U.S. patent application number 13/317943 was filed with the patent office on 2012-02-23 for porous cellulose aggregate and molding composition thereof.
This patent application is currently assigned to ASAHI KASEI CHEMICALS CORPORATION. Invention is credited to Hideki Amakawa, Ichiro Ibuki, Kazuhiro Obae.
Application Number | 20120045636 13/317943 |
Document ID | / |
Family ID | 37214814 |
Filed Date | 2012-02-23 |
United States Patent
Application |
20120045636 |
Kind Code |
A1 |
Obae; Kazuhiro ; et
al. |
February 23, 2012 |
Porous cellulose aggregate and molding composition thereof
Abstract
A porous cellulose aggregate characterized by having a secondary
aggregate structure resulting from aggregation of primary cellulose
particles, having a pore volume within a particle of 0.265 to 2.625
cm.sup.3/g, containing I-type crystals and having an average
particle size of over 30 to 250 .mu.m, a specific surface area of
0.1 to less than 20 m.sup.2/g, a repose angle of 25.degree. to less
than 44.degree. and a swelling degree of 5% or more, and
characterized by having the property of disintegrating in
water.
Inventors: |
Obae; Kazuhiro; (Tokyo,
JP) ; Amakawa; Hideki; (Tokyo, JP) ; Ibuki;
Ichiro; (Tokyo, JP) |
Assignee: |
ASAHI KASEI CHEMICALS
CORPORATION
Tokyo
JP
|
Family ID: |
37214814 |
Appl. No.: |
13/317943 |
Filed: |
November 1, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11918979 |
Oct 22, 2007 |
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PCT/JP2006/308414 |
Apr 21, 2006 |
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13317943 |
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Current U.S.
Class: |
428/221 |
Current CPC
Class: |
C08J 2397/02 20130101;
A61K 9/2054 20130101; A23V 2002/00 20130101; C08J 9/28 20130101;
A23L 29/262 20160801; Y10T 428/249921 20150401; A23V 2002/00
20130101; A23V 2250/5108 20130101; A61K 9/2018 20130101; A61K
9/2059 20130101; A23V 2200/254 20130101; C08J 2201/0504 20130101;
C08J 2301/02 20130101; A23P 10/28 20160801 |
Class at
Publication: |
428/221 |
International
Class: |
B32B 3/00 20060101
B32B003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 22, 2005 |
JP |
2005-124477 |
Claims
1. A porous cellulose aggregate having a medium pore diameter of
0.3-15 .mu.m.
2. A porous cellulose aggregate having a medium pore diameter of
3-15 .mu.m.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/918,979, filed on Oct. 22, 2077, which claims the benefit
under 35 U.S.C. Section 371, of PCT International Application No.
PCT/JP2006/308414, filed Apr. 21, 2006 and Japanese Application No.
2005-124477, filed Apr. 22, 2005, the contents of which are
incorporated herein by reference.
TECHNICAL FIELD
[0002] 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
[0003] 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.
[0004] 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 cm.sup.3/g to 2.625 cm.sup.3/g, containing type I crystals,
and having an average particle size of more than 30 .mu.m and 250
.mu.m or less, a specific surface area of 1.3-20 m.sup.2/g, a
repose angle of 25.degree. or more and less than 44.degree. 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 .mu.m. 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 .mu.m. 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
.mu.m 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 .mu.m 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 .mu.m or larger, and that
although a larger median pore diameter is better, it is at most 5
.mu.m 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 .mu.m 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 .mu.m 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.
[0005] 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 .mu.m
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.
[0006] 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 m.sup.2/g of above and a pore volume of 0.3
cm.sup.3 or above for pores with diameter 0.01 .mu.m or larger, and
having an average particle size of at most 100 .mu.m, 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.
[0007] 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 cm.sup.3/g, a particle size of 300 .mu.m or
less as cellulose powder having a good compactibility and
disintegration property.
[0008] 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 cm.sup.3/g, apparent tapping
specific volume of 1.4 cm.sup.3/g or above, a repose angle of
35-42.degree., 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 cm.sup.3 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 cm.sup.3/g,
the fluidity and disintegration property were good but the
compactibility was unsatisfactory, while with larger apparent
specific volume of 3.0-3.2 cm.sup.3/g, the compactibility was good
but the fluidity and disintegration property were poor.
[0009] Patent Document 6 describes .beta.-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 .mu.m and a specific surface area of
1.3 m.sup.2/g. The .beta.-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.
[0010] 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 cm.sup.3/g, substantially no
particles of 355 .mu.m or larger, and an average particle size of
30-120 .mu.m 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.degree. 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.
[0011] 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 .mu.m sieve and are retained on a 38 .mu.m 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.
[0012] 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 .mu.m or less, an
average particle size of 20-250 .mu.m, an apparent specific volume
of 4.0-7.0 cm.sup.3/g, and a repose angle of 54.degree. or less and
a specific surface area of 0.5-4 m.sup.2/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.degree..
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.
[0013] 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 .mu.m apparent specific volume of
over 7 cm.sup.3/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.degree.. 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.
[0014] In addition, the average particle size of the dispersed
cellulose particles in the cellulose dispersion must be 50 .mu.m 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 .mu.m or larger and less than 50 .mu.m,
which is quite different in terms of the production method.
[0015] In the range of 2.3-6.4 cm.sup.3/g of the apparent specific
volume for the cellulose powders described in these Patent
Documents 6-9, and in the range of over 7 cm.sup.3/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.
[0016] 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/cm.sup.3 (2.5 cm.sup.3/g in apparent specific
volume), spherical shape, an average particle size of 2-35 .mu.m
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
.mu.m, 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 .mu.m, and then drying the dispersion
containing thus obtained crystalline cellulose in a shape of liquid
droplets.
[0017] 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 cm.sup.3/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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] Patent Document 15 describes a method for grinding an active
ingredient that is hard to be soluble in water and
.beta.-1,4-glucan powder together. This method needs a long time
for grinding treatment until crystalline characteristics of
.beta.-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, .beta.-1,4-glucan powder that has lost the
crystalline characteristics has a problem of poor compression
compactibility.
[0023] 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 .beta.-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.
[0024] 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 .beta.-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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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. [0031]
Patent Document 1: International Patent Application No. 2005/073286
Pamphlet [0032] Patent Document 2: JP-A-1-272643 [0033] Patent
Document 3: JP-A-2-84401 [0034] Patent Document 4: JP-B-40-26274
(CA 699100 A) [0035] Patent Document 5: JP-A-53-127553 (U.S. Pat.
No. 4,159,345 A) [0036] Patent Document 6: JP-A-63-267731 [0037]
Patent Document 7: JP-A-6-316535 (U.S. Pat. No. 5,574,150) [0038]
Patent Document 8: JP-A-11-152233 [0039] Patent Document 9:
International Patent Application No. 02/02643 Pamphlet
(US20040053887 A1) [0040] Patent Document 10: International Patent
Application No. 2004/106416 Pamphlet (EP1634908) [0041] Patent
Document 11: JP-A-4-283520 [0042] Patent Document 12: JP-A-7-173050
(U.S. Pat. No. 5,505,983), [0043] U.S. Pat. No. 5,384,130) [0044]
Patent Document 13: JP-A-7-507692 (U.S. Pat. No. 5,976,600 A)
[0045] Patent Document 14: International Patent Application No.
02/36168 Pamphlet (US20040043964 A1) [0046] Patent Document 15:
JP-B-53-22138 (U.S. Pat. No. 4,036,990 A) [0047] Patent Document
16: JP-A-53-044617 [0048] Patent Document 17: JP-A-54-052718 [0049]
Patent Document 18: JP-A-03-264537 [0050] Patent Document 19:
JP-A-08-193027 [0051] Patent Document 20: JP-A-56-7713 [0052]
Patent Document 21: JP-A-60-25919 [0053] Patent Document 22:
JP-A-61-207341 [0054] Patent Document 23: JP-A-11-193229 (EP972513
B1) [0055] Patent Document 24: JP-A-11-35487 [0056] Patent Document
25: JP-A-2000-16934 [0057] Patent Document 26: JP-A-2000-247869
[0058] Patent Document 27: JP-A-2001-181195 [0059] Patent Document
28: JP-A-2001-316248 [0060] Patent Document 29: JP-A-2002-534455
(U.S. Pat. No. 6,630,150) [0061] Patent Document 30: JP-A-2003-161
[0062] Patent Document 31: JP-A-2003-55219
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0063] 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.
Means for Solving the Problem
[0064] 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.
[0065] That is, the present invention is as follows.
(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 cm.sup.3/g-2.625 cm.sup.3/g,
containing type I crystals, and having an average particle size of
more than 30 .mu.m and 250 .mu.m or less, a specific surface area
of 0.1 m.sup.2/g or more and less than 20 m.sup.2/g, a repose angle
of 25.degree. or more and less than 44.degree., 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.degree. and less than 44.degree. is
obtained by weighing 0.5 g of the aforementioned porous cellulose
aggregate and placing 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.degree. or larger and 36.degree. 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
.mu.m or larger and less than 50 .mu.m, average width of 2-30 .mu.m
and average thickness of 0.5-5 .mu.m, 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/s.sup.2.
(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 .mu.m or larger and
less than 50 .mu.m, average width of 2-30 .mu.m and average
thickness of 0.5-5 .mu.m, 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/s.sup.2. (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/s.sup.2. (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/s.sup.2. (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/s.sup.2. (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%, S.sub.10 of 5-20% and S.sub.10 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%, S.sub.10
of 5-20% and S.sub.18 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%,
S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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%, S.sub.10 of 5-20% and S.sub.18 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 (1)-(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
[0066] 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.
[0067] 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
[0068] FIG. 1 is the pore size distribution of the porous cellulose
aggregate (Example 1) of the present invention measured by mercury
porosimetry;
[0069] FIG. 2 is the pore size distribution of cellulose powder H
(Comparative Example 3) measured by mercury porosimetry;
[0070] FIG. 3 is an electron micrograph of cellulose particle K
(Comparative Example 6) at a magnification of .times.250;
[0071] FIG. 4 is an electron micrograph of cellulose powder M
(Comparative Example 8) at a magnification of .times.250;
[0072] FIG. 5 is an electron micrograph of cellulose particle K
(Comparative Example 6) at a magnification of .times.1500. From
this photo it is seen that the septa are film like and the
boundaries of the primary particles are unclear;
[0073] FIG. 6 is a particle cross section photograph of the porous
cellulose aggregate of the present invention (Example 1) by an
electron microscope; and
[0074] 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
[0075] The present invention will be described particularly
centered around the preferred mode as follows.
[0076] 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 .times.250 or
.times.1500 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.
[0077] 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.
[0078] 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.
[0079] 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.
[0080] In the porous cellulose aggregate of the present invention
the intraparticular pore volume must be 0.265 cm.sup.3/g-2.625
cm.sup.3/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 cm.sup.3/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.
[0081] When the intraparticular pore volume is 0.265 cm.sup.3 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.
[0082] 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 .mu.m or less and has extremely high aggregatability is
mixed with cellulose particles having the intraparticular pore
volume of 0.265 cm.sup.3/g 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.
[0083] When the intraparticular pore volume is less than 0.265
cm.sup.3/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.
[0084] 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 cm.sup.3/g.
[0085] Furthermore, if the pore volume exceeds 2.625 cm.sup.3/g, it
is not preferred because the apparent specific volume is increased
and the fluidity is decreased.
[0086] 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 cm.sup.3/g-1.500 cm.sup.3/g, and
especially preferred range is 0.265 cm.sup.3/g-1.000
cm.sup.3/g.
[0087] 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 .mu.m. 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 .mu.m or larger. Water permeability becomes larger
when the median pore diameter is 0.3 .mu.m 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 .mu.m.
[0088] 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 .mu.m 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 .mu.m and more preferred is 3-10
.mu.m.
[0089] 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.
[0090] In the porous cellulose aggregate of the present invention,
the average particle size must be over 30 .mu.m and 250 .mu.m or
less. When the average particle size is 30 .mu.m 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 .mu.m,
separation and segregation tend to occur in continuous compression
of a powder formulation mixed with an active ingredient having poor
fluidity.
[0091] The specific surface area of the porous cellulose aggregate
of the present invention must be 0.1 m.sup.2/g or larger and less
than 20 m.sup.2/g. At the specific surface area less than 0.1
m.sup.2/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 m.sup.2/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.
[0092] The repose angle of the porous cellulose aggregate of the
present invention must be 25.degree. or larger and less than
44.degree.. 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.degree. 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.degree.-42.degree. is
especially good. More preferable is a repose angle of
25.degree.-40.degree.. The repose angle of less than 25.degree. is
not preferable for separation and segregation of the active
ingredient.
[0093] 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 (V.sub.1) of about 10 g of a powder
slowly poured into a cylindrical container having a volume of 100
cm.sup.3, and the volume (V.sub.2) after standing for 8 hours after
adding about 50 cm.sup.3 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 (%)=(V.sub.2-V.sub.1)/V.sub.1.times.100
[0094] 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.
[0095] The apparent specific volume of the porous cellulose
aggregate of the present invention is preferably 2.0-6.0
cm.sup.3/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 cm.sup.3/g or larger, and to obtain a
higher fluidity the apparent specific volume is preferable 6.0
cm.sup.3/g or less. Especially preferred apparent specific volume
is 2.5-5.0 cm.sup.3/g.
[0096] 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.
[0097] 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.degree. and less than 44.degree., 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.degree., 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.
[0098] 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.
[0099] 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 .phi.410 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.
[0100] 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.
[0101] 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.degree.-45.degree. 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.degree.-55.degree., 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.degree. 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.degree. 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).
[0102] 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.degree.-55.degree. 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%.
[0103] Following is the description of the method for producing the
cellulose powder of the present invention.
[0104] 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 .mu.m or larger and less than 50
.mu.m, the average width is 2-30 .mu.m, and the average thickness
is 0.5-5 .mu.m. 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/s.sup.2. The porous cellulose aggregate of the present invention
can be obtained by the method for production including a step of
drying that cellulose dispersion.
[0105] The natural cellulose substance in the 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 .alpha.-cellulose, easiness to
obtain, the supply being stable and the like.
[0106] 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%, S.sub.10 is 5-20%
and S.sub.18 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%. S.sub.10 and
S.sub.18 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.
[0107] 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.
[0108] 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
.mu.m or above and less than 50 .mu.m, an average width of 2-30
.mu.m, an average thickness of 0.5-5 .mu.m, 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.
[0109] The primary cellulose particles in the present invention
mean particles having the size in the range of 1-500 .mu.m 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 .mu.m 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.
[0110] 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.
[0111] A method for making the primary cellulose particles have an
average width of 2-30 .mu.m, an average thickness 0.5-5 .mu.m 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 .mu.m and
an average thickness of 0.5-5 .mu.m. The cellulose dispersion is
preferably prepared containing particles that are not precipitated
by a centrifugal of condition centrifugal force of 4900 m/s.sup.2
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.
[0112] 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/s.sup.2 under which the % by weight of the particles is 10%
by weight or less.
[0113] The centrifugal condition of centrifugal force of 4900
m/s.sup.2 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.degree. 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 cm.sup.3, material: polypropylene co-polymer, tube
angle: 35.degree., the maximum radius: 10.5 cm, the minimum radius:
5.8 cm, rotation rate: 4100 rpm) are preferably used.
Centrifugal force (m/s.sup.2)=11.18.times.(rotation rate
(rpm)/1000).sup.2.times.rotation radius (cm).times.9.8
(m/s.sup.2)
[0114] To prepare a cellulose dispersion, in which the average
particle size of the primary cellulose particles is 10 .mu.m or
above and less than 50 .mu.m, an average width is 2-30 .mu.m and an
average thickness is 0.5-5 .mu.m (preferably, in addition to these,
particles that are not precipitated at the centrifugal condition of
centrifugal force of 4900 m/s.sup.2 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/s.sup.2.
[0115] When the average particle size of the primary cellulose
particles become 50 .mu.m 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.
[0116] When the average particle size of the primary cellulose
particles is 10 .mu.m 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 .mu.m, 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.
When the average width of the primary cellulose particles is less
than 2 .mu.m, 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
.mu.m, 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 .mu.m. When the width of the primary cellulose
particles is less than 2 .mu.m and the thickness is less than 0.5
.mu.m, 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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
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.
[0121] 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.
[0122] 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.
[0123] The water soluble macromolecule includes 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.
[0124] 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.
[0125] 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, macrogoallaurate, 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.
[0126] These water soluble macromolecules, surfactants and gas
generating substances may be added before drying and the timing of
addition is not particularly restricted.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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 B1 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.
[0132] 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 14.sup.th 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.
[0133] 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 HCl,
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, estradiol benzoate, ethinyl
estradiol, 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.
[0134] The oily or liquid 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.cndot.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-.alpha.-tocopherol,
dl-.alpha.-tocopherol acetate, d-.alpha.-tocopherol and
d-.alpha.-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.
[0135] 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, 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 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.
[0136] The finely ground active ingredient used in the present
invention means the one finely ground to 1-40 .mu.m 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 .mu.m and still more
preferable diameter is 1-10 .mu.m.
[0137] 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.
[0138] 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.
[0139] 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.cndot.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-.alpha.-tocopherol, dl-.alpha.-tocopherol acetate,
d-.alpha.-tocopherol and d-.alpha.-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.
[0140] 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 from the above group may be used alone or a combination of
two or more kinds may be used freely.
[0141] 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
oil, bleached beeswax, zinc oxide, titanium oxide, magnesium oxide,
.beta.-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, 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.
[0142] 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.
[0143] 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.
[0144] 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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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 jet-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.
[0160] 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.
[0161] A water soluble polymer as a solubilizer includes water
soluble polymers described in "Pharmaceutical additives" (published
by Yakuji Nippo Limited.), for example, hydroxypropylcellulose,
hydroxypropylmethylcellulose, 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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.degree. C.
and then water is removed by sublimation by heating under a high
vacuum (1.3.times.10.sup.-5-2.6.times.10.sup.-4 MPa).
[0176] 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).
[0177] 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.
[0178] 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
[0179] 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.
(1) Average Width (.mu.m) of Primary Cellulose Particles
[0180] 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 .times.250. The average of three representative primary
cellulose particles was calculated.
(2) Average Thickness (.mu.m) of Primary Cellulose Particles
[0181] 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 .times.1500. The
average of three representative primary cellulose particles was
calculated.
(3) Amount (% by Weight) of Particles that are not Precipitated
Under Centrifugal Condition of Centrifugal Force of 4900
m/s.sup.2
[0182] 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 cm.sup.3,
material: polypropylene co-polymer, tube angle: 35.degree., 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/s.sup.2,
in the temperature range of 15-25.degree. C. for 10 minutes. After
the centrifugation, the supernatant was transferred to a weighing
vial, dried at 110.degree. 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.degree. C. for 5 hours and the weight of the solid
after drying was measured (C(%)).
[0183] The amount of particles that are not precipitated under
centrifugal condition of centrifugal force of 4900 m/s.sup.2, D (%
by weight), was calculated from the following formula.
D (% by weight)=(B(g)/[A(g).times.(C(%)/100)]).times.100
(4) Average Particle Size (.mu.m) of Cellulose Dispersion
[0184] 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.
(5) Crystalline Form
[0185] 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 (.mu.m) of Dried Particles.
[0186] 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 (m.sup.2/g)
[0187] 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.degree. C. for 3 hours under reduced pressure.
(8) Intraparticular Pore Volume (cm.sup.3/g) and Median Pore
Diameter (.mu.m)
[0188] 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 .mu.m 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 .mu.m
was regarded as the median pore diameter from the obtained pore
size distribution and the value was recorded.
(9) Apparent Specific Volume (cm.sup.3/g)
[0189] The powder sample was poured into a 100 cm.sup.3 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 cm.sup.3.
(10) Observation of the Particle Surface and Pores by SEM
[0190] 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 .times.250-.times.1500. A sample was regarded .largecircle. 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 .mu.m or above. A sample having a structure
other than that was regarded X.
(11) Disintegration of Cellulose Particles in Water
[0191] 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 .largecircle. and not observed was X.
(12) Reactivity to a Drug
[0192] Aspirin (Japanese Pharmacopeia crystalline aspirin was
treated with a small grinder 0.5 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.degree. 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)).times.100
[0193] The sample showing a decomposition rate over 15%, which is
the decomposition rate of aspirin alone was judged to be
reactive.
(13) Repose Angle (.degree.)
[0194] Using a Sugihara type repose angle measuring device (slit
size: depth 10 mm.times.width 50 mm.times.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
[0195] The swelling degree was obtained from the volume (V.sub.1)
of about 10 g of powder which was slowly poured into a cylindrical
container having 100 cm.sup.3 capacity and the volume (V.sub.2) of
the same powder when about 50 cm.sup.3 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 (%)=(V.sub.2-V.sub.1)/V.sub.1.times.100
(14) Compression Compacting of a Cellulose Sample Alone
[0196] 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.
(15) Rotary Tablet Pressing of the Formulated Powder
[0197] 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 010 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.
(16) Variation of Tablet Mass (%)
[0198] 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).times.100. The smaller is the variation
coefficient, the smaller is the variation.
(17) Tablet Hardness (N)
[0199] 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.
(18) Disintegration Time (Second)
[0200] The disintegration test was conducted according to the
tablet disintegration test method, in the general test method of
the 14.sup.th edition of the Japanese Pharmacopeia. For a
cylindrical molded body or a tablet the disintegration time was
obtained in pure water at 37.degree. 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.
(19) Tablet Friability (% by Weight)
[0201] 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.times.(Wa-Wb)/Wa
(20) Incidence of Tablet Pressing Problems (%)
[0202] 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
[0203] 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 13.sup.th edition of the Japanese
Pharmacopeia to obtain the polymerization degree.
(22) Whiteness of Wood Pulp
[0204] This value is measured according to ISO (filter R457). 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 .mu.m.
(22) S.sub.10, S.sub.18 of Wood Pulp
[0205] A value measured according to Tappi T253m-60. S.sub.10:
[0206] 100 cm.sup.3 of 10% NaOH was placed in a glass container,
cooled to 20.degree. 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
cm.sup.3 of 0.4 N potassium dichromate and 30 cm.sup.3 of
concentrated sulfuric acid were added to 10 cm.sup.3 of the
filtered solution, and then 100 cm.sup.3 of pure water was added
and the mixture cooled in water for 30 minutes. After adding 10
cm.sup.3 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 (cm.sup.3). For 10 cm.sup.3 of 10% NaOH before
adding pulp, the titration described above was performed. The
volume of sodium thiosulfate at the endpoint was B (cm.sup.3).
S.sub.10 is calculated from the following formula.
S.sub.10(%)=(B-A).times.0.685/G
G=weight of pulp.times.(100-water content of pulp)/100
The water content of pulp is calculated by drying the pulp at
125.degree. C. for 1.5 hours.
S.sub.18:
[0207] Was measured according to the same method as S.sub.10 except
that 18% NaOH was used.
Example 1
[0208] 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 .mu.m, average thickness: about 8 .mu.m) 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/s.sup.2 to obtain the precipitates after discarding the
supernatant. The precipitates were dried at 40.degree. 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.degree. 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 .mu.m, average thickness was about 3 .mu.m and average particle
size was 38 .mu.m. This cellulose dispersion was spray dried
(dispersion supply rate: 6 kg/hr, inlet temperature:
180-220.degree. C., outlet temperature: 50-70.degree. 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.
[0209] 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 .mu.m.
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 .mu.m 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
[0210] 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 .mu.m,
average thickness of about 3 .mu.m, level off polymerization degree
of 140-220, water content of 5-10%, whiteness of 92-97%, viscosity
of 5-40 cps, S.sub.10 5-15%, S.sub.18 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.degree. 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 .mu.m, average thickness was about 2.5 .mu.m and
average particle size was 38 .mu.m. This cellulose dispersion was
spray dried (dispersion supply rate: 6 kg/hr, inlet temperature:
180-220.degree. C., outlet temperature: 50-70.degree. 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
[0211] 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 .mu.m,
average thickness of about 3 .mu.m, level off polymerization degree
of 140-220, water content of 5-10%, whiteness of 92-97%, viscosity
of 5-40 cps, S.sub.10 5-15%, S.sub.18 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.degree. 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 .mu.m, average thickness was about 2.5 .mu.m and
average particle size was 35 .mu.m. This cellulose dispersion was
spray dried (dispersion supply rate: 6 kg/hr, inlet temperature:
180-220.degree. C., outlet temperature: 50-70.degree. 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
[0212] 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 .mu.m, average thickness: about 8
.mu.m) 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/s.sup.2 to obtain the precipitates
after discarding the supernatant. The precipitates were dried at
40.degree. 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.degree.
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 .mu.m, average
thickness was about 1.5 .mu.m and average particle size was 31
.mu.m. This cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220.degree. C., outlet
temperature: 50-70.degree. 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
[0213] 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 .mu.m, average thickness: about 8
.mu.m) 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 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/s.sup.2 to obtain the precipitates
after discarding the supernatant. The precipitates were dried at
40.degree. 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.degree.
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 8 .mu.m, average
thickness was about 0.6 .mu.m and average particle size was 18
.mu.m. This cellulose dispersion was spray dried (dispersion supply
rate: 6 kg/hr, inlet temperature: 180-220.degree. C., outlet
temperature: 50-70.degree. 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.
Comparative Example 1
[0214] 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 .mu.m, average thickness: about 8
.mu.m) 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.degree. 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 .mu.m, average thickness was about 8 .mu.m and average
particle size was 36 .mu.m. This cellulose dispersion was spray
dried (dispersion supply rate: 6 kg/hr, inlet temperature:
180-220.degree. C., outlet temperature: 50-70.degree. 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.
[0215] 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.
Comparative Example 2
[0216] The similar operations were performed as Comparative Example
1 except that the hydrolysis condition was 3N hydrochloric acid
solution, at 40.degree. 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 .mu.m, the average
thickness was 8 .mu.m and the average particle size was 47
.mu.m.
Comparative Example 3
[0217] The similar operations were performed as Comparative Example
1 except that the hydrolysis condition was 3 N hydrochloric acid
solution, at 40.degree. 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 .mu.m,
the average thickness was 8 .mu.m and the average particle size was
49 .mu.m.
[0218] 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
.mu.m was derived from the gap between particles.
Comparative Example 4
[0219] The similar operations were performed as
[0220] Comparative Example 1 except that the hydrolysis condition
was 4 N hydrochloric acid solution, at 40.degree. 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 .mu.m, the average thickness was 8 .mu.m and the
average particle size was 44 .mu.m.
Comparative Example 5
[0221] 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.
Comparative Example 6
[0222] 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.degree. 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.degree. 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.
[0223] FIG. 3 shows an electron micrograph of the cellulose
particle K at a magnification of .times.250 and FIG. 5 shows an
electron micrograph at a magnification of .times.1500.
[0224] In the cellulose powder K, a "clear peak" was confirmed in
the range of 0.1-10 .mu.m 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.
Comparative Example 7
[0225] A commercially available dissolved pulp was shredded and
hydrolyzed in 7% hydrochloric acid solution at 105.degree. 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
KAISHA LTD. Type 15M (Commercial Name)) at a treatment pressure of
400 kg/cm.sup.2 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
.mu.m. 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
.mu.m 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.
[0226] In the cellulose particle L, a "clear peak" was confirmed at
0.1 .mu.m 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.
Comparative Example 8
[0227] 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 .mu.m, average thickness: about 8
.mu.m) 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.degree. 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 .mu.m, average thickness was about 8 .mu.m and average
particle size was 36 .mu.m. This cellulose dispersion was spray
dried (dispersion supply rate: 6 kg/hr, inlet temperature:
180-220.degree. C., outlet temperature: 50-70.degree. C.) to obtain
the cellulose powder M (corresponding to Example of Patent Document
4).
[0228] 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 .times.250 is shown in FIG. 4.
[0229] 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 .mu.m
in the pore size distribution from the results of the measurement
of the pore size distribution by the mercury porosimetry.
[0230] 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.
Comparative Example 9
[0231] Two kilograms of a commercially available kraft pulp was
shredded and hydrolyzed in 0.7% by weight hydrochloric acid aqueous
solution at 125.degree. 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.
[0232] The average fiber width of the primary cellulose particle in
cellulose water/ethanol dispersion before drying was 31 .mu.m, the
average thickness was 8 .mu.m and average particle size was 28
.mu.m. 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.
Comparative Example 10
[0233] A commercially available dissolved pulp was shredded and
hydrolized in 10% by weight hydrochloric acid aqueous solution at
105.degree. 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 .mu.m, an average thickness of 8 .mu.m, and an
average particle size of 33 .mu.m. 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.degree. C., a drum speed of 2 rpm,
and reservoir dispersion temperature of 100.degree. C.). This was
then crushed with a hammer mill and bulk particles were removed
with a sieve having a mesh size of 425 .mu.m, providing a Cellulose
Powder O (corresponds to Example 1 in Patent Document 7). Various
properties of the obtained Cellulose Powder O are shown in Table
1.
Comparative Example 11
[0234] An airjet sieve was used on the Cellulose Powder K obtained
from Comparative Example 10 and large particles were removed with a
75 .mu.m sieve and fine particles were removed with a 38 .mu.m
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.
Comparative Example 12
[0235] 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.degree. 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.
[0236] 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, MPa.
Comparative Example 13
[0237] 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.degree. 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
.mu.m. 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.degree. C., and an outlet
temperature of 85.degree. C. Large particles were removed with a
sieve having a mesh size of 177 .mu.m 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.
[0238] 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.
Comparative Example 14
[0239] 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.degree. 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 .mu.m, an average thickness of 8 .mu.m, and an
average particle size of 54 .mu.m. This was spray dried (dispersion
supply rate: 6 L/hr, inlet temperature: 180-220.degree. C., outlet
temperature: 50-70.degree. 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
[0240] 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.degree. 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 .mu.m.) 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 .mu.m. 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.degree. C., outlet
temperature: 50-70.degree. 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
[0241] 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.degree. 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 .mu.m. 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 .mu.m.) 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.degree. C., outlet
temperature: 50-70.degree. 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
[0242] 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.degree. 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 .mu.m. 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 .mu.m. 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.degree. C., outlet temperature: 50-70.degree. 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.
[0243] 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 .mu.m, while the
central pore diameters of the porous cellulose aggregates of the
present application are at least approximately 3.0 .mu.m. Thus, the
larger central pore diameters provide a faster water permeation
rate.
TABLE-US-00001 TABLE 1-1 Physical properties of Physical properties
of Physical properties of powder primary cellulose cellulose
dispersion Particle particle Average Amount of Specific Media
Intra- structure by Fiber Fiber particle fine surface Drug pore
particular SEM Cellulose width thickness size particles Crystal
area re- diameter pore volume (secondary powder (.mu.m) (.mu.m)
(.mu.m) (%) form (m.sup.2/g) activity (.mu.m) (cm.sup.3/g)
aggregation) Example 1 A 19 3 38 6 I 0.8 No 4.5 0.41 .smallcircle.
2 B 22 2.5 38 5 I 1.5 No 6.0 1.00 .smallcircle. 3 C 22 2.5 35 9 I
1.4 No 11.0 0.55 .smallcircle. 4 D 15 1.5 31 8 I 5.0 No 8.0 0.70
.smallcircle. 5 E 8 0.6 18 2 I 12.0 No 3.0 1.50 .smallcircle.
Comparative 1 F 39 8 Slurry not Slurry not I 1.4 No Not clear 0.264
x Example formed formed 2 G 39 8 47 13 I 1.5 No Not clear 0.245
.smallcircle. 3 H 39 8 49 11 I 1.7 No Not clear 0.24 .smallcircle.
4 I 39 8 44 14 I 1 No Not clear 0.245 .smallcircle. 5 J 39 8 37 15
I 1.1 No Not clear 0.203 .smallcircle. 6 K 39 8 Slurry not Slurry
not I 5 No 2 0.5067 x formed formed 7 L 0.4 0.3 1 70 I 24.1 Yes
Less than 0.89 x (Median 0.1 pore diameter Less than 0.1 .mu.m) 8 M
39 8 36 15 I 1 No Not clear 0.258 .smallcircle. 9 N 31 8 28 20 I
0.6 No Not clear 0.23 .smallcircle. 10 O 39 8 33 17 I 1.9 No Not
clear 0.24 .smallcircle. 11 P 39 8 Slurry not Slurry not I 2.4 No
Not clear 0.235 .smallcircle. formed formed 12 Q 39 8 Slurry not
Slurry not I 0.05 No Not clear 0.048 x formed formed 13 R 39 8 7 40
I 0.3 No Not clear 0.098 x 14 S 39 8 54 9 I 1.2 No Not clear 0.239
x 15 T 39 8 25 30 I 12.5 No 1.5 0.82 .smallcircle. 16 U 39 8 44 15
I 3.5 No 1 0.65 .smallcircle. 17 V 0.8 0.3 5 60 I 2.2 No 0.7 0.265
.smallcircle.
TABLE-US-00002 TABLE 1-2 Physical properties of powder Physical
properties of cylindrical Average Apparent molded body Property to
Swelling particle specific Repose 10 MPa 20 MPa 20 MPa Cellulose
disintegrate in degree size volume angle Hardness Hardness
Disintegration powder water (%) (.mu.m) (cm.sup.3/g) (.degree. C.)
(N) (N) (Second) Example 1 A Disintegration 28.0 51 4.2 39 89 230
16 2 B Disintegration 10.0 230 5.1 40 95 260 10 3 C Disintegration
38.0 90 3.5 34 65 170 5 4 D Disintegration 48.0 31 3.0 28 70 180 10
5 E Disintegration 6.0 150 5.5 42 145 410 30 Comparative 1 F No
disintegration 0.5 28 4.5 55 90 254 289 Example 2 G Disintegration
0.0 45 5.3 51 110 309 76 3 H Disintegration 1.0 38 6.3 54 72 203
110 4 I Disintegration 0.0 105 4.4 44 66 190 35 5 J Disintegration
21.0 203 3.1 36 52 150 16 6 K No disintegration -4.5 174 2.1 35 45
127 245 7 L No disintegration -5.0 48 4.5 48 80 225 210 8 M
Disintegration 19.0 49 3.2 44 57 161 12 9 N Disintegration 40.0 35
2 41 40 113 11 10 O Disintegration 0.0 47 5.4 56 101 188 150 11 P
Disintegration 1.0 50 6.3 59 106 210 220 12 Q No disintegration 0.0
220 1.1 26 0 0 -- 13 R No disintegration 1.0 93 1.3 32 5 10 -- 14 S
Disintegration 0.0 50 7.5 50 108 280 268 15 T Disintegration 2 31 4
43 145 409 75 16 U Disintegration 3 248 5 38 90 254 22 17 V
Disintegration 4 190 2 26 60 169 9
Example 6 and Comparative Examples 18-28
[0244] 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 O 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.
[0245] 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.
TABLE-US-00003 TABLE 2 Physical properties of tablets that are
obtained by high speed tabletting Variation of Hardness of
Friability Tablet pressing Cellulose tablet weight tablet of tablet
trouble rate powder (%) (N) (%) (%) Example 6 A 0.8 60 0.4 0
Comparative 18 F 2.3 65 0.6 0 Example 19 G 1.8 67 0.6 0 20 I 1.1 42
6.0 30 21 J 0.6 38 15.0 88 22 K 0.7 32 12.0 48 23 L 1.5 48 5.0 15
24 M 1.1 35 19.0 72 25 N 0.8 30 22.7 90 26 O 2.4 55 0.9 0 27 P 2.3
57 0.8 0 28 S 3.5 100 0.1 0
Embodiments 7, 8 and Comparative Examples 29-39
[0246] 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 .mu.m
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.
[0247] 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 0.2-0.50 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.degree., 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.
TABLE-US-00004 TABLE 3 Physical properties of tablets that are
obtained by high speed tabletting Variation of Hardness of
Friability Tablet pressing Disintegration Cellulose tablet weight
tablet of tablet trouble rate time powder (%) (N) (%) (%) (sec)
Example 7 C 0.5 52 0.5 0 11 8 D 0.2 57 0.3 0 15 Comparative 29 G
2.1 70 0.1 0 44 Example 30 I 1.6 50 0.4 0 35 31 J 0.5 40 2.0 30 28
32 K 0.4 35 5.0 40 55 33 L 1.9 60 0.3 0 50 34 M 1.5 45 0.7 0 25 35
N 0.9 29 15.0 80 23 36 O 3.1 65 0.2 0 45 37 P 3.5 68 0.1 0 50 38 S
2.0 69 0.1 0 59 39 V 0.2 50 0.6 0 26
Embodiment 9, 10, and Comparative Examples 40-51
[0248] 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.
[0249] 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.
TABLE-US-00005 TABLE 4 Physical properties of tablets that are
obtained by high speed tabletting Variation of Hardness of
Friability Tablet pressing Disintegration Cellulose tablet weight
tablet of tablet trouble rate time powder (%) (N) (%) (%) (sec)
Example 9 B 0.5 70 0.4 0 15 10 E 0.7 100 0.1 0 20 Comparative 40 G
2.3 63 0.5 0 40 Example 41 I 1.6 50 7.0 50 35 42 J 0.3 44 8.0 60 20
43 K 0.2 38 13.0 80 80 44 L 1.7 64 0.6 0 75 45 M 1.5 49 10.0 70 16
46 N 0.7 30 21.0 88 15 47 O 3.1 90 0.2 0 50 48 P 4.0 95 0.2 0 76 49
S 2.0 97 0.2 0 85 50 T 0.8 100 0.1 0 42 51 U 0.7 70 0.5 0 25
Embodiment 11, 12, and Comparative Examples 52-63
[0250] 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.
[0251] 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.
TABLE-US-00006 TABLE 5 Physical properties of tablets that are
obtained by high speed tabletting Variation of Hardness of
Friability Tablet pressing Disintegration Cellulose tablet weight
tablet of tablet trouble rate time powder (%) (N) (%) (%) (sec)
Example 11 B 0.7 75 0.3 0 25 12 E 0.8 105 0.1 0 60 Comparative 52 G
1.8 51 0.9 0 79 Example 53 I 1.2 45 2.5 5 65 54 J 0.6 44 5.0 30 30
55 K 0.5 40 10.0 40 110 56 L 2.1 70 0.4 0 100 57 M 1.1 48 1.9 21 29
58 N 0.7 35 25.0 50 25 59 O 2.3 85 0.2 0 90 60 P 2.6 88 0.3 0 105
61 S 1.9 90 0.1 0 119 62 T 0.8 105 0.1 0 90 63 U 0.7 73 0.5 0
35
Embodiment 13
[0252] 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-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. 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 .mu.m 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.
Comparative Example 64
[0253] 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
[0254] 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
[0255] 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.
Comparative Example 67
[0256] 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.
Comparative Example 68
[0257] 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.
Comparative Example 69
[0258] 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.
TABLE-US-00007 TABLE 6 Physical properties of compression molded
body Cellulose Effusion of liquid Disintegration particle
components property Example 13 A No effusion Disintegration
Comparative K No effusion No disintegration Example 64 Comparative
L No effusion No disintegration Example 65 Comparative M Effusion
Disintegration Example 66 Comparative N Effusion Disintegration
Example 67 Comparative G Effusion Disintegration Example 68
Comparative S No effusion No disintegration Example 69
Embodiment 14
[0259] 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.
Comparative Example 70
[0260] 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.
Comparative Example 71
[0261] 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.
Comparative Example 72
[0262] 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.
Comparative Example 73
[0263] 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.
Comparative Example 74
[0264] 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.
Comparative Example 75
[0265] 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.
TABLE-US-00008 TABLE 7 Physical properties of compression molded
body Elution rate after Condition of Condition of 3 minutes
Cellulose molded body disintegration (%) Example 14 A No effusion,
Disintegration 97 solidification Comparative K No effusion, No 35
Example 70 solidification disintegration Comparative L No effusion,
No 38 Example 71 solidification disintegration Comparative M
Effusion, not done Cannot Example 72 no solidification be done
Comparative N Effusion, no not done Cannot Example 73
solidification be done Comparative G Effusion, not done Cannot
Example 74 no solidification be done Comparative S No effusion, No
10 Example 75 solidification disintegration
Embodiment 15
[0266] 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.
Comparative Example 76
[0267] An elution test was performed on just ethenzamide crushed
according to Example 15. The results are shown in Table 8.
TABLE-US-00009 TABLE 8 Physical properties of compression molded
body Elution rate after 1 hour Cellulose (%) Example 15 A 100
Comparative Ethenzamide 9 Example 76 material powder
Embodiment 16
[0268] 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.degree. 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.
Comparative Example 77
[0269] 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.
Comparative Example 78
[0270] 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.
Comparative Example 79
[0271] 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.
TABLE-US-00010 TABLE 9 Physical properties of compression molded
body Cellulose Cloudiness Disintegration Elution rate particle of
vial property (%) Example 16 A None Disintegration 95 Comparative K
None No disintegration 32 Example 77 Comparative L None No
disintegration 30 Example 78 Comparative M Present Disintegration
18 Example 79
Embodiment 17
[0272] 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 .mu.m 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.degree..
[0273] 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 .mu.m 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=1.0/1.0/47.6/20.4/30.0/0.5). The results are shown in
Table 10.
[0274] 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.
Comparative Examples 80-83
[0275] 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.
Embodiment 18
[0276] 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
.mu.m; 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.degree..
[0277] 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 .mu.m; 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.
[0278] 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.
Comparative Examples 84-87
[0279] 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.
Embodiment 19
[0280] Acetaminophen (powder type, API Corporation, crushed with a
compact crusher so that the resulting acetaminophen has an average
particle size of 16 .mu.m) was used as a component model C having
low fluidity. The repose angle was measured to be 55.degree..
[0281] 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 .mu.m) 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.
[0282] 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.
Comparative Examples 88-91
[0283] 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.
[0284] 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.
TABLE-US-00011 TABLE 10 Repose angle (.degree.) Drug content CV
Component Before the addition After addition of value of the final
Tablet weight CV Tablet hardness Cellulose model of cellulose
cellulose powder (%) (N) Example 17 A A 47 42 1.4 0.5 60
Comparative Example 80 K 39 3.0 0.3 32 Comparative Example 81 M 46
2.0 1.1 30 Comparative Example 82 N 44 2.5 0.8 15 Comparative
Example 83 G 49 1.5 2.5 55 Example 18 A B 50 43 0.8 0.8 55
Comparative Example 84 K 40 2.0 0.6 25 Comparative Example 85 M 47
1.6 1.8 20 Comparative Example 86 N 45 1.9 1.1 9 Comparative
Example 87 G 50 1.1 3.0 51 Example 19 A C 55 44 0.6 1.5 74
Comparative Example 88 K 42 1.8 1.4 40 Comparative Example 89 M 48
1.1 2.5 32 Comparative Example 90 N 46 1.2 1.8 17 Comparative
Example 91 G 52 0.8 3.5 56
INDUSTRIAL APPLICABILITY
[0285] 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.
* * * * *