting in tablets
weighing 180 mg. Tablets were sampled 10 minutes after
initiation of tablet pressing, and tablet weight,
hardness, friability, tablet pressing trouble rates,

and disintegration times (no disk) were measured. The
physical properties of the obtained tablet are shown in
Table 4.
Since, in this formula, a drug hard to be
soluble in water is crushed, water disintegration
properties were inferior and fluidity was inferior,
making it difficult to reduce variations in tablet
weight. Furthermore, this formula results in tablet
pressing troubles in the form of capping at high
pressures, thus making it an example of a formula in
which practical implementation with a high drug content
is difficult. Out of the Comparative Examples, the
Comparative Examples 40, 41, 64, 47-51 provided a
practical tablet hardness of 50 N or higher, but the
variation of 1.6-4.0% in tablet weight was much higher
than the 0.5-0.7% of the embodiments, making practical
implementation difficult. With the Comparative
Examples 50, 51, tablet hardness and tablet weight
variations were similar to those of the porous
cellulose aggregates of the present invention, but the
disintegration time at similar hardnesses was inferior.
With lower drug solubility in water, the disintegration
time is the rate-limiting factor, and elution time for
the drug is increased. For quick absorption in the
body, quick disintegration is necessary. As the water
solubility of the drug goes lower, it is clear that the
difference in disintegration time between the porous
cellulose aggregates of the present invention and the

porous cellulose aggregates of Patent Document 1
increases. Thus, the present invention is superior to
the porous cellulose aggregates of Patent Document 1
especially in terms of the quick disintegration of
drugs hard to be soluble in water.



(Embodiment 11, 12, and Comparative Examples 52-63)
The following were placed in a 5 L scale V-
type mixer (Dalton Co., Ltd) and mixed for 30 minutes:
55 parts of ascorbic acid (from Ebisu Co., Ltd.,
crushed); 30 parts by weight of the cellulose powder B
and E obtained from Examples 2 and 5 and the cellulose
powder G, I-P, and S-U obtained from the Comparative
Examples 2, 4-11, and 14-16; 1.5 parts by weight of
sodium croscarmellose (Kiccolate ND-2HS (Commercial
Name) produced by NICHIRIN CHEMICAL INDUSTRIES, LTD.
and distributed by Asahi Kasei Chemicals Corporation);
and 13 parts of granular lactose (Super-Tab (Commercial
Name) from Lactose New Zealand). Then, 2.0 parts by
weight external ratio of magnesium stearate (plant-
based, made by TAIHEI CHEMICAL INDUSTRIAL CO., LTD.)
are added and mixed for 5 minutes to obtain a
formulated powder. The total intake for the powders
was 2 kg. The formulated powder was used in a rotary
tablet press (Clean Press - 12HUK (Commercial Name)
from KIKUSUI SEISAKUSHO LTD, 12 stations). Pressing
was performed with an 8 mm diameter, 12R punch with a
turn table speed of 54 rpm and a compression force of
10 kN, resulting in tablets weighing 180 mg. Tablets
were sampled 10 minutes after initiation of tablet
pressing, and tablet weight, hardness, friability,
tablet pressing trouble rates, and disintegration times
(no disk) were measured. The physical properties of
the obtained tablet are shown in Table 5.

The drug used in this formula provides
relatively good fluidity even when crushed. However,
as the drug content is increased the fluidity of the
formula gradually decreases, thus making it more
difficult to reduce variations in tablet weight when
higher drug content is used. Also, the drug used in
this formula leads to tablet pressing troubles, i.e.,
sticking at low pressures and capping at high
pressures, making it an example of a formula with which
tablets are difficult to practically implement at
higher drug contents. Out of the Comparative Examples,
the Comparative Examples 52, 56, 59-63 provided a
practical tablet hardness of 50 N or higher, but other
than the Comparative Examples 62, 63, the variation of
1.8-2.6% in tablet weight was much higher than the 0.7-
0.8% of the embodiments, making practical
implementation difficult. With the Comparative
Examples 62, 63, tablet hardness and tablet weight
variations were similar to those of the porous
cellulose aggregates of the present invention, but the
disintegration time at similar hardnesses was inferior.
The drug used in this formula has relatively high water
solubility but water-repelling magnesium stearate must
be added to avoid tablet pressing troubles. In these
cases, the wettability of the tablet to water is
reduced, tending to delay disintegration time even if
the water solubility of the drug is high. Especially
in cases where the wettability of the tablet or the

like is obstructed by an a water-repellant additive or
the like in the formula, the difference in
disintegration times between the porous cellulose
aggregates of the present invention and the porous
cellulose aggregates of Patent Document 1 clearly
increases. Thus the present invention is superior to
the porous cellulose aggregates of Patent Document 1.



[0159]
(Embodiment 13)
Five grams of cellulose powder A was added to
20 g of an active component solution in which an
ibuprofen polyethyleneglycol solution (1:5 ratio) is
diluted by 10 with ethanol (Wako Pure Chemical
Industries, Ltd., reagent), and this was mixed in a
beaker with a magnetic stirrer for 5 minutes. The
resulting mixed solution was vacuum dried with an
evaporator to produce a powder. A die (from KIKUSUI
SEISAKUSHO LTD, made with SUS 2, 3) was filled with 0.2
g of the obtained powder, and a circular flat punch
(from KIKUSUI SEISAKUSHO LTD, made with SUS 2, 3) with
a diameter of 0.8 cm was used to apply compression
until the pressure reached 100 MPa (PCM-IA (Commercial
Name) from AIKOH ENGINEERING CO., LTD. was used with a
compression rate of 1 cm/min). The cylindrical molded
body was released after the target pressure was
maintained for 10 seconds. The surface of the
compression-molded molded body was observed and no
effusion of fluid components was observed. Also, 100
mL of pure water was placed in a beaker and stirred
with a stirrer. A sieve with a mesh size of 1000 µm
was placed over the stirrer, and the molded body was
placed on the sieve and left for one minute and
observed. The results are shown in Table 6.
[0160]
(Comparative Example 64)

A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced
with the cellulose powder K (corresponds to Example 2
in Patent Document 2). Fluid component effusion and
disintegration tests were conducted. The results are
shown in Table 6.
(Comparative Example 65)
A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced
with the cellulose powder L (corresponds to Example 2
in Patent Document 3). Fluid component effusion and
disintegration tests were conducted. The results are
shown in Table 6.
(Comparative Example 66)
A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced
with the cellulose powder M (corresponds to the
embodiment in Patent Document 4). Fluid component
effusion and disintegration tests were conducted. The
results are shown in Table 6.
[0161]
(Comparative Example 67)
A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced

with the cellulose powder N (corresponds to Example 1
in Patent Document 5). Fluid component effusion and
disintegration tests were conducted. The results are
shown in Table 6.
[0162]
(Comparative Example 68)
A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced
with the cellulose powder G (corresponds to Example 5
in Patent Document 9). Fluid component effusion and
disintegration tests were conducted. The results are
shown in Table 6.
[0163]
(Comparative Example 69)
A molded body with a fluid component was
produced using operations similar to those from Example
13 except that the cellulose particles A were replaced
with the cellulose powder S (corresponds to Example 2
in Patent Document 10). Fluid component effusion and
disintegration tests were conducted. The results are
shown in Table 6.


[0165]
(Embodiment 14)
Cellulose particles A were used. A
commercially available ibuprofen (an active component
indicated as being almost completely insoluble in water
according to Japanese Pharmacopeia 14) was dissolved in
polyethylene glycol (Macrogol 400 from Sanyo Kasei Co.,
Ltd.) at a proportion of 1:5, and then diluted by 10
with ethanol. This was added to the cellulose
particles A to result in 10% by weight. The mixture
was stirred in a die. A die (from KIKUSUI SEISAKUSHO
LTD, made with SUS 2, 3) was filled with 0.2 g of the
obtained powder, and a circular flat punch (from
KIKUSUI SEISAKUSHO LTD, made with SUS 2, 3) with a
diameter of 0.8 cm was used to apply compression until

the pressure reached 100 MPa (PCM-1A (Commercial Name)
from AIKOH ENGINEERING CO., LTD. was used with a
compression rate of 1 cm/min). The cylindrical molded
body was released after the target pressure was
maintained for 10 seconds. Fluid component effusion on
the surface of the molded body was observed, drug
elution from the cylindrical molded body (elution tests
were conducted with a JASCO Corporation ultraviolet
absorption spectrometer at paddle speed 100 rpm and 900
mL of Pharmacopeia I liquid, in which fluid absorbance
was measured and the elution rate was calculated 3
minutes after) and disintegration time of the
cylindrical molded bodies was measured. The results
are shown in Table 7. There was no effusion of
polyethylene glycol from the cylindrical molded body,
and the disintegration property was good with a high
drug elution rate after 3 minutes, and it was confirmed
that the dissolution was quick.
[0166]
(Comparative Example 70)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder K (corresponds to Example 2 in Patent Document
2). Fluid component effusion on the surface of the
molded body was observed, the rate of drug elution from
the cylindrical molded body was measured, and
disintegratability was observed. The results are shown

in Table 7. Effusion of the fluid component was not
observed on the surface of the cylindrical molded body,
but in the elution test the tablets did not
disintegrate in 3 minutes and floated on the liquid
surface instead and the disintegration property was
poor.
[0167]
(Comparative Example 71)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder L (corresponds to Example 2 in Patent Document
3). Fluid component effusion on the surface of the
molded body was observed, the rate of drug elution from
the cylindrical molded body was measured, and
disintegratability was observed. The results are shown
in Table 7. Effusion of the fluid component was not
observed on the surface of the cylindrical molded body,
but in the elution test the tablets did not
disintegrate in 3 minutes and floated on the liquid
surface instead and disintegratability was poor.
[0168]
(Comparative Example 72)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder IM (corresponds to the embodiment in Patent
Document 4). Fluid component effusion on the surface

of the molded body was observed, the rate of drug
elution from the cylindrical molded body was measured,
and disintegratability was observed. The results are
shown in Table 7. Effusion of the fluid component was
observed on the surface of the cylindrical molded body,
and elution tests could not be performed since tablets
could not be formed.
[0169]
(Comparative Example 73)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder N (corresponds to Example 1 in Patent Document
5). Fluid component effusion on the surface of the
molded body was observed, the rate of drug elution from
the cylindrical molded body was measured, and
disintegratability was observed. The results are shown
in Table 7. Effusion of the fluid component was
observed on the surface of the cylindrical molded body.
Tablets were not formed and elution tests could not be
conducted.
[0170]
(Comparative Example 74)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder G (corresponds to Example 5 in Patent Document
9). Fluid component effusion on the surface of the

molded body was observed, the rate of drug elution from
the cylindrical molded body was measured, and
disintegratability was observed. The results are shown
in Table 7. Effusion of the fluid component was
observed on the surface of the cylindrical molded body.
Tablets were not formed and elution tests could not be
conducted.
[0171]
(Comparative Example 75)
A molded body was produced using operations
similar to those from Example 14 except that the
cellulose particles A were replaced with the cellulose
powder S (corresponds to Example 2 in Patent Document
10). Fluid component effusion on the surface of the
molded body was observed, the rate of drug elution from
the cylindrical molded body was measured, and
disintegratability was observed. The results are shown
in Table 7. Effusion of the fluid component was not
observed on the surface of the cylindrical molded body,
but disintegratability was not good, with no
disintegration in 3 minutes in the effusion test.


[0173]
(Embodiment 15)
A solution was formed by dissolving
ethenzamide (API Corporation, powder grade crushed with
a compact crusher) in ethanol (Wako Pure Chemical
Industries, Ltd., reagent chemical) at a proportion of
5:95. One gram of cellulose particles A was added to
10 mL of the solution, and this was stirred for 3
minutes with a magnetic stirrer. The resulting
dispersion was placed in an evaporator to perform
complete solvent removal, resulting in a powder sample.
This powder was used as in Example 14 except that
compression was performed at 50 MPa when forming the
cylindrical molded body. An elusion test was
performed. The results are shown in Table 8.

[0174]
(Comparative Example 76)
An elution test was performed on just
ethenzamide crushed according to Example 15. The
results are shown in Table 8.

[0176]
(Embodiment 16)
Cellulose particles A were used. A
commercial ibuprofen (an active component indicated as
being almost completely insoluble in water according to
Japanese Pharmacopeia 14) was dissolved in ethanol
(Wako Pure Chemical Industries, Ltd., reagent chemical)
at a proportion of 1:5, and this was added to the
cellulose particles A to result in 10% by weight. The
mixture was stirred in a die. The ethanol was
completely removed from the resulting wet powder
mixture using an evaporator, providing a dry powder. A
die (from KIKUSUI SEISAKUSHO LTD, made with SUS 2, 3)
was filled with 0.2 g of the obtained powder, and a

circular flat punch (from KIKUSUI SEISAKUSHO LTD, made
with SUS 2, 3) with a diameter of 0.8 cm was used to
apply compression until the pressure reached 100 MPa
(PCM-1A (Commercial Name) from AIKOH ENGINEERING CO.,
LTD. was used with a compression rate of 1 cm/min).
The cylindrical molded body was released after the
target pressure was maintained for 10 seconds. One
hundred of the cylindrical molded bodies were placed in
a bottle and sealed for 2 weeks at 40°C. Fogging on the
bottle was observed. Also, for the obtained
cylindrical molded bodies, tests were conducted for
elution of active components (elution tests were
conducted with a JASCO Corporation ultraviolet
absorption spectrometer at paddle speed 100 rpm and 900
mL of Pharmacopeia I liquid, in which fluid absorbance
was measured 1 minute after and the elution rate was
calculated 3 minutes after starting the test) and
disintegration property of the molded bodies was
observed. The results are shown in Table 9.
[0177]
(Comparative Example 77)
Operations similar to those of Example 16
were performed except that cellulose particles A were
replaced with cellulose powder K (corresponds to
Example 2 of Patent Document 2). Clouding of bottles
after sealing in the cylindrical molded bodies was
observed, elution tests were performed, and
disintegratability was observed. The results are shown

in Table 9. No clouding of bottles was observed, but
the tablets did not disintegrate in 1 minute and
floated on the liquid surface instead.
[0178]
(Comparative Example 78)
Operations similar to those of Example 16
were performed except that cellulose particles A were
replaced with cellulose powder L (corresponds to
Example 2 of Patent Document 3). Clouding of bottles
after sealing in the cylindrical molded bodies was
observed, elution tests were performed, and
disintegratability was observed. The results are shown
in Table 9. No clouding of bottles was observed, but
the tablets did not disintegrate in 1 minute and
floated on the liquid surface instead.
[0179]
(Comparative Example 7 9)
Operations similar to those of Example 16
were performed except that cellulose particles A were
replaced with cellulose powder M (corresponds to the
embodiment of Patent Document 4). Clouding of bottles
after sealing in the cylindrical molded bodies was
observed, elution tests were performed, and
disintegratability was observed. The results are shown
in Table 9. Clouding of the bottle was observed due to
the recrystallization on the bottle walls of sublimated
ibuprofen.


[0181]
(Embodiment 17)
Twenty grams of acetaminophen (powder type,
API Corporation, crushed with a compact crusher so that
the resulting acetaminophen has an average particle
size of 16 µm and 20 g of talc (Wako Pure Chemical
Industries, Ltd.) were placed in a polyethylene bag and
mixed thoroughly by hand for 3 minutes. In addition to
this 40 g of mixed powder, the following were placed in
a 5 L capacity V-type mixer (Dalton Co., Ltd) and mixed
for 30 minutes: 952 g of 100 mesh lactose (Pharmatose
100M (Commercial Name) from DMV Corporation); and 408 g
of Japanese Pharmacopeia corn starch (NIPPON STARCH
CHEMICAL CO., LTD.). This was used as a component
model A having low fluidity. After 30 minutes of
mixing, the repose angle was measured to be 47°.
Next, 20 g of acetaminophen (powder type, API
Corporation, crushed with a compact crusher so that the

resulting acetaminophen has an average particle size of
16 µm and 20 g of talc (Wako Pure Chemical Industries,
Ltd.) were placed in a polyethylene bag and mixed
thoroughly by hand for 3 minutes. In addition to this
40 g of mixed powder, the following were placed in a 5
L capacity V-type mixer (Dalton Co., Ltd) and mixed for
30 minutes: 952 g of 100 mesh lactose (Pharmatose 100M
(Commercial Name) from DMV Corporation); 408 g of
Japanese Pharmacopeia corn starch (NIPPON STARCH
CHEMICAL CO., LTD.); and 600 g of porous cellulose
particles A. After 30 minutes of mixing, 10 g of
magnesium stearate (0.5% external ratio) was added and
the result was mixed for 5 more minutes. The repose
angle was measured for the final formula powder (final
composition: acetaminophen/talc/100 mesh lactose/corn
starch/porous cellulose aggregate/magnesium
stearate=l.0/1.0/47.6/20.4/30.0/0.5). The results are
shown in Table 10.
The final formulated powder was used in a
rotary tablet press (LIBRA-II (Commercial Name) from
KIKUSUI SEISAKUSHO LTD, 36 stations, 410 mm turn table
diameter). Pressing was performed with an 8 mm
diameter, 12R punch with a turn table speed of 50 rpm
(108,000 tablets an hour) and a compression force of 10
kN, resulting in tablets weighing 180 mg. Tablets were
sampled 10 minutes after initiation of tablet pressing,
and tablet weight variation, hardness, and friability
were measured. The physical properties of the obtained

tablet are shown in Table 10.
[0182]
(Comparative Examples 80-83)
Operations similar to those from Example 17
were performed except that the porous cellulose
particles A were replaced with the cellulose powder K,
M, N, or G. The results are shown in Table 10.
[0183]
(Embodiment 18)
The following were placed in a 5 L scale V-
type mixer (Dalton Co., Ltd) and mixed for 30 minutes:
200 g of acetaminophen (powder type, API Corporation,
crushed with a compact crusher so that the resulting
acetaminophen has an average particle size of 16 µm;
760 g granular lactose (SUPER-TAB (Commercial Name)
made by Lactose New Zealand, sold by Asahi Kasei
Chemicals Corporation); and 40 g of sodium
croscarmellose (Kiccolate ND-2HS (Commercial Name)
produced by NICHIRIN CHEMICAL INDUSTRIES, LTD. and
distributed by Asahi Kasei Chemicals Corporation).
This was used as a component model B having low
fluidity. After 30 minutes of mixing, the repose angle
was measured to be 50°.
Next, the following were placed in a 5 L
capacity V-type mixer (Dalton Co., Ltd) and mixed for
30 minutes: 200 g of acetaminophen (powder type, API
Corporation, crushed with a compact crusher so that the
resulting acetaminophen has an average particle size of

16 µm; 760 g granular lactose (SUPER-TAB (Commercial
Name) made by Lactose New Zealand, sold by Asahi Kasei
Chemicals Corporation); 40 g of sodium croscarmellose
(Kiccolate ND-2HS (Commercial Name) produced by
NICHIRIN CHEMICAL INDUSTRIES, LTD. and distributed by
Asahi Kasei Chemicals Corporation); and 1000 g of
porous cellulose particles A. After 30 minutes of
mixing, 10 g of magnesium stearate (0.5% external
ratio) was added to the formula powder and the result
was mixed for 5 more minutes. The repose angle was
measured for the final formula powder (final
composition: acetaminophen/granular lactose/sodium
croscarmellose/porous cellulose aggregate/magnesium
stearate=10/38.0/2.0/50.0/0.5). The results are shown
in Table 10.
Next, the final formulated powder was used in
a rotary tablet press (Libra-II (Commercial Name) from
KIKUSUI SEISAKUSHO LTD, 36 stations, 410 mm turn table
diameter). Pressing was performed with an 8 mm
diameter, 12R punch with a turn table speed of 50 rpm
(108,000 tablets an hour) and a compression force of 10
kN, resulting in tablets weighing 180 mg. Tablets were
sampled 10 minutes after initiation of tablet pressing,
and tablet weight variation, hardness, and friability
were measured. The physical properties of the obtained
tablet are shown in Table 10.
[0184]
(Comparative Examples 84-87)

Operations similar to those from Example 18
were performed except that the porous cellulose
particles A were replaced with the cellulose powder K,
M, N, or G. The results are shown in Table 10.
[0185]
(Embodiment 19)
Acetaminophen (powder type, API Corporation,
crushed with a compact crusher so that the resulting
acetaminophen has an average particle size of 16 µm)
was used as a component model C having low fluidity.
The repose angle was measured to be 55°.
Next, 200 g of acetaminophen (powder type,
API Corporation, crushed with a compact crusher so that
the resulting acetaminophen has an average particle
size of 16 µm) and 18000 g of porous cellulose
particles A were mixed for 30 minutes in a 5 L capacity
V-type mixer (Dalton Co., Ltd). After 30 minutes of
mixing, 10 g each (0.5% external ratio each) of light
anhydrous silicic acid and magnesium stearate were
added to the formula powder and mixed for 5 more
minutes. The repose angle was measured for the final
formula powder (final composition: acetaminophen/porous
cellulose aggregate/light anhydrous silicic
acid/magnesium stearate=10/90/0.5/0.5). The results
are shown in Table 10.
Next, the final formulated powder was used in
a rotary tablet press (LIBRA-II (Commercial Name) from
KIKUSUI SEISAKUSHO LTD, 36 stations, 410 mm turn table


diameter). Pressing was performed with an 8 mm
diameter, 12R punch with a turn table speed of 50 rpm
(108,000 tablets an hour) and a compression force of 2
kN, resulting in tablets weighing 180 mg. Tablets were
sampled 10 minutes after initiation of tablet pressing,
and tablet weight variation, hardness, and friability
were measured. The physical properties of the obtained
tablet are shown in Table 10.
[0186]
(Comparative Examples 88-91)
Operations similar to those from Example 19
were performed except that the porous cellulose
particles A were replaced with the cellulose powder K,
M, N, or G. The results are shown in Table 10.
Out of the Comparative Examples, the
Comparative Examples with a practical tablet hardness
of 50 N or higher had significant variations in tablet
weight, making practical implementation difficult. The
ones with less variation in drug content in the final
powder and tablet weight did not provide practical
hardness, making practical implementation difficult.



INDUSTRIAL APPLICABILITY
[0188]
A high-fluidity porous cellulose aggregate,
and a compacting composition containing the cellulose
particles thereof and at least one type of active
ingredient according to the present invention provides
superior compactibility and disintegration property.
In the present invention: the porous structure has a
crystal structure I and an aggregation of primary
particles; the specific surface area is in a
predetermined range; the intraparticular pore volume is
large; disintegration takes place quickly in water; the
repose angle is low. The present invention can be used
effectively primarily in the medical field.

WE CLAIM:
1. A porous cellulose aggregate characterized in that the said aggregate is
having a secondary aggregate structure formed by aggregation of primary
cellulose particles, a pore volume within a particle of 0.265 cm3/ g-2.625 cm3/g,
containing type I crystals, and having an average particle size of more than 30
µm and 250 µm or less, a specific surface area of 0.1 m2 / g or more and less
than 20 m2 / g, a repose angle of 25° or more and less than 44°, a swelling
degree of 5% or more, and properties to disintegrate in water.
2. The porous cellulose aggregate as claimed in claim 1, wherein a cylinder-like
molded body obtained by compressing said porous cellulose aggregates at 10
MPa has a hardness of 70-160 N and a repose angle of over 36° and less than
44°.
3. The porous cellulose aggregate as claimed in claim 1, wherein a cylinder-like
molded body obtained by compressing said porous cellulose aggregates to 10
MPa has a hardness of 60-100 N and a repose angle of 25° or above and 36°
or less.

4. A method for producing the porous cellulose aggregate as claimed in any one
of claims 1-3 comprising:
a step of obtaining a dispersion (hereinafter may also be designated as a
cellulose dispersion) containing a natural cellulose material in which primary
cellulose particles have an average particle size of 10 µm or larger and less than
50 µm, average width of 2-30 µm and average thickness of 0.5-5 µm, and
a step of drying thus obtained cellulose dispersion.
5. The method as claimed in claim 4, wherein said cellulose dispersion contains
10% by weight or less of particles that is not sedimented at a centrifugal
condition of centrifugal force of 4900 m/s2.
6. The method as claimed in claim 4, wherein shearing and stirring are performed
during a step of subjecting said natural cellulose substance to a mechanical
treatment such as crushing and grinding, or a chemical treatment such as
hydrolysis, or a combination of both treatments, or stirring is performed during a
step after these treatments.
7. The method as claimed in claim 4, wherein shearing and stirring are performed
during a step of subjecting said natural cellulose substance to a mechanical
treatment such as crushing and grinding, and then during the step of hydrolysis.


8. The method as claimed in claim 4, wherein said natural cellulose substance is
subjected to stirring during a step of hydrolysis, or during the step thereafter.
9. The method as claimed in claim 6, wherein said cellulose dispersion contains
10% by weight or less of particles that are not sedimented at a centrifugal
condition of centrifugal force of 4900 m/s2.

10. The method as claimed in claim 7, wherein said cellulose dispersion contains
10% by weight or less of particles that are not sedimented at a centrifugal
condition of centrifugal force of 4900 m/s2.
11. The method as claimed in claim 8, wherein said cellulose dispersion contains
10% by weight or less of particles that are not sedimented at a centrifugal
condition of centrifugal force of 4900 m/s2.
12. The porous cellulose aggregate as claimed in claim 1, wherein said natural
cellulose substance is a wood pulp having a level-off polymerization degree of
130-250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-10%.
13. The porous cellulose aggregate as claimed in claim 1, wherein said natural
cellulose substance is a wood pulp having a level-off polymerization degree of
130-250, a whiteness of 90-99%, S10 of 5-20% and S18 of 1-10%.

14. The method for producing the porous cellulose aggregate as claimed in claim
4, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
15. The method for producing the porous cellulose aggregate as claimed in claim
5, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
16. The method for producing the porous cellulose aggregate as claimed in claim
6, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
17. The method for producing the porous cellulose aggregate as claimed in claim
7, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.

18. The method for producing the porous cellulose aggregate as claimed in claim
8, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
19. The method for producing the porous cellulose aggregate as claimed in claim
9, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
20. The method for producing the porous cellulose aggregate as claimed in claim
10, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.
21. The method for producing the porous cellulose aggregate as claimed in claim
11, wherein said natural cellulose substance is a wood pulp having a level-off
polymerization degree of 130-250, a whiteness of 90-99%, S10 of 5-20% and S18
of 1-10%.

22. A compacting composition comprising one or more groups of active
ingredients and the porous cellulose aggregate as claimed in any one of claims
1-3.
23. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate as claimed in claim 1.
24. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate as claimed in claim 1.
25. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can be obtained by the
method as claimed in claim 4.
26. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can be obtained by the
method as claimed in claim 5.
27. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can obtained by the method
as claimed in any one of claims 6-8.

28. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can be obtained by the
method as claimed in claim 9.
29. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can be obtained by the
method as claimed in claim 10.
30. A compacting composition wherein comprising one or more groups of active
ingredients and the porous cellulose aggregate that can be obtained by the
method as claimed in claim 11.
31. The compacting composition as claimed in claim 22 that is a tablet.
32. The compacting composition as claimed in any one of claims 23 - 26 that is a
tablet.
33. The compacting composition as claimed in claim 27 that is a tablet.

34. The compacting composition as claimed in any one of claims 28-30 that is a
tablet.


A porous cellulose aggregate characterized in that the said aggregate is having a
secondary aggregate structure formed by aggregation of primary cellulose
particles, a pore volume within a particle of 0.265 cm3 / g-2.625 cm3 / g,
containing type I crystals, and having an average particle size of more than 30
µm and 250 µm or less, a specific surface area of 0.1 m2 / g or more and less
than 20 m2 / g, a repose angle of 25° or more and less than 44°, a swelling
degree of 5% or more, and properties to disintegrate in water.

Documents:

03905-kolnp-2007-abstract.pdf

03905-kolnp-2007-claims.pdf

03905-kolnp-2007-correspondence others.pdf

03905-kolnp-2007-description complete.pdf

03905-kolnp-2007-drawings.pdf

03905-kolnp-2007-form 1.pdf

03905-kolnp-2007-form 2.pdf

03905-kolnp-2007-form 3.pdf

03905-kolnp-2007-form 5.pdf

03905-kolnp-2007-gpa.pdf

03905-kolnp-2007-international search report.pdf

03905-kolnp-2007-others.pdf

03905-kolnp-2007-translated copy of priority document.pdf

3905-KOLNP-2007-ABSTRACT 1.1.pdf

3905-KOLNP-2007-ABSTRACT.pdf

3905-KOLNP-2007-CANCELLED PAGES.pdf

3905-KOLNP-2007-CLAIMS 1.1.pdf

3905-KOLNP-2007-CLAIMS.pdf

3905-KOLNP-2007-CORRESPONDENCE 1.1.pdf

3905-KOLNP-2007-CORRESPONDENCE OTHERS 1.2.pdf

3905-KOLNP-2007-CORRESPONDENCE OTHERS 1.3.pdf

3905-kolnp-2007-correspondence.pdf

3905-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

3905-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

3905-KOLNP-2007-DRAWINGS 1.1.pdf

3905-kolnp-2007-examination report.pdf

3905-KOLNP-2007-FORM 1.1.1.pdf

3905-KOLNP-2007-FORM 1.pdf

3905-kolnp-2007-form 18.1.pdf

3905-KOLNP-2007-FORM 18.pdf

3905-KOLNP-2007-FORM 2.1.1.pdf

3905-KOLNP-2007-FORM 2.pdf

3905-KOLNP-2007-FORM 3.1.1.pdf

3905-kolnp-2007-form 3.pdf

3905-kolnp-2007-form 5.pdf

3905-KOLNP-2007-FORM-27.pdf

3905-kolnp-2007-gpa.pdf

3905-kolnp-2007-granted-abstract.pdf

3905-KOLNP-2007-GRANTED-CLAIMS.pdf

3905-kolnp-2007-granted-description (complete).pdf

3905-kolnp-2007-granted-drawings.pdf

3905-kolnp-2007-granted-form 1.pdf

3905-kolnp-2007-granted-form 2.pdf

3905-kolnp-2007-granted-specification.pdf

3905-KOLNP-2007-OTHERS 1.1.pdf

3905-KOLNP-2007-OTHERS.pdf

3905-KOLNP-2007-PRIORITY DOCUMENT.pdf

3905-KOLNP-2007-REPLY TO EXAMINATION REPORT 1.1.pdf

3905-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

3905-kolnp-2007-reply to examination report1.1.pdf

3905-kolnp-2007-translated copy of priority document.pdf


Patent Number 250145
Indian Patent Application Number 3905/KOLNP/2007
PG Journal Number 50/2011
Publication Date 16-Dec-2011
Grant Date 12-Dec-2011
Date of Filing 12-Oct-2007
Name of Patentee ASAHI KASEI CHEMICALS CORPORATION
Applicant Address 1-2, YURAKU-CHO 1-CHOME, CHIYODA-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 HIDEKI AMAKAWA C/O. ASAHI KASEI KABUSHIKI KAISHA 1-2, YURAKU-CHO, 1-CHOME, CHIYODA-KU, TOKYO 100-8440
2 KAZUHIRO OBAE C/O. ASAHI KASEI KABUSHIKI KAISHA 1-2, YURAKU-CHO, 1-CHOME, CHIYODA-KU, TOKYO 100-8440
3 ICHIRO IBUKI C/O. ASAHI KASEI KABUSHIKI KAISHA 1-2, YURAKU-CHO, 1-CHOME, CHIYODA-KU, TOKYO 100-8440
PCT International Classification Number C08J 9/28
PCT International Application Number PCT/JP2006/308414
PCT International Filing date 2006-04-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2005-124477 2005-04-22 Japan