Novel excipient and pharmaceutical composition containing the same

An excipient for use in manufacture of tablets, capsules, powders, microgranules and granules which consists essentially of a microcrystalline cellulose having an average degree of polymerization of 60 to 375 and obtained through acid hydrolysis or alkaline oxidative degradation of a celulosic substance selected from linters, pulps and regenerated fibers, said microcrystalline cellulose being a white cellulosic powder having an apparent specific volume of 1.6 to 3.1 cc/g, a repose angle of 35.degree. to 42.degree., a 200-mesh sieve residue of 2 to 80% by weight and a tapping apparent specific volume of at least 1.4 cc/g and a pharmaceutical composition comprising a pharmaceutically active ingredient and the excipient. This excipient has improved flowability and moldability or compressibility whereby excellent pharmaceutical preparations may be easily provided. In addition, pharmaceutical compositions obtained using such excipient are excellent in various pharmaceutical characteristics such as rate of disintegration, rate of dissolution, etc.

The present invention relates to a pharmaceutical excipient for use in 
manufacture of tablets, capsules, powders, microgranules and granules. 
More specifically, when the excipient of the present invention is used for 
manufacture of tablets, it permits high-speed direct compression and 
provides tablets in which the uneveness of the weight of the main 
ingredient content is remarkably reduced and which have an increased rate 
of disintegration and an improved rate of dissolution of the main 
ingredient. 
When the excipient of the present invention is used for manufacture of 
capsules, it exerts effects of improving the homogeneousness in a powdery 
mix to be encapsulated, increasing the speed of mixing the ingredients, 
reducing the unevenness of the filled weight of the powdery mix in 
resulting capsules and increasing quantities of the powdery mix when 
encapsulated, shortening the disintegration time of the resulting capsules 
and preventing prolongation of the disintegration time of the resulting 
capsules which prolongation is caused with the lapse of time. 
When the excipient of the present invention is used for manufacture of 
powders, it provides powders in which the uneven distribution of the main 
ingredient is reduced remarkably and the flowability of a powdery mix is 
enhanced and which are excellent in the adaptability to the packeting 
operation and can be taken with ease. 
When the excipient of the present invention is used for manufacture of 
microgranules and granules, it can reduce the necessary amount of a binder 
at the step of wet granulation and improve the strength of the resulting 
particles or granules even with the reduced quantity of the binder while 
effectively preventing dusting of microgranules or granules, and it can 
provide particles and granules having excellent disintegrating 
characteristics in high yields. 
Further, the present invention relates to a pharmaceutical composition for 
tablets, capsules, powders, microgranules or granules, which comprises an 
excipient having novel powder characteristics as a binder or 
disintegrating agent, and a main pharmaceutical ingredient and other 
pharmaceutical additives. 
Conventional solid pharmaceutical compositions generally comprise (i) a 
main ingredient (pharmaceutically active ingredient), (ii) an excipient, 
(iii) a binder, (iv) a disintegrating agent and (v) other additives. 
As the excipient, there have been used various substances such as lactose, 
starches, calcium phosphate and glucose. Methyl cellulose (MC), 
hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), 
microcrystalline cellulose and the like have been used as the binder. As 
the disintegrating agent, there have been used starches, calcium 
carboxymethyl cellulose (CMC-Ca), ion exchange resins and the like. These 
substances have merits and demerits in properties thereof, and therefore, 
none of them can be used as versatile additives effective as an excipient, 
a binder and a disintegrating agent concurrently. 
For example, lactose, a typical instance of the excipient suitable for 
direct compressing has a high apparent density close to that of a main 
ingredient and it has a very good flowability if it is crystalline. 
However, lactose is very poor in the moldability or compressibility and 
tablets formed by using lactose as an excipient cannot be practically 
applied. Also starch is poor in the moldability or compressability when it 
is used alone. Each of MC, HPC and PVP, that have been used as binders, 
shows a sufficient effect as an excipient in the direct compression when 
used in a large quantity and has a sufficient moldability or 
compressibility. Each of these binders, however, is poor in flowability 
and is highly swollen on absorption of water so that in tablets formed by 
using MC, HPC or PVP, the stability is degraded with the lapse of time. If 
the moldability is enhanced so as to improve the strength of tablets, the 
disintegration time is inevitably prolonged. A conventional disintegrating 
agent such as CMC-Ca or an ion exchange resin is poor in the moldability 
or compressibility. In general, an ion exchange resin per se has a good 
flowability but its flow characteristics are insufficient for improving 
the flowability of a pharmaceutical composition comprising a large 
quantity of a main ingredient and other additives. Finely divided silica 
is effective for improving the flowability, but if this flow modifier is 
incorporated in a large quantity, such undesirable phenomena as capping 
and sticking are readily caused to occur at the tableting step and the 
bulk of a powdery mix is undesirably increased. An inorganic excipient 
such as calcium phosphate has a good flowability and a high apparent 
density, but capping is readily caused when the direct compression 
operation is carried out at a high speed. Further, since the excipient is 
composed of an inorganic substance, main parts of a tablet compressing 
machine, such as a die and a punch, are readily worn. Accordingly, use of 
such inorganic excipient is not preferred from the practical viewpoint. 
A high-speed direct compression machine has recently been developed for 
enhancing the productivity, but the excellent capacities of this newly 
developed high-speed direct compressing machine cannot be sufficiently 
exerted because of such defects of conventional excipients as (i) poor 
flowability, (ii) high bulk, (iii) insulfficient strength if the 
compression time is short, and (v) generation of large quantities of 
dusts. 
Recently, the effectiveness and reliability of medicines are strictly 
evaluated and checked, and efforts have been intensively made to (i) 
reduce the weight unevenness in tablets and (ii) eliminate the unevenness 
of the main ingredient content in tablets. These objects will be attained 
if there is found an excipient having a high apparent density and an 
excellent flowability and such excipient is incorporated into a 
pharmaceutically active ingredient (often referred to as "main 
ingredient"). However, an excipient suitable for direct compression 
meeting these requirements satisfactorily has not been developed in the 
art. 
Under such background, it has been eagerly desired in the art to develop a 
novel excipient having a high moldability or compressibility, a small bulk 
(high apparent density) and a good flowability and being capable of 
increasing a rate of disintegration and accelerating dissolution of the 
main ingredient, which is applicable to the wet method as well as the dry 
method in preparation of pharmaceutical products and which has 
well-balanced general properties. 
It is therefore a primary object of the present invention to provide a 
novel excipient having a high moldability or compressibility, a small bulk 
and a good flowability and providing tablets and capsules in which the 
unevenness of the weight and the unevenness of the main ingredient content 
are remarkably reduced, especially easily-disintegratable tablets 
according to the direct compression method. 
Another object of the present invention is to provide an excipient useful 
for manufacture of powders, microgranules, granules, and tablets according 
to the method of compression with wet granulation. 
Still another object of the present invention is to provide a 
pharmaceutical composition which makes it possible to manufacture tablets, 
capsules, powders, microgranules and granules having high quality. 
In accordance with the present invention, the foregoing and other objects 
can be attained by an excipient consisting essentially of a 
microcrystalline cellulose having an average degree of polymerization of 
60 to 375 and obtained through acid hydrolysis or alkaline oxidative 
degradation of a cellulosic substance selected from linters, pulps and 
regenerated fibers, microcrystalline cellulose being a white cellulosic 
powder having an apparent specific volume of 1.6 to 3.1 cc/g, a repose 
angle of 35.degree. to 42.degree., a 200-mesh sieve residue of 2 to 80% by 
weight and a tapping apparent specific volume of at least 1.4 cc/g. 
This white cellulosic powder is prepared, for example, according to the 
following method. 
Refined linters are hydrolyzed at 125.degree. C. for 150 minutes in a 0.7% 
aqueous solution of hydrochloric acid, and the hydrolysis residue is 
neutralized, washed and filtered to obtain a wet filter cake. The cake is 
sufficiently pulverized in a kneader, and ethanol in a volume larger than 
the volume of the pulverized cake is added to the pulverized cake. The 
mixture is compressed and filtered, and the residue is air-dried. The 
resulting cellulose powder mass is finely pulverized by a hammer mill and 
passed through a 40-mesh sieve to obtain a cellulosic powder having a 
degree of polymerization of 180, an apparent specific volume of 2.0 cc/g, 
a repose angle of 40.degree., a 200-mesh sieve residue of 12% by weight 
and a tapping apparent specific volume of 1.6 cc/g. 
Of course, it must be noted that the method for preparing the 
microcrystalline cellulosic powder of the present invention is not limited 
to the above-mentioned method and the microcrystalline cellulosic powder 
of the present invention is not limited to products obtained according to 
the above-mentioned method. 
In order for an excipient to have a moldability sufficient for forming 
tablets according to the direct compression method, it is important that 
the excipient should have an average degree of polymerization (hereinafter 
referred to as "DP") in the range of from 60 to 375. If DP is lower than 
60, the moldability is insufficient and provides a powdery mix in which 
capping tends to readily occur in the direct compression. Accordingly, use 
of an excipient having such a low DP value is not preferred from the 
practical viewpoint. If DP is higher than 375, fibrous characteristics are 
manifeste in the excipient and the requirements of the flowability and 
bulk density (apparent specific volume) described in detail hereinafter 
are not satisfied. 
The excipient should have an apparent specific volume of 1.6 to 3.1 cc/g as 
determined according to the method described hereinafter. If the apparent 
specific volume is larger than 3.1 cc/g, the bulk of the resulting powder 
mix is large and it is not suitable for high-speed direct compression. If 
the apparent specific volume is smaller than 1.6 cc/g, the specific 
gravity is close to that of the main ingredient but the resulting powder 
mix is too compact and the quantity of plastic deformation at the step of 
compression molding is too small. Further, in this case, entanglements of 
granules are reduced and the resulting powdery mix becomes poor in the 
moldability with increased tendency to cause capping. 
The excipient should also have a repose angle of 35.degree. to 42.degree. 
as measured according to the conical deposition method. The repose angle 
is one of factors determining flow characteristics of powder. In case of 
microcrystalline cellulose having a repose angle smaller than 35.degree., 
the flowability of the resulting powdery mix is indeed improved remarkably 
and the powdery mix flows smoothly from a hopper, but because of too high 
flowability of the microcrystalline cellulose, separation and/or 
segregation of the ingredients is caused in the hopper and no substantial 
effect of reducing the unevenness of the main ingredient content can be 
attained. When the repose angle exceeds 42.degree., the flowability 
becomes insufficient and bridging is caused in the powdery mix in the 
hopper, and therefore, flow-out of the powdery mix from the hopper is 
inhibited, weight variations in tablets become conspicuous and high-speed 
direct compression is impossible. 
The particle size of microcrystalline cellulose should be such that the 
content of the 200-mesh sieve residue is 2 to 80% by weight as determined 
according to the sieve analysis method. When microcrystalline cellulose 
having a 200-mesh sieve residue of lower than 2% by weight is used as an 
excipient the flowability of the resulting powdery mix is poor and the 
requirement of the repose angle of at least 42.degree. is not satisfied in 
this microcrystalline cellulose. Further, generation of dusts is 
conspicuous at the tableting step. If the 200-mesh sieve residue exceeds 
80% by weight, the particle is coarse and the flowability is enhanced, but 
the adaptability to the compression molding is degraded. 
If the tapping apparent specific volume is lower than 1.40 cc/g, the 
moldability of the resulting powdery mix is insufficient. The upper limit 
of the tapping apparent density is naturally defined by the upper limit of 
the apparent specific volume of 3.1 cc/g. If the tapping apparent density 
is not higher than this value, no particular trouble or disadvantage is 
brought about. 
A capsule is one of typical pharmaceutical preparations as well as a 
tablet. Also in the field of manufacture of capsules, a high-speed 
encapsulating machine has been developed for improving the productivity. 
However, since there is not an excellent encapsulation additive matchable 
with the capacity of the machine, the capacity of this machine is not 
sufficiently exerted. This is due mainly to insufficient flowability of a 
powdery mix to be encapsulated. 
Large capsules give an unpleasant feeling when they are orally administered 
and smaller capsules are preferred, and reduction of the size in capsules 
is desired also by manufactures and dealers because reduction of the size 
in capsules results in enhancement of the productivity, rationalization of 
packaging costs and reduction of transportation costs. However, in 
actuality, reduction of the size in capsules involves various 
difficulties, which are concerned with such properties of powdery mixes to 
be encapsulated as (i) the bulk (apparent specific volume), (ii) 
flowability, (iii) particle size, (iv) surface characteristics and (v) 
compressibility. 
In case of an encapsulating machine as in other medicine manufacturing 
machines treating powders, the quantity of powder to be encapsulated is 
expressed by the volume rather than by the weight. Accordingly, in 
general, as the bulk of powder is small, a unit weight of powder to be 
encapsulated is increased and the size of capsules can be reduced. The 
encapsulating machine includes various types, for example, an auger type, 
a disc type and a compressing type. The flowability of powder is very 
important irrespective of the type of the encapsulating machine. For 
example, in case of an auger type machine, powder should be smoothly 
filled in capsules with movement of an auger, and in case of a disc type 
machine, powder should be smoothly filled in capsules by free flow owing 
to its own weight. Further, in case of a compressing type machine, powder 
should be smoothly and completely filled with nozzles in holes formed by 
punching. As is seen from the foregoing illustration, the flowability of 
powder is very important in any of encapsulating methods. Also the 
particle size of powder is important. In case of an auger type machine, 
too fine powder grates a screw and the flowability is degraded. Further, 
in case of a compressing type machine, too fine powder leaks out from a 
spacing between a nozzle and a spindle and adheres to them, and therefore, 
friction heat is generated by the vertical movement of the spindle and it 
is impossible to continue the operation for a long time. Too coarse 
particles fall down from a nozzle during the filling operation in case of 
a compressing type machine, resulting in unevenness of the filled weight. 
The compressibility of powder is especially important in case of a 
compressing type machine, and if the compressibility is insufficient, the 
filled weight is uneven in resulting capsules. 
In addition to the foregoing problems involved in the manufacturing 
equipments, there is another problem important from the pharmaceutical 
viewpoint. More specifically, when a powdery mix to be encapsulated is 
prepared, it is necessary to mix the respective ingredients as 
homogeneously as possible. Even when the same weight of the powdery mix is 
filled in the respective capsules, if the content of the pharmaceutically 
active ingredient (main ingredient) is not uniform in the powdery mix, the 
uniformity of the filled weight becomes insignificant. Accordingly, it is 
very important to increasing the mixing speed and attain homogeneousness 
in the resulting powdery mix. 
As-prepared capsules are disintegrated in a short time and are excellent in 
the availability. However, if they are allowed to stand still for a long 
time, moisture permeates into capsules through gelatin walls and the 
filled powder adsorbs water or is caked or solidified, and as a result, 
the disintegration time is prolonged. This difference of the 
disintegration time between as-prepared capsules and capsules allowed to 
stand still for a long time will result in the difference of availability 
of capsules as medicinal products and hence, should be eliminated. 
Influences of powder characteristics of microcrystalline cellulose as the 
excipient on capsules will now be described. 
When the apparent specific volume of powder is larger than 3.1 cc/g, the 
flowability is degraded and the bulk is increased, and it is impossible to 
increase the unit weight to be encapsulated. If the apparent specific 
volume is smaller than 1.6 cc/g, it is possible to increase the filled 
weight and enhance the flowability, but compressibility is substantially 
lost in the resulting powder mix. Accordingly, in order to attain high 
flowability and high compressibility and increase the filled weight, it is 
necessary that the apparent specific volume of powder should be in the 
range of from 1.6 to 3.1 cc/g. 
If the repose angle of powder is larger than 42.degree., the flowability of 
the powdery mix to be encapsulated is degraded and the unevenness of the 
filled weight becomes conspicuous. Further, the filling easiness of the 
powdery mix is degraded and it is impossible to increase the unit weight 
to be encapsulated. 
The particle size of powder should be such that the 200-mesh sieve residue 
is 2 to 80% by weight. When the 200-mesh sieve residue exceeds 80% by 
weight, in case of a compressing type encapsulating machine, no good 
compressibility is manifested, and leakage of powder from a nozzle becomes 
conspicuous, resulting in increase of the unevenness of the filled weight. 
In case of a disc type encapsulating machine, when the powdery mix is 
shaken by a vibrator, separation of the excipient powder from the main 
ingredient is caused. When the 200-mesh sieve residue is lower than 2% by 
weight, troubles are caused due to too fine a particle size. For example, 
in case of a disc type encapsulating machine, powder is filled in a 
spacing between a capsule and a disc and smooth disposal of capsules 
becomes impossible. In case of a compressing type encapsulating machine, 
powder is filled in a spacing between a spindle and a nozzle and smooth 
vertical movement of the spindle becomes impossible, and the unevenness of 
the filled weight becomes conspicuous. 
A good compressibility necessary for encapsulation according to a 
compressing type machine is not attained when the tapping apparent 
specific volume is smaller than 1.4 cc/g, and in this case, it is 
necessary to elevate the compression pressure and the disintegration time 
of resulting capsules becomes too long. From the viewpoint of the filling 
easiness, there is no upper limit of the tapping apparent specific volume, 
and if other powder characteristics are selected in optimum ranges, the 
upper limit of the tapping apparent specific volume will naturally be 
determined. In general, the upper limit of the tapping apparent specific 
volume is about 2.6 cc/g. 
When the excipient of the present invention is applied to powders, the 
packeting operation can be facilitated because the excipient gives good 
flowability and bulk to the powdery mix. Further, at the powder preparing 
step, the excipient of the present invention shows a good compatibility 
with the pharmaceutically active ingredient (main ingredient) and other 
excipient and additives, and the main ingredient can be uniformly 
distributed in the powdery mix by short-time mixing. Moreover, even if the 
powdery mix is subjected to a long-period storage test, agglomeration or 
caking is not caused but a dry and incohesive state is maintained in the 
powdery mix. These advantages attained by application of the excipient of 
the present invention to powders are especially conspicuous when 
microcrystalline cellulose having an apparent specific volume of 1.6 to 
3.1 cc/g, a repose angle of 35.degree. to 42.degree., preferably 
38.degree. to 41.degree., and a 200-mesh sieve residue of 2 to 80% by 
weight, preferably 5 to 40% by weight, is used as the excipient. 
Another prominent feature of the excipient of the present invention is that 
when the excipient of the present invention is applied to the wet 
granulation method (namely, final products are tablets according to the 
method of compression with wet granulation, microgranules, granules, and 
granule-filled capsules), granulation is possible with a reduced amount of 
a binder, the strength of granules is increased while preventing dusting, 
and the fatal defect of conventional cellulosic excipients, namely poor 
disintegrating property, can be overcome and the disintegrating property 
of tablets and granules can be greatly improved. These effects are 
manifested conspicuously especially when the average degree of 
polymerization of microcrystalline cellulose aggregates is 60 to 375, 
especially 70 to 180, and the 200-mesh sieve residue is 2 to 80% by 
weight, preferably 10 to 30% by weight. The apparent specific volume has 
an influence on the amount of a binder necessary for granulation. As the 
apparent specific volume of microcrystalline cellulose is small, 
granulation is possible with a small amount of a binder, but in order to 
attain good strength and disintegrating property in granules, it is 
preferred that the apparent specific volume of microcrystalline cellulose 
is 1.6 to 3.1 cc/g, especially 1.9 to 2.8 cc/g. 
When tablets are prepared according to the direct compression method, a 
pharmaceutical composition to be tableted comprises a main ingredient, an 
excipient, a binder and a disintegrating agent, and mutual relations among 
these ingredients cannot be neglected. For example, when the flowability 
of the main ingredient is extremely poor, if the concentration of the main 
ingredient exceeds a certain level, the flowability of the powdery mix is 
drastically reduced, and direct compression becomes difficult or the 
weight of the main ingredient content becomes extremely uneven in the 
resulting tablets. When the repose angle, which is one factor useful for 
evaluating the flowability of powder, is larger than 50.degree. with 
respect to a main ingredient used, if the main ingredient content exceeds 
65% by weight based on the pharmaceutical composition, the repose angle of 
the pharmaceutical composition exceeds 47.degree. even by using 
microcrystalline cellulose (excipient) of the present invention if the 
excipient content is lower than 15% by weight based on the composition, 
and it is impossible to feed smoothly the powdery mix by using an oven, a 
feed chute or the like, resulting in increase of the unevenness of the 
tablet weight or main ingredient content. When the content of the above 
main ingredient is lower than 65% by weight based on the composition, good 
results are obtainable when microcrystalline cellulose of the present 
invention is incorporated in an amount of 15% by weight or less based on 
the composition. However, in this case, if the content of microcrystalline 
cellulose of the present invention is lower than 10% by weight based on 
the composition, the practical strength of resulting tablets is not 
increased and the disintegration time of the tablets is long. Thus, it has 
been found that microcrystalline cellulose of the present invention should 
be incorporated in an amount of at least 10% by weight based on the 
composition. On the other hand, when a main ingredient having a repose 
angle smaller than 50.degree. and a relatively good flowability is used, 
even if the main ingredient content exceeds 80% by weight based on the 
composition, a good flowability can be maintained in the powdery mix in a 
hopper. Also in this case, however, it is necessary that microcrystalline 
cellulose of the present invention should be incorporated in an amount of 
at least 10% by weight based on the composition. 
In the manufacture of capsules and powders where powder is directly 
subjected to a molding operation as in case of the direct compression 
method, from the viewpoints of the flowability in a hopper and the 
uniformity of the filled weight or packeted weight, conditions described 
above with respect to the tablet compressing method should similarly be 
satisfied. Namely, when a main ingredient having a repose angle larger 
than 50.degree. is used in an amount larger than 65% by weight based on 
the composition, in order to attain a good flowability in the powdery mix, 
it is necessary that microcrystalline cellulose of the present invention 
should be incorporated in an amount of at least 15% by weight based on the 
composition. When the content of the above ingredient is lower than 65% by 
weight based on the composition or when the repose angle of the main 
ingredient is smaller than 50.degree., if microcrystalline cellulose of 
the present invention is incorporated in an amount of 10% by weight based 
on the composition, good flowability, filling property and compression 
moldability can be maintained. 
Tablets and capsules obtained by using the pharmaceutical composition of 
the present invention are characterized by a short disintegration time, a 
storage stability and a high speed of dissolution of the main ingredient. 
Effects attained when the pharmaceutical composition of the present 
invention is applied to the manufacture of granules, fine particles and 
tablets through the wet granulation step will now be described. 
First of all, there can be mentioned an advantage that the resulting 
granules or tablets disintegrate very promptly. In addition, the 
adaptability to extrusion granulation can be remarkably improved and the 
strength of resulting granules and tablets is increased and dusting can be 
reduced. In conventional processes for the manufacture of granules or 
microgranules, in order to reduce the dusting and obtain products 
excellent in strength, it is necessary to increase the amount of a binder 
incorporated but this results in a fatal defect of a long disintegration 
time. In view of this fact, it will readily be understood that the present 
invention is highly progressive over the conventional techniques. 
The foregoing effects attained by the pharmaceutical composition of the 
present invention for manufactures of granules, microgranules and tablets 
according to the wet method are advantageously obtained when 
microcrystalline cellulose of the present invention is incorporated in an 
amount of 1 to 50% by weight, preferably 2 to 40% by weight based on the 
composition. 
The pharmaceutical composition of the present invention may be formed into 
medicinal products according to any of conventional processes for the 
manufacture of solid medicines. More specifically, microcrystalline 
cellulose of the present invention is incorporated into at least one main 
ingredient, other additives are added according to need, and the resulting 
composition is molded into tablets, pills and granules according to a 
known wet or dry method. For example, when tablets are prepared according 
to the method of compression with wet granulation, microcrystalline 
cellulose may be incorporated afterwards. Further, capsules and powders 
can be prepared from the pharmaceutical composition of the present 
invention according to known methods. 
Further, film- or sugar-coated tablets may optionally be prepared by 
coating tablets of the pharmaceutical composition of the present invention 
with a film or sugar. It also is possible to pulverize tablets once 
prepared according to the present invention, mix the resulting powder with 
other main ingredient, excipient, disintegrating agent, colorant, 
lubricant and like additives and mold the mixture into tablets again. 
Still further, a syrup may be prepared by dispersing and suspending the 
pharmaceutical composition of the present invention in an appropriate 
dispersion medium. 
Powder characteristics mentioned in the instant specification and appended 
claims are those determined according to the following methods. 
Sieving: 
A sample (50 g) is sieved and classified for 20 minutes by using a JIS 
standard sieve attached to a low-tap type sieving and shaking machine 
manufactured by Yanagimoto Seisakusho, Japan and the particle size 
distribution and average particle size of the sample are determined 
according to this method. 
Apparent specific volume: 
A value determined by using a powder tester Model PT-D manufactured by 
Hosokawa Funtai Kogaku Kenkyusho, Japan. 
Tapping apparent specific volume: 
A value obtained when 50 g of a sample powder is charged in a Tap Denser 
KYT-1000 manufactured by Seishin Kigyo K. K. and the charged powder is 
tapped until the equilibrium state is attained. 
Degree of polymerization: 
A value determined according to the cuprammonium solution 
viscosity-measuring method specified by JIS. 
Repose angle: 
A value determined according to the conical deposition method using a 
powder tester Model PT-D manufactured by Hosokawa Funtai Kogaku Kenkyusho.

The present invention will now be described in detail by reference to the 
following Examples that by no means limit the scope of the invention. 
EXAMPLE 1 
Commercially available dissolving pulp (1 Kg) was finely divided and 
hydrolyzed in a 10% aqueous solution of hydrochloric acid at 105.degree. 
C. for 20 minutes. The acid-insoluble residue was recovered by filtration, 
washed, air-dried and pulverized by an ordinary hammer mill. The 
pulverized product was passed through a 50-mesh sieve to remove coarse 
particles and obtain 600 g of microcrystalline cellulose (A) having an 
average particle size of 35.mu., a whiteness of 90, DP of 180, an apparent 
specific volume of 2.78 cc/g, a tapping apparent specific volume of 1.90 
cc/g, a 200-mesh sieve residue of 22% by weight and a repose angle of 
41.degree.. 
Commercially available dissolving pulp (1 Kg) was finely divided and 
hydrolyzed in a 1% aqueous solution of sulfuric acid at 115.degree. C. 
under pressure for 35 minutes, and the acid-insoluble residue was 
recovered by filtration, washed, air-dried and pulverized by a hammer 
mill. Coarse particles were removed by passing the pulverized product 
through a 50-mesh sieve to obtain 700 g of microcrystalline cellulose (B) 
having an average particle size of 35.mu., a whiteness of 90, DP of 390, 
an apparent specific volume of 3.33 cc/g, a tapping apparent specific 
volume of 2.41 cc/g, a 200-mesh sieve residue of 25% by weight and a 
repose angle of 47.degree.. 
Commercially available kraft pulp (1 Kg) was finely divided and hydrolyzed 
in a 1% aqueous solution of hydrochloric acid at 120.degree. C. under 
pressure for 30 minutes, and the acid-insoluble residue was recovered by 
filtration, washed, air-dried and pulverized by a hammer mill. Coarse 
particles were removed by passing the pulverized product through a 60-mesh 
sieve to obtain 650 g of microcrystalline cellulose (C) having an average 
particle size of 32.mu., a whiteness of 92, DP of 130, an apparent 
specific volume of 1.96 cc/g, a tapping apparent specific volume of 1.58 
cc/g, a 200-mesh sieve residue of 17% by weight and a repose angle of 
35.degree.. 
Rayon yarn waste (1 Kg) was finely divided and hydrolyzed in a 1% aqueous 
sulfuric acid solution at 105.degree. C. for 120 minutes, and a product 
(D) was obtained in the same manner as described above with respect to the 
product (C). The yield was 52%. The product (D) was microcrystalline 
cellulose having an average particle size of 20.mu., a whiteness of 88, DP 
of 40, an apparent specific volume of 1.40 cc/g, a tapping apparent 
specific volume of 1.32 cc/g, a 200-mesh sieve residue of 5% by weight and 
a repose angle was 34.degree.. 
In a 5-liter capacity V-blender, 800 g of commercially available 
pharmacopoeial crystalline ascorbic acid (having a repose angle of 
39.degree.), 95 g of commercially available DMV lactose, 100 g of 
microcrystalline cellulose (A), (B), (C) or (D) and 5 g of magnesium 
stearate were mixed, and the mixture were compressed and molded into 
tablets by using a high-speed direct compressing machine (Model RT-S22-T35 
manufactured by Kikusui Seisakusho) comprising 12 R punches of 8 mm 
diameter. The rotation speed of a turn table was 30 rpm. Properties of 
obtained tablets (each having a weight of 220 mg) are shown in Table 1. 
Table 1 
______________________________________ 
Micro- Repose Tablet Disinte- 
crystalline 
Angle of Weight Tablet gration 
Cellulose 
Powdery Dispersion Hardness 
Time 
Sample Mix (n = 20) (n = 20) 
(seconds) 
______________________________________ 
A 39.degree. 
1.1% 4.0 Kg &lt;30 
B 43.degree. 
3.0% 4.2 Kg 180 
C 36.degree. 
0.8% 3.9 Kg &lt;15 
D 36.degree. 
0.8% capping -- 
______________________________________ 
The sample B having a large apparent specific volume and a large repose 
angle was defective in that the weight unevenness was not moderated and 
the tablet weight dispersion was as high as 3%. In the sample D having low 
DP and too small an apparent specific volume, the compressibility was low 
and capping was caused. In each of the samples A and C, the disintegration 
time was very short. 
EXAMPLE 2 
Tablets were molded in the same manner as in Example 1 except that the 
rotation speed of the turn table was changed as indicated in Table 2. The 
composition of the powdery mix was the same as in Example 1. For 
comparison, a commercially available excipient (microcrystalline cellulose 
sold under tradename "Avicel PH-101" and manufactured by F M C Corporation 
was similarly tested. The tablets were evaluated based on the weight 
dispersion (average weight=220 mg; n=20). Obtained results are shown in 
Table 2. 
Table 2 
______________________________________ 
Weight Dispersion 
RPM RPM RPM RPM 
20 30 40 50 
______________________________________ 
Sample A 0.8% 1.0% 1.1% 1.3% 
Sample B 2.4% 3.0% 5.2% 7.2% 
Sample C 0.8% 0.8% 0.9% 1.2% 
Sample D 0.8% 0.8% 0.8% 0.9% 
Avicel PH-101 
2.1% 2.8% 4.5% 4.9% 
______________________________________ 
Notes: 
.sup.1 In case of the sample D, capping was caused in each run. 
.sup.2 In case of each of the samples A, B and C, the tablet hardness was 
3 to 4 Kg in each run. 
When the sample B having such a large apparent specific volume of 3.33 cc/g 
that in order to attain the same filled weight, the depth of the lower 
punch had to be increased was subjected to high-speed direct compression, 
the weight uneveness became conspicuous and no good results were obtained. 
In case of the commercially available excipient (Avicel PH-101), no 
satisfactory results were obtained because of too large an apparent 
specific volume (3.3 cc.g). 
EXAMPLE 3 
Powdery mixes having a composition indicated in Table 3 were prepared by 
using the same ascorbic acid as used in Example 1 and microcrystalline 
cellulose samples (A) and (D) obtained in Example 1. 
Table 3 
______________________________________ 
Powdery 
Micro- Sodium Repose 
Sample Main crystalline 
Lauryl Angle of 
No. Ingredient 
Cellulose Sulfate 
Powdery Mix 
______________________________________ 
1 1000 g 990 g (A) 10 g 36.degree. 
2 1000 g 990 g (D) 10 g 35.degree. 
______________________________________ 
Continuous direct compression was carried out in the same manner as 
described in Example 1. In case of sample No. 2, when the molding pressure 
was elevated, capping was caused. Accordingly, in each run no substantial 
pressure was applied but the sample was compressed only very lightly. 
Tablets (having a hardness of about 2 kg) discharged from a discharge 
opening were sampled at predetermined intervals. The sampled brittle 
tablets were precisely weighed in a 500 ml-capacity Erlenmeyer flask and 
300 ml of pure water was charged therein. The flask was sealed and the 
charge was shaken for 120 minutes by using a shaker. The content was 
filtered through a membrane filter having a pore diameter of 0.2.mu.. The 
filtrate was appropriately diluted, and the absorbance of the diluted 
extract was measured at a wavelength of 245 nm by using a Shimazu-Baush & 
Lomb spectrophotometer "Spectronic SSUV" and the main ingredient content 
was determined according to the calibration method. Obtained results are 
shown in Table 4. As a result of preliminary experiments, it was confirmed 
that the recovery was substantially 100%. 
Table 4 
__________________________________________________________________________ 
Main Ingredient Content (%) 
(average value, n = 5) 
Theore- 
Sample 
tical 
At 10 20 30 40 
No. Value 
Start Minutes 
Minutes 
Minutes 
Minutes 
__________________________________________________________________________ 
1 50.0 49.7 49.9 50.1 50.1 49.8 
(.delta.=0.75) 
(.delta.=0.81) 
(.delta.=0.70) 
(.delta.=0.77) 
(.delta.=0.82) 
2 50.0 50.1 50.5 52.2 50.7 48.3 
(.delta.=0.91) 
(.delta.=1.1) 
(.delta.=1.3) 
(.delta.=2.2) 
(.delta.=3.5) 
__________________________________________________________________________ 
As will be apparent from the foregoing data, in case of microcrystalline 
cellulose having too high a flowability, separation of the ingredients was 
caused while the powdery mix flowed in a hopper, and in the initial stage, 
the main ingredient content was close to the theoretical value, but with 
the lapse of time, the main ingredient content was increased and the 
unevenness of the main ingredient content become conspicuous, and in the 
final stage, the main ingredient content was lower than the theoretical 
value. Thus, it was confirmed that in case of microcrystalline cellulose 
having too high a flowability, variations of the main ingredient content 
were conspicuous in resulting tables. 
EXAMPLE 4 
Refined linters (1 kg) were sufficiently disentangled and hydrolyzed in a 
0.8% aqueous solution of hydrochloric acid at 120.degree. C. under 
pressure for 45 minutes, and the acid-insoluble residue was recovered by 
filtration, washed, air-dried and pulverized at a rate of 1.3 kg/hr by 
using a Nara-type free pluverizer (Model M-2). Coarse particles were 
removed by passing the pulverized product through a 50-mesh sieve to 
obtain a free-flowing white powder (E) having an average particle size of 
32.mu., DP of 160, an apparent specific volume of 2.3 cc/g, a tapping 
apparent specific volume of 1.71 cc/g, a repose angle of 39.5.degree. and 
a 200-mesh sieve residue of 13% by weight. 
An air-dried product of hydrolyzed linters obtained under the same 
conditions as described above was pulverized by a microjet mill pulverizer 
Model FSS manufactured by Seishin Kigyo K.K., Japan while adjusting the 
air feed rate and the powder feed rate, to obtain samples (F), (G) and (H) 
having properties shown in Table 5. 
Table 5 
______________________________________ 
Sample (F) 
Sample (G) 
Sample (H) 
______________________________________ 
Apparent specific 
3.32 2.90 1.93 
volume (cc/g) 
Tapping apparent 
2.30 1.94 1.60 
specific volume 
(cc/g) 
Ropose angle (degrees) 
44 42 45 
200-Mesh sieve 23 19 1.8 
residue (% by weight) 
______________________________________ 
Commercially available kraft pulp was finely divided and hydrolyzed in a 2% 
aqueous solution of sulfuric acid (bath ratio =15) at 125.degree. C. under 
pressure for a time indicated in Table 6, and the acid-insoluble residue 
was recovered by filtration, washed, dried for 10 hours by hot air 
maintained at 60.degree. C. and pulverized by a hammer mill. Coarse 
particles were removed by passing the pulverized product through a 50-mesh 
sieve. In this manner, samples (I), (J), (K) and (L) shown in Table 6 were 
obtained. The degree of pulverization was changed in the samples by 
changing the speed of the hammer mill and the mesh size of a discharge 
screen at the pulverizing step. 
Table 6 
______________________________________ 
Sample 
Sample Sample Sample 
(I) (J) (K) (L) 
______________________________________ 
Hydrolysis time (minutes) 
5 10 25 80 
Apparent specific volume 
3.50 3.00 2.53 1.89 
(cc/g) 
Tapping apparent 
2.42 2.01 1.72 1.52 
specific volume (cc/g) 
Repose angle (degrees) 
45 42 38 43 
200-Mesh sieve residue 
48 32 15 &lt;2.0 
(% by weight) 
DP 390 240 140 138 
______________________________________ 
Rayon yarn waste (1 Kg) was finely divided and hydrolyzed in an aqueous 
solution of hydrochloric acid having a concentration of 0.3, 0.6 or 1.2% 
(bath ratio=13) at 100.degree. C. for 40 minutes. The hydrolyzed product 
was washed with warm water or washed by filtration or decantation. When 
the 0.6% or 1.2% aqueous solution was used, the washed hydrolyzed product 
was treated with a colloid mill (25 clearances per 100 mils). The 
hydrolyzed product was then subjected to suction filtration, air-dried and 
pulverized by the same jet mill as described above. In this manner, 
samples (M), (N), (O), (P) and (Q) having properties shown in Table 7 were 
obtained. 
Table 7 
______________________________________ 
Sample 
Sample Sample Sample 
Sample 
(M) (N) (O) (P) (Q) 
______________________________________ 
Hydrochloric acid 
0.3 0.6 0.6 1.2 1.2 
concentration (%) 
Colloid mill 
not not used not used 
used used used 
Apparent specific 
2.01 1.92 1.89 1.76 1.74 
volume (cc/g) 
Tapping apparent 
1.83 1.74 1.63 1.42 1.35 
specific volume 
(cc/g) 
Repose angle 
42 40 38 38 39 
(degrees) 
200-Mesh sieve 
10 9.2 7.3 5.1 2.5 
residue (% by 
weight) 
DP 70 68 67 55 54 
______________________________________ 
Powdery mixes shown in Table 8 were prepared by using the above 
microcrystalline cellulose samples (E) to (Q) as the excipient and 
commercially available pharmacopoeial powdery ascorbic acid (repose 
angle=58.degree. to 60.degree.) as the main ingredient. 
Table 8 
______________________________________ 
Excipient Amount of Amount of Main 
Sample Excipient Ingredient 
______________________________________ 
(E) 600 g (20%) 2400 g (80%) 
(F) 600 g (20%) 2400 g (80%) 
(G) 600 g (20%) 2400 g (80%) 
(H) 600 g (20%) 2400 g (80%) 
(I) 600 g (20%) 2400 g (80%) 
(J) 600 g (20%) 2400 g (80%) 
(K) 600 g (20%) 2400 g (80%) 
(L) 600 g (20%) 2400 g (80%) 
(M) 600 g (20%) 2400 g (80%) 
(N) 600 g (20%) 2400 g (80%) 
(O) 600 g (20%) 2400 g (80%) 
(P) 600 g (20%) 2400 g (80%) 
(Q) 600 g (20%) 2400 g (80%) 
______________________________________ 
Each of the so prepared powdery mixes was charged in a hopper and a 
preliminarily closed discharge port was then opened and the state of 
flow-out of the powdery mix was examined. 
In case of the excipients (E), (G), (J), (K), (M), (N), (O), (P) and (Q), 
all of the charged powder substantially flowed out by its own weight. In 
case of the excipients (F), (H) and (L), the powder flowed out when gently 
vibrated, but in case of the excipient (I), bridging was often caused in 
the hopper and no free flow-out was observed. 
EXAMPLE 5 
The filling test was carried out by using an encapsulating machine ZANASI 
LZ-64 and capsules No. 3. As the powder to be encasulated, there were used 
an excipient sample alone and a powdery mix comprising 500 g of pulverized 
aspirin (repose angle=60.degree.), 500 g of the excipient sample 5 g of 
magnesium stearate. Obtained results are shown in Tables 9 and 10. More 
specifically, results obtained when the filled weights were uniformalized 
are shown in Table 9, and results when the filled weights were not 
particularly uniformalized and the powders were freely filled are shown in 
Table 10. 
Table 9 
______________________________________ 
Filled Weight Dispersion (.delta. mg) 
excipient alone 
powdery mix 
(average filled 
(average filled 
weight = weight = 
Excipient Sample 
165 .+-. 5 mg) 
190 .+-. 10 mg) 
______________________________________ 
(I) 4.3 7.3 
(J) 2.0 3.2 
(K) 1.9 3.0 
(L) 2.2 4.0 
(slight creaking) 
(P) 1.6 2.7 
(Q) 2.3 3.9 
(slight creaking) 
______________________________________ 
Table 10 
______________________________________ 
Filled Weight (mg) 
Excipient Sample 
excipient alone 
powdery mix 
______________________________________ 
(I) 148 181 
(J) 160 190 
(control) (control) 
(K) 185 196 
(L) 212 219 
(slight creaking) 
(P) 220 225 
(Q) 219 224 
(slight creaking) 
______________________________________ 
In case of the excipients (J), (K) and (P) where the filled weight 
dispersion was small as shown in Table 9, even if the filling speed was 
elevated (from 700 capsules per hour to 10000 capsules per hour), the 
filled weight dispersion could be maintained at a sufficiently low level. 
In case of the excipients (L) and (Q) where the spindle creaked because of 
the presence of large quantities of fine particles, if the filling speed 
was elevated, creaking became conspicuous and the filled weight dispersion 
became large. 
Sample capsules shown in Table 9 were allowed to stand still at a 
temperature of 40.degree. C. and a relative humidity of 72% for 2 weeks, 
and the moisture absorption after this accelerated test and the 
disintegration time before and after the accelerated test were determined 
to obtain results shown in Table 11. Water maintained at 37.degree. C. was 
used for measuring the disintegration time. Incidentally, data shown in 
Table 11 are those obtained with respect to the powdery mix-filled 
capsules. 
Table 11 
______________________________________ 
Disintegration Time 
(minutes) 
Moisture Absorption* 
before after 
Excipient Sample 
% test test 
______________________________________ 
(I) 2.67 24.0 &gt;30 
(J) 2.48 5.0 5.3 
(K) 2.40 &lt;5.0 &lt;5.0 
(L) 2.37 &lt;5.0 &lt;5.0 
(P) 2.36 &lt;5.0 &lt;5.0 
(Q) 2.36 15.0 15.7 
______________________________________ 
*the amount of moisture absorbed in the capsule per se was excluded. 
EXAMPLE 6 
Commercially available pharmacopoeial crystalline ascorpic acid was 
pulverized by a crusher to obtain fine powder having a size not exceeding 
40.mu.. This powder had a repose angle as large as 53.degree. and it was 
sticky and cohesive and poor in the flowability. 
Pharmaceutical compositions having a recipe shown in Table 12 were prepared 
by using this pulverized ascorbic acid as the main ingredient and 
microcrystalline cellulose shown in Table 13 and they were subjected to 
direct compression in the same manner as described in Example 1 to obtain 
results shown in Table 14 (average tablet weight x=250 mg.+-.10 mg). 
Table 12 
______________________________________ 
Micro- Content 
cry- Crystal- 
Mag- (%) of 
Main stalline line nesium Mycrocry- 
Recipe 
Ingredient 
Cellulose 
Lactose 
Stearate 
stalline 
No. (g) (g) (g)* (g) Cellulose 
______________________________________ 
1 500 200 295 5 20 
2 650 130 215 5 13 
3 650 180 165 5 18 
4 690 250 55 5 25 
______________________________________ 
*DMV #200 
Table 13 
______________________________________ 
Microcrystalline Cellulose 
Sample Sample Sample Sample 
(R) (S) (T) (U) 
______________________________________ 
Average Degree of 
180 200 130 40 
Polymerization 
Apparent Specific 
2.78 3.30 1.96 1.40 
Volume (cc/g) 
Repose Angle (degrees) 
41 47 35 34 
200-Mesh Sieve 
22 22 17 5 
Residue (% by weight) 
Tapping Apparent 
1.90 2.41 1.58 1.32 
Specific Volume 
(cc/g) 
______________________________________ 
Table 14 
______________________________________ 
Micro- Tablet 
crystalline 
Repose Angle 
Weight Tablet 
Run Recipe Cellulose (degrees) of 
Dispersion 
Hardness 
No. No. Sample Powdery Mix 
(%) (Kg) 
______________________________________ 
1 (R) 39 1.5 4.3 
2 1 (S) 47 3.5 4.8 
3 1 (T) 39 1.4 4.0 
4 1 (U) 39 1.2 capping 
5 2 (R) 49 3.9 3.4 
6 2 (S) 50 6.0 3.6 
7 2 (T) 48 3.7 3.3 
8 2 (U) 47 3.5 capping 
9 3 (R) 40 1.7 4.3 
10 3 (S) 47 3.7 4.7 
11 3 (T) 40 1.3 4.1 
12 3 (U) 39 1.1 capping 
13 4 (R) 45 2.0 4.8 
14 4 (S) 50 5.2 5.0 
15 4 (T) 41 1.5 4.7 
16 4 (U) 42 1.4 capping 
______________________________________ 
Notes: 
.sup.1 The rotation number of the turn table was 30 rpm. 
.sup.2 The tablet hardness was the maximum hardness. 
As will be apparent from the results shown in Table 14, only runs Nos. 1, 
3, 9, 11, 13 and 15 gave satisfactory tablets. Namely, only when 
microcrystalline cellulose meeting the requirements specified in the 
present invention was used, satisfactory tablets were obtained. From the 
results shown in Table 14, it will readily be understood that in case of a 
main ingredient having a respose angle larger than 50.degree. and being 
poor in the flowability, when the amount of microcrystalline cellulose of 
the present invention is at least 10% by weight if the main ingredient 
content is lower than 65% by weight or when the amount of microcrystalline 
cellulose of the present invention is at least 15% by weight if the 
content of the main ingredient content is 65% by weight or higher, direct 
compression can be accomplished advantageously with much reduced 
unevenness of the tablet weight. 
EXAMPLE 7 
Four pharmaceutical compositions having a recipe shown in Table 15 were 
separately blended for 30 minutes in a 5-liter capacity V-blender. Then, 
each composition was transferred into a 10-liter capacity kneader and a 
predetermined amount of a binder solution was added thereto. The resulting 
slurry was fed to a lateral type extruder and extruded through a screen 
having a mesh size of 1 mm to obtain wet granules. The granules were dried 
for 10 hours with hot air maintained at 60.degree. C. to reduce the water 
content in the granules to about 2%, and then, the dried granules were 
passed through 12-mesh sieve and 60-mesh sieve. Thus, four kinds of dry 
granules were obtained. 
When these dry granules were subjected to the disintegration test (n=6) 
according to the method specified in 8th Revised Japanese Pharmacopeia JP, 
it was found that the disintegration times were 3.1 minutes, 10.6 minutes, 
2.5 minutes and 2.2 minutes, respectively. Further, 10 g of the dry 
granules were sealed in a Kayagski-type tablet abrasion tester and the 
tester was rotated for 20 minutes, and then, the tested granules were 
passed through a 60-mesh sieve and the amount of dust formed was 
determined. It was found that the amounts of dust were 2.1%, 1.8%, 2.0% 
and 4.3%, respectively. 
Table 15 
______________________________________ 
Amount 
Added Amount Added 
Microcry- (g) of Amount (g) 
(g) of 1 % 
stalline Microcry- of Solution of 
Recipe 
Cellulose stalline Lactose* for 
Methyl Cellu- 
No. Sample Cellulose Ordinary Use 
lose as Binder 
______________________________________ 
1 (R) 400 1600 1600 
2 (S) 400 1600 1760 
3 (T) 400 1600 1550 
4 (U) 400 1600 1500 
______________________________________ 
*lactose for ordinary use was used as a substitute for a water-soluble 
main ingredient. 
In case of recipe No. 2, when the slurry was laterally extruded, slight 
creaking was caused and the granules split slightly. In case of recipe No. 
4, slight separation of water was observed. In case of recipes No. 1 and 
3, extrudability was excellent. 
EXAMPLE 8 
To the granules obtained in Example 7 was added magnesium stearate in an 
amount of 1.0% by weight based on the total weight of the granules and 
magnesium stearate and tablets were prepared from the mixture under the 
same tableting conditions as described in Example 1. Properties of the 
obtained tablets are shown in Table 16. 
Table 16 
______________________________________ 
Wear 
Recipe 
Tablet Hardness 
Disintegration 
Rate 
No. (Kg) Time (minutes) 
(%) Remarks 
______________________________________ 
1 7.8 5 1.9 
2 8.2 &gt;12 1.5 
3 7.6 3 1.8 
4 3.2 -- 12.3 capping 
______________________________________ 
EXAMPLE 9 
Commercially available pharmacopeial phenacetin was pulverized for 20 
minutes by a crusher to obtain a 60-mesh passable main ingredient (respose 
angle=49.degree.). 
Seven powdery mixes were prepared by mixing 600 g of this main ingredient 
with 5 g of magnesium stearate and 395 g of corn starch, 100-mesh passable 
lactose, calcium phosphate, methyl cellulose (MC), polyvinyl pyrrolidone 
(PVP), lowly substituted hydroxypropyl cellulose (l-HPC) or 
microcrystalline cellulose (R) shown in Table 13 as an excipient and/or 
binder. 
Tablets were prepared from these powdery mixes according to the direct 
compression method described in Example 1. Obtained results are shown in 
Table 17. 
Table 17 
______________________________________ 
Weight Disintegra- 
Dispersion 
Hardness tion Time 
Wear Rate 
Additive (%) (Kg) (minutes) 
(%) 
______________________________________ 
Corn starch 
4.3 capping -- -- 
Lactose 100% 
2.1 0.0 -- -- 
Calcium 2.4 3.0 &gt;20 8.0 
phosphate 
MC 5.9 4.1 15 4.3 
PVP 7.8 4.5 12 5.1 
l-HPC 12.3 6.2 7 2.3 
Sample (U) 
1.6 9.8 &lt;1 0.9 
Control 2.5 7.1 8 0.7 
(Avicel pH-101) 
______________________________________ 
From the results shown in Table 17, it will readily be understood that 
tablets prepared from a pharmaceutical composition comprising 
microcrystalline cellulose of the present invention have a high hardness 
and a short disintegration time with much reduced weight unevenness and 
therefore, they are very excellent in properties required of tablets.