Uncoated tablets and method of producing the same

A compression-moldable composition comprising an active ingredient, an excipient and an oily or fatty substance having a lower melting point of about 20.degree. to 90.degree. C. is compression-molded into uncoated tablets without coating to improve the abrasion resistance. The oily or fatty substance includes a higher fatty acid or a salt thereof, a wax, a fatty acid ester, a hardened oil, a polyalkylene oxide, etc., and the amount thereof is about 0.01 to 10% by weight. The composition may comprise (1) a granulated powder containing the active ingredient and the excipient, and the powdery or granular oily or fatty substance having a lower melting point, or (2) a granulated powder containing the active ingredient, the excipient and said oily or fatty substance. Compression-molding of the composition improves the abrasion resistance of the tablet and significantly inhibits the development of powder by wearing or abrasion even when the oily or fatty substance is used in a small amount of about 0.1 to 0.5% by weight.

FIELD OF THE INVENTION 
The present invention relates to an uncoated tablet having an improved 
abrasion resistance and usable in a variety of fields such as foods and 
drugs, and a method of producing such a tablet. 
BACKGROUND OF THE INVENTION 
Tablets can be classified into two major categories, i.e. (i) an uncoated 
tablet prepared by compression-molding fine granules, granules or a mixed 
powder and (ii) a coated tablet prepared by coating an uncoated tablet 
with a film or sugar. When the uncoated tablet has a curved surface, it 
may have problems with moldability. Thus, the uncoated tablet is usually 
molded into a flat form in order to insure productivity and handling 
efficiency. 
Since the coated tablet has a smooth and mechanically strong surface, no 
powder is broken out due to wear or abrasion. Therefore, the coated tablet 
has advantages that it can be employed in a visual examination machine 
with a high handling and packaging efficiency, as well as in an automatic 
compounding machine in a hospital or pharmacy with an excellent handling 
efficiency. The coating layer of the coated tablet, however, suppresses 
disintegration of the tablet and dissolution of an active ingredient, thus 
it is unsuitable for a pharmaceutical preparation wherein fast 
disintegration or dissolution is required. Further, the coated tablet has 
disadvantages of being high costed owing to a large number of production 
steps. 
On the contrary, though the above-mentioned uncoated tablet can be 
advantageously produced with ease and simplicity and with a low production 
cost, the surface thereof is worn or abraded in preparation or 
transportation process, and powder thus produced is attached or affixed to 
the surface of the uncoated tablet or remained in a package. Thus, the 
commercial value of the products is significantly reduced. Further, 
because of the powder attached or affixed to the tablet, the working 
efficiency in a visual examination machine and packaging efficiency may be 
reduced. Furthermore, the uncoated tablet also confronts with a lower 
working efficiency in an automatic compounding machine. 
Regarding the techniques to suppress such development of powder due to 
wearing and abrading of an uncoated tablet, Japanese Patent Publication 
No. (JP-B) 25926/1992 discloses a coating method which comprises preparing 
a suspension or dispersion containing a higher fatty acid ester having a 
high melting point of 70.degree. C. or more, a cellulose derivative 
soluble in a hydrophilic solvent and the hydrophilic solvent and coating 
the surface of an uncoated tablet with said suspension or dispersion in a 
proportion of 0.02 to 0.8% by weight on the dried basis. 
This technique, however, requires a number of steps, that is, a step for 
preparing beforehand uncoated tablets by compression-molding, a step for 
preparing said suspension or dispersion by emulsifying or dispersing said 
higher fatty acid ester in a hydrophilic solvent using, if necessary, a 
surfactant, and a coating step for coating the tablets with said 
suspension or dispersion. Further, since the technique is a kind of 
coating techniques for coating the surface of tablets, the producing steps 
are complicated and an additional equipment for coating is further 
required to be arranged in the producing line of tablets. 
It should be generally understood, as described in the above-mentioned 
literature, that even when a composition containing a lubricant is 
compressed and molded into a tablet, uncoated tablets having a practically 
satisfied abrasion resistance can not be obtained. 
European Patent Application No. EP-546358 A2 discloses a stabilized 
pharmaceutical composition for oral use which is obtained by 
compression-molding a composition comprising the benzimidazole compound 
and an oily substance having a lower melting point, in order to 
suppressing decomposition of a benzimidazole compound as an active 
ingredient due to deformation of crystals caused by, for example, 
pressure. 
U.S. Pat. No. 5,055,304 corresponding to Japanese Patent Application 
Laid-open No. (JP-A) 308231/1989 discloses a stabilized pharmaceutical 
composition which is obtained by compressing and molding a composition 
comprising disodium adenosine triphosphate and an oily substance having a 
lower melting point in order to suppressing the decomposition of disodium 
adenosine triphosphate. 
In these literatures, said oily substances having lower melting points are 
used for stabilizing the active ingredients, and improvements in an 
abrasion resistance of an uncoated tablet were never taught by means of 
adding an oily substance having a lower melting point. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of the present invention to provide an 
uncoated tablet having an improved abrasion resistance without a coating 
layer of a coating composition and a method of producing the same. 
It is another object of the invention to provide an uncoated tablet having 
a high abrasion resistance and capable of suppressing development of 
powder due to abrasion or wearing in spite of an exceedingly small amount 
of an additive and a method of producing such a tablet. 
A still another object of the present invention is to provide an uncoated 
tablet which maintains readily disintegrating and/or dissolving properties 
with high abrasion resistance imparted and a method of producing the same. 
It is a further object of the invention to provide a method for producing 
efficiently an uncoated tablet having an improved abrasion resistance with 
an easy and simple operation and requiring no complicated steps. 
A still further object of the present invention is to provide a method of 
improving the abrasion resistance of an uncoated tablet by imparting an 
improved or enhanced abrasion resistance to said uncoated tablet. 
After a great research effort to obtain an uncoated tablet having the 
advantages both of an uncoated tablet and a coated tablet as mentioned 
above, the inventors of the present invention found that when a 
compression-moldable composition containing an oily or fatty substance of 
a lower melting point is compressed and molded into a tablet without 
coating, the resulting uncoated tablet has a significantly improved 
abrasion resistance even when a small amount of said oily or fatty 
substance is employed. Thus, the present invention was accomplished based 
on the above findings. 
Accordingly, an uncoated tablet having an improved abrasion resistance of 
the present invention comprises an active ingredient, an excipient and an 
oily or fatty substance having a lower melting point. Said oily or fatty 
substance includes, for example, a hydrophilic or water-soluble substance 
and a fat-soluble or water-insoluble substance. The melting point of said 
oily or fatty substance may be, for example, about 20.degree. to 
90.degree. C. The content of said oily or fatty substance is selected 
from, for example, about 0.01 to 10% by weight based on the total weight 
of the uncoated tablet depending on the objects, and even when the 
proportion of said substance is as small as 0.1% by weight or more and 
less than 0.5% by weight, the abrasion resistance of the uncoated tablet 
can be remarkably improved. 
According to the method of the invention, an uncoated tablet improved in an 
abrasion resistance can be produced by incorporating an oily or fatty 
substance having a lower melting point into a compression-moldable 
composition. Said method includes, for instance, (1) a method which 
comprises compressing and molding the compression-moldable composition 
comprising a granulated powder containing an active ingredient and an 
excipient, and said oily or fatty substance having a lower melting point, 
and (2) a method which comprises compressing and molding the 
compression-moldable composition comprising a granulated powder containing 
an active ingredient, an excipient and the oily or fatty substance. In the 
method (1), the oily or fatty substance in powdery or granular form may be 
used. Said granulated powder may be obtained by, for example, a 
wet-granulation. 
Further, the present invention also provides a method of improving an 
abrasion resistance of an uncoated tablet by way of incorporating an oily 
or fatty substance having a lower melting point into an active ingredient. 
Said method may comprise compression-molding a moldable composition 
comprising 0.1% by weight or more and less than 0.5% by weight of said 
oily or fatty substance based on the total weight of the uncoated tablet 
to improve the abrasion resistance of the tablet.

DETAILED DESCRIPTION OF THE INVENTION 
As used through out in this specification, the term "granulated powder" 
means to also include comminuted powder obtainable by comminuting or 
milling granulated preparations such as fine granules and granules in a 
conventional manner such as comminuting and classifying. In cases where 
the oily or fatty substance is not a single compound but a mixture, the 
substance does not show a distinct melting point but softens at a specific 
temperature. The term "melting point" as used in this specification 
includes, within the meaning thereof, the softening point of such a 
mixture as well. 
The oily or fatty substance having a lower melting point can be selected 
from a variety of substances with a high safety, for example, compounds 
generally approved as pharmaceutical additives. Among them, preferable 
examples of the oily or fatty substance include an oily or fatty substance 
having a lower melting point and being liable to be plastically deformed 
or expandable under a molding pressure. The specifically preferred oily or 
fatty substance includes a substance capable of being pulverized to fine 
powder. 
The melting point of said oily or fatty substance is, for example, usually 
about 20.degree. to 90.degree. C., and preferably about 20.degree. to 
80.degree. C., and more preferably about 20.degree. to 60.degree. C. The 
melting point of the oily or fatty substance is frequently about 
40.degree. to 75.degree. C. When the melting point of said substance is 
less than 20.degree. C., the strength of the uncoated tablet is 
occasionally reduced depending on an amount of said substance to be added, 
and, contrarily, when the melting point of said substance exceeds 
90.degree. C., the abrasion resistance of the uncoated tablet may not be 
so remarkably increased in case of molding under a conventional 
compression-molding pressure. 
The oily or fatty substance having a lower melting point may be a 
hydrophilic or water-soluble substance such as a polymer of an alkylene 
oxide and a derivative of a poly(alkylene oxide) as mentioned hereinafter, 
or a fat-soluble or water-insoluble substance such as a hydrocarbon, a wax 
and a fatty acid ester. 
As examples of the oily or fatty substance having a lower melting point, 
there may be mentioned a hydrocarbon, a higher fatty acid or a salt 
thereof, a higher alcohol, a wax, a hardened oil, a fatty acid ester, a 
higher alcohol ether of a polyhydric alcohol, a homopolymer or copolymer 
of an alkylene oxide and the like. 
The hydrocarbon includes an aliphatic hydrocarbon of about 17 to 60 carbon 
atoms, for example, straight or branched hydrocarbons such as 
n-heptadecane, n-octadecane, n-nonadecane, n-icosane, n-henicosane, 
n-docosane, n-tricosane, n-tetracosane, n-pentacosane, n-triacontane, 
n-tetracontane, n-pentacontane and n-hexacontane; a mixture of these 
hydrocarbons. 
The higher fatty acid may be a saturated fatty acid or an unsaturated fatty 
acid. As examples of the higher fatty acid, there may be mentioned a 
saturated fatty acid such as caprylic acid, lauric acid, myristic acid, 
palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, 
cerotic acid and montaic acid; an unsaturated fatty acid such as elaidic 
acid, isooleic acid and erucic acid; a higher fatty acid obtainable from a 
naturally-occurring fat and oil; and a mixture of said fatty acids. The 
higher fatty acid may have, for example, about 10 to 40 carbon atoms and 
preferably about 10 to 30 carbon atoms, and a saturated higher fatty acid 
of about 12 to 22 carbon atoms is practically preferred among them. 
The higher fatty acid can also be used as a salt, for example, a salt with 
an alkali metal such as sodium and potassium, a salt with an alkaline 
earth metal such as calcium, and others. 
The higher alcohol includes a saturated alcohol and an unsaturated alcohol. 
Examples of species of the higher alcohol include lauryl alcohol, 
tetradecyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, 
arachyl alcohol, higher alcohols collectable from naturally-occurring fats 
and oils and a mixture of these alcohols. The higher alcohol may contain, 
for example, about 10 to 35 of carbon atoms. Among them, a saturated 
higher alcohol of about 16 to 22 carbon atoms may be practically employed. 
Examples of the wax include paraffin wax, carnauba wax, candelilla wax, 
beeswax, montan wax, spermaceti wax, shellac wax, microcrystalline wax, 
petrolatum and so on. 
As examples of the hardened oil, there may be mentioned a hardened 
vegetable oil such as castor oil, rapeseed oil, cottonseed oil, soybean 
oil, coconut oil, palm kernel oil and palm oil; a hardened animal oil such 
as beef oil and whale oil; and the like. 
The fatty acid ester may be an ester of monohydric higher alcohol with a 
fatty acid (wax ester) such as cetyl palmitate, ceryl palmitate, myricyl 
palmitate, ceryl cerotate and melissyl melissate. As the fatty acid ester, 
an ester of a polyhydric alcohol having two or more hydroxyl groups in the 
molecule with a fatty acid is frequently used. Examples of said polyhydric 
alcohol include alkylene glycols such as ethylene glycol and propylene 
glycol; poly(alkylene glycol) such as diethylene glycol, triethylene 
glycol, poly(ethylene glycol), dipropylene glycol, tripropylene glycol, 
poly(propylene glycol) and copolymers of these glycols; polyhydric 
alcohols such as glycerin, polyglycerin and pentaerythritol; sugars such 
as sorbitol, sucrose and raffinose; intramolecular dehydrates derived from 
sorbitol such as 1,5-sorbitan, 1,4-sorbitol and 3,6-sorbitan; di- or 
trialkanolamines such as diethanolamine and triethanolamine. Said fatty 
acid is exemplified as saturated fatty acid such as acetic acid, propionic 
acid, butyric acid, pelargonic acid, lauric acid, myristic acid, palmitic 
acid, heptadecylic acid, stearic acid, behenic acid, nonadecanoic acid and 
undecylic acid; and unsaturated fatty acid such as oleic acid, sorbic 
acid, linoleic acid, linolenic acid, arachidonic acid and stearolic acid. 
Typical examples of the fatty acid ester of polyhydric alcohol include 
sorbitan fatty acid esters having a molecular weight of about 400 to 900 
(for example, sorbitan monostearate, sorbitan tristearate, sorbitan 
monooleate, sorbitan sesquistearate, sorbitan monopalmitate, etc.); 
polyoxyalkylene sorbitan fatty acid esters having a molecular weight of 
about 1,000 to 1,500 (e.g. polyoxyethylene sorbitan tripalmitate, etc.); 
polyoxyalkylene sorbitol fatty acid esters such as polyoxyethylene 
sorbitol hexastearate, polyoxyethylene sorbitol hexaoleate, 
polyoxyethylene sorbitol tristearate, polyoxyethylene sorbitol 
tetralaurate and others; polyoxyalkylene sorbitol beeswax derivatives such 
as polyoxyethylene sorbitol beeswax derivatives, etc.; polyoxyalkylene 
hydrous lanolin derivatives such as polyoxyethylene lanolin derivatives, 
etc.; alkylene glycol fatty acid esters including propylene glycol fatty 
acid esters having molecular weights of about 200 to 700 (for example, 
propylene glycol monopalmitate, propylene glycol monostearate, propylene 
glycol dilaurate, propylene glycol dimyristate, propylene glycol 
dipalmitate, propylene glycol distearate, etc.) and ethylene glycol fatty 
acid esters having molecular weights of about 500 to 1,200 (e.g. ethylene 
glycol monolaurate, ethylene glycol monopalmitate, ethylene glycol 
monomargarate, ethylene glycol monostearate, ethylene glycol dilaurate, 
ethylene glycol dimyristate, ethylene glycol dipalmitate, ethylene glycol 
dimargarate and the like); polyoxyalkylene castor oil derivatives having 
molecular weights of about 3,500 to 4,000 (for example, polyoxyethylene 
castor oil derivatives, etc.); polyoxyalkylene fatty acid esters having 
molecular weights of about 1,900 to 2,200 (e.g. polyoxyethylene stearate, 
polyoxyethylene oleate, polyoxyethylene palmitate, polyoxyethylene 
linoleate, and so on); glycerol fatty acid esters having molecular weights 
of about 300 to 600 (for instance, glycerol monofatty acid esters such as 
glycerol monoacetate, glycerol monopropionate, glycerol monocaprylate, 
glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, 
glycerol monostearate, glycerol monooleate and glycerol monolinoleate; 
glycerol difatty acid esters such as glycerol dicaprylate, glycerol 
dilaurate, glycerol dimyristate, glycerol dipalmitate and glycerol 
distearate; and glycerol trifatty acid esters such as glycerol 
tricaprylate, glycerol trilaurate, glycerol trimyristate, glycerol 
tripalmitate and glycerol tristearate); polyglycerol fatty acid esters; 
sucrose fatty acid esters having a molecular weight of about 400 to 1,300 
(e.g. sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate, 
sucrose monostearate, sucrose distearate, sucrose trimyristate, sucrose 
tripalmitate, sucrose tristearate, etc.); and the like. 
The higher alcohol ether of polyhydric alcohol includes, for example, 
ethers formed by etherification of a polyhydric alcohol (set forth as 
alcohol components of the fatty acid ester of polyhydric alcohol mentioned 
above) with a higher alcohol (for instance, the higher alcohols mentioned 
above, as well as oleyl alcohol, octyl alcohol, decyl alcohol and the 
like). 
Typical examples of the ether mentioned above include polyoxyethylene 
higher alcohol ethers (e.g. polyoxyethylene lauryl alcohol ether, 
polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol 
ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene octyl alcohol 
ether, polyoxyethylene decyl alcohol ether, etc.); polyoxypropylene 
polyoxyethylene higher alcohol ethers (e.g. polyoxypropylene 
polyoxyethylene cetyl alcohol ether, polyoxypropylene polyoxyethylene 
stearyl alcohol ether, polyoxypropylene polyoxyethylene oleyl alcohol 
ether, polyoxypropylene polyoxyethylene octyl alcohol ether, 
polyoxypropylene polyoxyethylene lauryl alcohol ether, etc.). 
The polymer of alkylene oxide may be homopolymers of alkylene oxides such 
as ethylene oxide, propylene oxide, trimethylene oxide and 
tetrahydrofuran, or copolymers of alkylene oxides. Preferred alkylene 
oxide includes ethylene oxide. 
As the homopolymer of alkylene oxide, use is made of those having a 
molecular weight of about 1,000 to 50,000 and preferably about 1,500 to 
30,000 (e.g. polyethylene glycol 6,000) and so on. 
The copolymer of an alkylene oxide includes, for example, a copolymer of 
two or more species of the above-mentioned alkylene oxides, which has a 
molecular weight of about 1,000 to 50,000. Said copolymer of alkylene 
oxide may be a random copolymer or a block copolymer. As the copolymer, a 
copolymer containing an oxyethylene unit obtainable by copolymerizing 
ethylene oxide and other alkylene oxide, practically a copolymer formed 
with ethylene oxide and propylene oxide can be employed. Examples of said 
copolymer include a poly(ethylene oxide-propylene oxide) copolymer [for 
example, PEP-101 (trade name, Freund Industrial Co., Ltd.; Japan) and 
Pullronic F68 (trade name, Asahi Denka Co., Ltd.; Japan)] and the like. 
The content of the oxyethylene unit in the copolymer is, for example, 
about 50 to 95% by weight, preferably about 60 to 90% by weight. 
Preferred examples of the alkylene oxide polymer include a homo- or 
copolymer of ethylene oxide, especially polyethylene glycol. 
These oily or fatty substances having lower melting points can be used 
singly or in combination. When two or more species of oily or fatty 
substances having lower melting points are used as a mixture, one or more 
of the oily or fatty substances can have melting points of less than 
20.degree. C. or more than 90.degree. C., as far as said mixture remains 
solid in the prescribed melting point of 20.degree. to 90.degree. C. 
The practically preferable oily or fatty substance having a lower melting 
point includes a higher fatty acid, a wax, a fatty acid ester, a higher 
alcohol ether of a polyhydric alcohol, a homopolymer or copolymer of an 
alkylene oxide. Among these substances, a homopolymer or copolymers of an 
alkylene oxide may advantageously employed. 
When a fat-soluble or water-insoluble oily or fatty substance is used, the 
sustained releasability of the active ingredient can be liable to exhibit. 
On the contrary, use of a hydrophilic or water-soluble oily or fatty 
substance remarkably improves, even when the amount of said substance is 
small, the abrasion resistance of the uncoated tablet with high 
disintegration and solubility, thus the effects of the active ingredient 
can be exhibited readily. Therefore, when demanded is an uncoated tablet 
which has high disintegrating properties and solubility maintained and is 
capable of acting readily, the uncoated tablet may preferably comprise a 
hydrophilic oily or fatty substance, especially water-soluble oily or 
fatty substance. 
The hydrophilic or the water-soluble oily or fatty substance include, for 
example, a higher alcohol ether of a polyhydric alcohol, an alkylene oxide 
derivative formed by reacting a fatty acid ester having one or more of 
hydroxyl groups with an alkylene oxide (particularly, ethylene oxide), a 
homo- or copolymer of an alkylene oxide and others. Preferred examples of 
the oily or fatty substance include an oily or fatty substance having an 
oxyalkylene unit such as oxyethylene unit. More specifically, a 
water-soluble oily or fatty substance such as a polyhydric alcohol, 
especially a homo- or copolymer of an alkylene oxide having oxyethylene 
unit is preferred. As the water-soluble oily or fatty substance, 
polyethylene glycol may advantageously be employed. 
The content of the oily or fatty substance having a lower melting point in 
the uncoated tablet is depending on a kind of the active ingredient or 
properties of the additive, and is for example, from about 0.01 to 10% by 
weight, preferably from about 0.1 to 5% by weight, and more preferably 
from about 0.1 to 3% by weight based on the total weight of the tablet. 
The abrasion resistance of the uncoated tablet would not be so much 
improved when the content of the oily or fatty substance is less than 
0.01% by weight, and, contrarily, the physical or chemical properties of 
the uncoated tablet and dissolution properties of the active ingredient 
may be adversely affected when the content of the oily or fatty substance 
exceeds 10% by weight. 
As mentioned above, in order to improve the sustained releasability, 
tablets containing a large amount of a lipid such as a fatty acid ester 
have been well known. Still, the uncoated tablet of the present invention 
is characterized in that it exhibits an excellent abrasion resistance by 
means of adding a small or slight amount of the oily or fatty substance 
having a lower melting point. Accordingly, an uncoated tablet can be 
improved in the abrasion resistance with development of powder being 
significantly suppressed even when the content of the oily or fatty 
substance having a lower melting point based on the total weight of the 
tablet is extremely small, for example, 0.1% by weight or more and less 
than 0.5% by weight (preferably about 0.1 to 0.45% by weight, and more 
preferably about 0.2 to 0.4% by weight). Further, when a small amount of 
an hydrophilic or water-soluble oily or fatty substance is incorporated 
into the tablet, the disintegration of the uncoated tablet and dissolution 
of the active ingredient are not suppressed. 
The present invention can be applied to uncoated tablets in a variety of 
fields, including drugs for human beings such as medicines (drugs) and 
quasi drugs; animal drugs; agrochemicals containing, for example, a 
bactericide, an insecticide, a herbicide, a raticide, a repellent, a plant 
growth regulator, etc. as an active ingredient; a diet containing an amino 
acid, a peptide, a nucleic acid, an organic acid or others as an active 
ingredient; and so on. Thus the active ingredient used in the present 
invention is not critically restricted. 
Examples of the drug include central nervous drugs such as antipyretic, 
analgesic and/or antiinflammatory agents, hypnotics and sedatives, 
psychotropics and neuropharmaceuticals, agent for peripheral nervous; 
peripheral nervous drugs such as skeletal muscle relaxants and autonomic 
drugs; circulatory drugs such as cardiotonics, antiarrhythmic agents, 
diuretics and vasodilators; respiratory organ drugs such as 
bronchodilators and antitussives; digestive organ drugs such as 
digestants, intestinal function controlling agents and antacids; hormones; 
antihistaminics; metabolic drugs such as vitamins; antiulcer drugs; 
antibiotics; chemotherapeutic agents; and so on. 
Among such drugs for doctors and pharmacy, a drug having a comparatively 
high stability for environmental factors such as light or requiring no 
corrigent and others is frequently administered as an uncoated tablet. The 
present invention can be applied suitably to such drugs. 
Examples of active ingredients in such drugs and the like include delapril 
hydrochloride, ipriflavone, manidipine hydrochloride, dexamethasone, 
alprazolam, diazepam, amlexanox, sodium liothyronine, perlapine, 
prednisolone, griseofulvin, estazolam, vinpocetine, labetalol 
hydrochloride, idebenone, fursultiamine, chlordiazepoxide, pyridoxal 
phosphate, ranitidine hydrochloride, nifedipine, lovastatin, cefaclor, 
cimetidine, fluoxetine hydrochloride, enalapril maleate, naproxen, 
captopril, terfenadine, atenolol, verapamil hydrochloride, ciprofloxacin 
hydrochloride, diclofenac sodium, piroxicam, pravastatin sodium, 
famotidine, nicardipine hydrochloride, ticlopidine hydrochloride, 
teprenone, ofloxacin, ketotifen fumarate, oxatomide, azulene, mecobalamin, 
cefixime, indeloxazine hydrochloride, nicergorine, loxoprofen sodium, 
alfacalcidol, diltiazem hydrochloride, bifemelane hydrochloride, 
azelastine hydrochloride, domperidone, fluconazole, norfloxacin, 
(.+-.)-7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)- 7-phenylheptanoic acid, 
(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid, 
2-(7-chloro-1,8-naphthyridin-2-yl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl) 
carbonylmethylisoindolin-1-one (hereinafter abbreviated as Compound A), 
(+)-1L-[1(OH),2,4,5/3]-5-[2-hydroxy-1( 
hydroxymethyl)ethyl]amino-1-C-(hydroxymethyl)-1,2,3,4-cyclohexanetrol or 
N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose, hereinafter abbreviated 
as Compound B), 
(.+-.)-3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic 
acid, 5-[4-[2- (5-ethyl-2pyridyl) ethoxy]benzyl]-2,4-thiazolidindione 
hydrochloride, 
3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8 
-yl) -1-propanone fumarate, 
2-(6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazine-4-yl) pyridine 
1-oxide, 2-[[[3-methyl-4-(2,2,3,3-tetrafluoropropoxy)-2-pyridyl]methyl]thi 
o]benzimidazole, 
N-[4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl]-N'-(2,4-d 
ichlorophenyl)urea, sodium 
1-hydroxy-2-(3-pyridinyl)ethylidynebisphosphonate, 2 
-ethyl-2-[(7-methyl-[1,2,4]triazolo 
[1,5-b]pyridazin-6-yl)-oxymethyl]butanesulfonamide, indomethacin, 
salicylic acid, trepibutone, amoxanox, aspirin, valproic acid, ketoprofen, 
ibuprofen, probenecid, isosorbide dinitrate, quinidine, morphine, 
dihydrocodeine phosphate, ephedrine, scopolamine, chlorpromazine, 
phenylpropanolamine hydrochloride, chlorpheniramine maleate, 
sulfanilamide, molsidomine, sulfadiazine, acetaminophen, theophyline, 
caffeine, cephalexin, ampicillin, sulfisoxazole, cefotiam hexetil 
hydrochloride, cyclandelate, propranolol, haloperidol, chlorothiazide, 
hydrochlorothiazide, sucralfate, vitamins such as riboflavin, ascorbic 
acid, etc., minerals, amino acids, peptides or proteins (for example, 
insulin, vasopressin, interferon, IL-2, urokinase, serratiopeptidase, 
somatostatin, growth hormone and growth factors), and the like. 
The proportion of the active ingredient to be contained in the uncoated 
tablet of the present invention can be suitably selected from a wide level 
depending on species of the active ingredient or others, and is, for 
example, about 0.001 to 90% by weight, preferably about 0.01 to 50% by 
weight, and more preferably about 0.1 to 25% by weight based on the total 
weight of the tablet. 
The uncoated tablet of the present invention usually contains an excipient 
in addition to the oily or fatty substance having a lower melting point 
and the active ingredient. As examples of the excipient, there may be 
mentioned lactose, starch, corn starch, crystalline cellulose [e.g. Avicel 
PH101 (trade name, Asahi Kasei Co., Ltd.), etc.], powder sugar, granulated 
sugar, mannitol, light silicic anhydride, magnesium carbonate, calcium 
carbonate, L-cysteine and so on. These excipients can be used 
independently or in combination. The content of the excipient may range, 
for example, from about 25 to 99.5% by weight, preferably from about 40 to 
99% by weight, and more preferably from about 50 to 96% by weight. 
The uncoated tablet of the present invention may further comprise 
conventional additives usable in solid pharmaceutical preparations. Such 
additives include, for example, binders (e.g. sucrose, gelatin, gum 
arabic, methylcellulose, hydroxypropylcellulose, 
hydroxypropylmethylcellulose, carboxymethylcellulose, 
carboxymethylcellulose sodium, polyvinylpyrrolidone, pullulan, dextrin, 
etc.); disintegrators (e.g. carboxymethylcellulose calcium, croscarmellose 
sodium [for example, Acdisol (trade name, Asahi Kasei Co., Ltd.)], 
crosslinked insoluble polyvinylpyrrolidone [e.g. Colidone CL (trade name, 
BASF Ltd.)], low-substituted hydroxypropylcellulose, partial alpha-starch, 
etc.); enteric polymers (for instance, hyrdroxypropylmethylcellulose 
phthalate, cellulose acetate phthalate, carboxymethylethylcellulose and so 
on); water-insoluble polymers (e.g. aminoalkylmethacrylate copolymers, 
methacrylic acid copolymers, etc.); lubricants (for example, magnesium 
stearate, talc and the like); surfactants (e.g. anionic surfactants such 
as sodium alkylsulfates, etc., and nonionic surfactants such as 
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid 
esters, polyoxyethylene castor oil derivatives, etc.); colorants (for 
instance, tar pigments, caramel, iron red oxide, titanium oxide, 
riboflavin, etc.); corrigents (e.g. sweeteners, flavors and the like); 
adsorbents; preservatives; wetting agents; antistatic agents; 
disintegration retarders; and others. 
The uncoated tablet of the present invention may frequently be comprised of 
the binder. The amount of the binder to be used is, for example, about 0.5 
to 30% by weight, and preferably about 1 to 10% by weight based on the 
total weight of the tablet. 
In the uncoated tablet of the invention, the oily or fatty substance having 
a lower melting point is presumably dispersed in the uncoated tablet and 
is expanded (extended) and developed at least on the surface of the 
tablet. In such an uncoated tablet, the oily or fatty substance having a 
lower melting point may be dispersed independently or in combination with 
other ingredients such as the active ingredient and excipient. The oily or 
fatty substance can also be expanded and/or developed not only on the 
surface but also over the whole of the tablet including the neighborhood 
of the surface of the tablet. 
Further, the oily or fatty substance having a lower melting point may be 
typically dispersed in the tablet in the powdery or granular form. In such 
a tablet, it is presumed that the powdery or granular oily or fatty 
substance at least on the surface of the tablet would be expanded or 
extended by means of the compression-molding pressure (compacting 
pressure). 
The uncoated tablet of the present invention has an outstanding feature of 
having a high abrasion resistance without coating of a coating 
composition. That is, according to the invention, the frictional force of 
the tablet by an external force is reduced by the oily or fatty substance, 
and the abrasion resistance of the tablet can be enhanced. Thus wear or 
attrition of said tablet is significantly reduced and the development of 
powder can be suppressed. Further, the strength of the tablet is not 
diminished, probably because the plastically-deformed oily or fatty 
substance having a lower melting point by compression-mold fixes 
surrounding particles. Therefore, when the tablet is orally administered, 
the disintegration of the tablet and the dissolution of the active 
ingredient are not sustained, thus readily-acting tablets can also be 
obtained. Furthermore, the tablet has a high working efficiency in 
operation of an automatic compounding machine in a hospital or pharmacy 
without development of powder in a distribution stage, accordingly the 
commercial value of the tablet can be enhanced. 
As apparent from the abrasion resistance test of the examples mentioned 
below, the uncoated tablet of the invention shows a reflectance of about 
0.01 to 0.3, preferably about 0.01 to 0.2, and more preferably about 0.03 
to 0.1, on condition that 50 g of the uncoated tablets in a white bottle 
(inner volume of 80 ml) is shaken for 30 minutes at a shaking rate of 220 
times per minute and amplitude of 40 mm, and the reflectance at a wave 
length of 500 nm is determined as an extent or degree of hazing 
(cloudiness) at the bottom of the bottle. On the contrary, the reflectance 
of an uncoated tablet containing no oily or fatty substance having a lower 
melting point is 0.4 or more. 
The uncoated tablet improved in the abrasion resistance of the present 
invention can be produced by incorporating the oily or fatty substance 
into the active ingredient, specifically into a compression-moldable 
composition containing said active ingredient, by means of, for example, 
blending, mixing or granulating, followed by subjecting the mixture to 
molding. The uncoated tablet can usually be produced by 
compression-molding a moldable composition comprising the above-mentioned 
active ingredient, excipient, oily or fatty substance having a lower 
melting point, and, if necessary, additives as above. Thus, an improved 
and/or enhanced abrasion resistance of the uncoated tablet can be realized 
by incorporating the oily or fatty substance having a lower melting point 
into the active ingredient by an incorporating means such as blending, 
mixing, combining, adding or granulating. 
The uncoated tablet can also be produced by subjecting said 
compression-moldable composition comprising the oily or fatty substance 
having a lower melting point directly to pressure-molding 
(compression-molding). In such a manner, the oily or fatty substance 
having a lower melting point may be added as liquid or solid. The oily or 
fatty substance having a lower melting point may usually be added as 
powdery or granular form, for example, with a mean particle size of about 
1,000 .mu.m or less, preferably about 0.1 to 750 .mu.m, and more 
preferably about 1 to 500 .mu.m. When powdery or granular oily or fatty 
substance having a lower melting point is employed, such an excellent 
uncoated tablet as mentioned above can be obtained by such a simple and 
easy manner of blending or mixing and compression-molding. 
According to the method of the invention, a compression-moldable 
composition comprising a granulated powder containing the active 
ingredient and the excipient, and the oily or fatty substance having a 
lower melting point (preferably powdery or granular oily or fatty 
substance having a lower melting point) can also be compressed and molded 
into uncoated tablets. Said method is characterized in that the oily or 
fatty substance having a lower melting point is admixed to the granulated 
powder, and the mixture is compressed and molded into tablets, while the 
oily or fatty substance is not used for granulation. While lipids such as 
a fatty acid ester and a wax conventionally employed as a component of 
tablets are usually used in the granulation. 
The granulated powder may be prepared by a conventional manner such as a 
wet-granulation and a dry-granulation, with use of a binder. The 
granulated powder may preferably be obtained by wet-granulating techniques 
such as a stirring-granulation and a fluidized-bed granulation wherein 
granulation can be conducted without the use of the oily or fatty 
substance having a lower melting point or, if used, with only a slight 
amount of said substance. The typical examples of the granulated powder 
usually include fine granules, granules and comminuted powder obtainable 
from granulated preparations. The mean particle size of the granulated 
powder is, for example, about 0.1 to 10,000 .mu.m, preferably about 10 to 
2,000 .mu.m, and most preferably about 74 to 1,400 .mu.m. 
The composition including such granulated powder and the oily or fatty 
substance having a lower melting point can be prepared by a conventional 
manner such as blending or mixing, and thus obtained compression-moldable 
composition is compression-molded into uncoated tablets. 
When the oily or fatty substance having a lower melting point is soluble or 
dispersible in water, a hydrophilic solvent (e.g. alcohols such as 
methanol and isopropanol, acetone and the like), or a hydrophobic solvent 
(e.g. hexane, ethers such as diethylether, esters such as ethyl acetate, 
etc.), said oily or fatty substance can be used as a solution or 
dispersion. The preferable examples of the solvent include a hydrophilic 
solvent, and water can advantageously be employed. The preferred oily or 
fatty substance includes a hydrophilic oily or fatty substance capable of 
dissolving or dispersing in the preferred solvent as above, especially a 
water-soluble oily or fatty substance. 
When the solution or dispersion containing the oily or fatty substance 
having a low melting point is employed, the granulated powder comprising 
the active ingredient, the excipient and the oily or fatty substance 
having a lower melting point is obtainable by a wet-granulating means such 
as a stirring-granulation and a fluidized-bed granulation. 
The compression-moldable composition may further comprise other additives 
such as disintegrators and lubricants in addition to the above-mentioned 
components. 
The compacting pressure (compression-molding pressure) can be selected from 
the range where the abrasion resistance of the uncoated tablet is not 
adversely affected, and is usually about 100 to 5,000 kg/cm.sup.2 and 
preferably about 500 to 3,000 kg/cm.sup.2. 
Typically preferred embodiments of the method of the present invention 
include (1) a process which comprises pressure-molding the moldable 
composition comprising the granulated powder containing the active 
ingredient, excipient and others, and the powdery or granular oily or 
fatty substance having a lower melting point, (2) a process which 
comprises pressure-molding the moldable composition containing the 
granulated powder comprising the active ingredient, the excipient and the 
oily or fatty substance having a lower melting point, and the like. In 
these processes, the moldable composition, especially the granulated 
powder, may frequently further comprise the binder. 
Thus, the uncoated tablet of the present invention can significantly be 
improved in the abrasion resistance with less probability of development 
of powder, therefore, the working efficiency and/or packaging efficiency 
in a visual examination machine and automatic compounding machine can 
extremely be enhanced. 
According to the present invention, a small amount of the oily or fatty 
substance having a lower melting point significantly enhance the abrasion 
resistance of the uncoated tablet without coating, therefore, even when a 
frictional or impact force acts on the tablet in production, 
transportation, compounding or the other processes, the development or 
occurrence of fine powder or powder dust due to wear or abrasion can 
efficaciously be inhibited. Further, the uncoated tablet is also superb in 
tablet characteristics such as strength, disintegrating properties and 
solubility. Furthermore, even when said oily or fatty substance is 
incorporated into the tablet in an exceedingly small amount, the uncoated 
tablet can be quite improved in the abrasion resistance and the 
development of powder or powder dust can efficiently be suppressed. When a 
water-soluble oily or fatty substance is employed as the oily or fatty 
substance, the disintegration properties and/or dissolving properties can 
also be advanced. 
According to the method of the invention, the uncoated tablet having such 
excellent characteristics as above can efficiently be produced by a simple 
operation and easy manner of compression-molding, without coating of a 
coating composition and a complicated process. Further, an elevated 
abrasion resistance can be imparted to the uncoated tablet by 
incorporating a small amount of the oily or fatty substance having a lower 
melting point. 
The following examples are intended to describe the present invention in 
further detail and should by no means be interpreted as defining the scope 
of the invention. 
EXAMPLES 
Examples 1 to 6 
A fluidized-bed granulator (model:FD-3S, manufactured by Powrex 
Corporation, Japan) was charged with 32.0 g of 
2-(7-chloro-1,8-naphthyridin-2-yl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ca 
rbonylmethylisoindolin-1-one (Compound A), 756.8 g of lactose and 144.0 g 
of corn starch, and the charge was fluidized-bed granulated while 451.2 g 
of an aqueous solution of 6% by weight of hydroxypropylcellulose was 
sprayed at a feed air temperature of 70.degree. C., under a pressure of 
1.0 kg/cm.sup.2 and at a rate of 10 g per minute, and the granulation 
products were dried and cooled to a temperature of 45.degree. C. with 
fluidization or floating. The resulting granules were comminuted with a 
mill (Power Mill, with a screen of 1.2 mm .phi., Showa Chemical Ltd., 
Japan) to prepare comminuted powder. Further, the preparation process as 
above was repeated to obtain 6 batches of comminuted powder. 
Subsequently, using the comminuted powder thus obtained, mixed powders each 
containing different amount of polyethylene glycol 6,000 were prepared. 
That is, a mixture of 2.8 g of magnesium stearate, a predetermined amount 
of pulverized product of polyethylene glycol 6,000 [milled with an 
Atomizer (Fuji Paudal Co., Ltd.); screen size: 1 mm .phi.] and corn starch 
was sieved with a round sieve No. 30 (sieve opening of 500 .mu.m), and the 
sieved was blended with 840.0 g of the comminuted powder in a Tumbler 
Mixer (model: TM-15, Showa Chemical Ltd., Japan) for 5 minutes to prepare 
910 g of a mixed powder. 
The amount of polyethylene glycol 6,000 to be added in each Example was, 
respectively, 0.9 g (Example 1, corresponding to 0.1% by weight based on 
the total weight), 1.8 g (Example 2, 0.2% by weight), 3.6 g (Example 3, 
0.4% by weight), 5.5 g (Example 4, 0.6% by weight), 9.1 g (Example 5, 1.0% 
by weight) and 27.3 g (Example 6, 3.0% by weight) and corn starch was 
added to adjust the total weight to 910 g. 
These mixed powders were compression-molded with a rotary tablet machine 
(Clean Press Correct 19K, Kikusui Seisakusho Co., Ltd., Japan) with a 
punch of 7 mm .phi. at a compacting pressure of 1,000 kg per punch and a 
thickness of the tablet of about 2.5 mm to prepare uncoated tablets 
(weight: 130.0 mg per tablet). 
Said tablets contain, per tablet, 120.0 mg of the comminuted powder 
(comprising 4.0 mg of Compound A, 94.6 mg of lactose, 18.0 mg of corn 
starch and 3.4 mg of hydroxypropylcellulose), 0.4 mg of magnesium 
stearate, about 0.13 to 3.9 mg of polyethylene glycol 6,000 and about 9.5 
to 5.7 mg of corn starch. 
Comparative Example 1 
An uncoated tablet was prepared in the same manner as in Example 1 except 
that the corn starch was used instead of polyethylene glycol 6,000. The 
tablets thus obtained contain 120.0 mg of the comminuted powder obtained 
in Example 1, 9.6 mg of corn starch and 0.4 mg of magnesium stearate, per 
tablet (130.0 mg). 
Comparative Example 2 
A comminuted powder was prepared in the same manner as in Example 1, except 
for using lactose instead of the active ingredient of Example 1. Namely, 
using 788.8 g of lactose, 144.0 g of corn starch and 451.2 g of an aqueous 
solution of 6% by weight of hydroxypropylmethylcellulose, the mixture was 
fluidized-bed granulated and dried, and the dried granules were comminuted 
to prepare comminuted powder in the same manner as in Example 1. 
Corn starch (67.2 g) and magnesium stearate (2.8 g) were added to 840.0 g 
of the comminuted powder thus PG,36 obtained, and 910 g of the resulting 
mixture was tabletted as in Example 1 to provide uncoated tablets. 
The uncoated tablets contain, per tablet (130.0 mg), 120.0 mg of the 
comminuted powder (composed of 98.6 mg of lactose, 18.0 mg of corn starch 
and 3.4 mg of hydroxypropylcellulose), 9.6 mg of corn starch and 0.4 mg of 
magnesium stearate. 
Example 7 
The same fluidized-bed granulator as used in Example 1 was charged with 
820.8 g of lactose and 160.0 g of corn starch, and the charge was 
fluidized-bed granulated while 510.4 g of an aqueous solution of 6% by 
weight of hydroxypropylcellulose containing 1.6 g of (+)-1L-[1(OH), 
2,4,5/3]-5-[2-hydroxy-1-(hydroxymethyl) 
ethyl]amino-1-C-(hydroxymethyl)-1,2,3,4cyclohexanetrol, namely, 
N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose, Compound B) was sprayed 
at a feed air temperature of 70.0.degree. C., at a pressure of 1.0 
kg/cm.sup.2 and a rate of 10 g per minute, and the granulation product was 
dried and cooled to 45.degree. C. with fluidization or floating. The 
resulting granules were comminuted with the same mill (Power Mill) used in 
Example 1 to prepare a comminuted powder. 
To 886.2 g of the comminuted powder thus obtained were added 17.5 g of corn 
starch, 2.8 g of magnesium stearate and 3.5 g of polyethylene glycol 6,000 
(about 0.38% by weight based on the total weight) milled with the Atomizer 
used in Example 1, and a mixed powder (910 g) was obtained in the same 
manner as in Example 1. The mixed powder was compression-molded in the 
same manner as Example 1 to provide uncoated tablets. 
The uncoated tablets comprise, per tablet (130 mg), 126.6 mg of the 
comminuted powder (containing 0.2 mg of Compound B, 102.6 mg of lactose, 
20.0 mg of corn starch and 3.8 mg of hydroxypropylcellulose), 2.5 mg of 
corn starch, 0.4 mg of magnesium stearate and 0.5 mg of polyethylene 
glycol 6,000. 
Comparative Example 3 
To the comminuted powder obtained in Example 7 were added 21.0 g of corn 
starch and 2.8 g of magnesium stearate, and a mixed powder (910 g) was 
prepared in the same procedure as in Example 1. The mixed powder was 
compressed and molded into uncoated tablets in the same manner as in 
Example 1. 
The uncoated tablets obtained include 126.6 mg of the comminuted powder 
obtained in Example 7, 3.0 mg of corn starch and 0.4 mg of magnesium 
stearate per tablet (130.0 mg). 
Example 8 
Corn starch (58.1 g), magnesium stearate (2.8 g) and 9.1 g (1.0% by weight 
based on the total weight) of powdery stearic acid (m.p. 56.degree. to 
72.degree. C.) as an oily or fatty substance having a lower melting point 
were added to 840 g of the comminuted powder containing Compound A 
obtained in Example 1, and 910 g of a mixed powder was prepared according 
to the same procedure as in Example 1. The powdery stearic acid was 
prepared by pulverizing stearic acid with a mortar and sieving with a 
round sieve No. 100. 
Uncoated tablets were produced in the same manner as in Example 1 using the 
mixed powder thus obtained. The tablets include, per tablet (130.0 mg), 
120.0 mg of the comminuted powder prepared in Example 1, 8.3 mg of corn 
starch, 0.4 mg of magnesium stearate and 1.3 mg of stearic acid. 
Example 9 
The procedures of Example 8 were repeated except that 9.1 g (1.0% by weight 
based on the total weight) of carnauba wax (trade name: Polishing Wax-103, 
Freund Industries Ltd., m.p. 80.degree. to 86.degree. C.) was used as an 
oily or fatty substance having a lower melting point instead of stearic 
acid. Thus uncoated tablets were obtained. 
Example 10 
Except for using 9.1 g (1.0% by weight based on the total weight) of 
ethylene oxide-propylene oxide copolymer (trade name: PEP-101, Freund 
Industrial Co., Ltd., m.p. 50.degree. to 54.degree. C.) comminuted with a 
mortar and passed through a round sieve No. 100 as an oily or fatty 
substance having a lower melting point instead of stearic acid, the 
procedure of Example 8 was repeated to provide uncoated tablets. 
Example 11 
An uncoated tablet was obtained in the same procedures as in Example 8 
except that 9.1 g (1.0% by weight based on the total weight) of 
polyoxyethylene [160]-polyoxypropylene [30] (trade name: Pullronic F68, 
Asahi Denka Ltd., Japan, m.p. 46.degree. to 56.degree. C.) comminuted with 
a mortar and sieved with a round sieve No. 100 was used instead of stearic 
acid as an oily or fatty substance with a lower melting point. 
Example 12 
Example 1 was followed with the use of 840 g of the comminuted powder 
containing Compound A prepared in accordance with Example 1, 63.7 g of 
corn starch, 2.8 g of magnesium stearate and 3.5 g (approximately 0.38% by 
weight based on the total weight) of polyethylene glycol 4,000 (m.p. 
53.degree. to 57.degree. C.) milled with the Atomizer used in Example 1 as 
an oily or fatty substance having a lower melting point, to prepare 910 g 
of a mixed powder. The resulting mixed powder (910 g) was tabletted in the 
same manner as Example 1 to provide uncoated tablets. 
Each tablet (weight: 130.0 mg) thus obtained includes 120.0 mg of the 
comminuted powder obtained in Example 1, 9.1 mg of corn starch, 0.4 mg of 
magnesium stearate and 0.5 mg of polyethylene glycol 4,000. 
Example 13 
The procedures of Example 1 were repeated using 840 g of the comminuted 
powder containing Compound A obtained in accordance with Example 1, 63.7 g 
of corn starch, 2.8 g of magnesium stearate and 3.5 g (about 0.38% by 
weight based on the total weight) of polyethylene glycol 20,000 (m.p. 
56.degree. to 64.degree. C.) milled with the Atomizer used in Example 1, 
to prepare a mixed powder (910 g). Then the mixed powder (910 g) was 
compressed and molded into uncoated tablets in the same manner as in 
Example 1. 
The formulation of each tablet (weight: 130.0 mg) is 120.0 mg of the 
comminuted powder obtained in Example 1, 9.1 mg of corn starch, 0.4 mg of 
magnesium stearate and 0.5 mg of polyethylene glycol 20,000. 
Example 14 
A comminuted powder was obtained in the same procedure as in Example 1, 
except that the fluidized-bed granulator used in Example 1 was charged 
with 800.0 g of lactose and 160.0 g of corn starch, and that 510.4 g of an 
aqueous solution of 6% by weight of hydroxypropylcellulose containing 1.6 
g of Compound B and 20.8 g of polyethylene glycol 6,000 comminuted with 
the Atomizer was sprayed for fluidized-bed granulation. 
In the same manner as in Example 1, 910 g of a mixed powder was prepared 
from 886.2 g of the comminuted powder, 21.0 g of corn starch and 2.8 g of 
magnesium stearate. The mixed powder was compression-molded in the same 
manner as Example 1 to provide uncoated tablets. 
The tablets thus obtained contain, per tablet (130.0 mg), 126.6 mg of the 
comminuted powder (comprising 0.2 mg of Compound B, 100.0 mg of lactose, 
20.0 mg of corn starch, 2.6 mg of polyethylene glycol 6,000 (2.0% by 
weight) and 3.8 mg of hydroxypropylcellulose), 3.0 mg of corn starch and 
0.4 mg of magnesium stearate. 
The abrasion resistance of the tablets obtained in Examples and Comparative 
Examples, and the amount of the drug in powder developed or produced by 
wearing or abrasion of the tablets of Example 6 and Comparative Example 1 
were determined as follows. 
(1) Determination of the abrasion resistance 
A white bottle of inner volume of 80 ml was charged with 50 g of the 
uncoated tablets and sealed. Then the bottle was installed vertically in a 
shaker (trade name: Reciproshaker, Taiyo Kagaku Co., Ltd., Japan) and 
shaken for 30 minutes at a shaking rate of 220 times per minute and with 
an amplitude of 40 mm. 
After completion of shaking, the uncoated tablets were taken out of the 
bottle with attention and an extent (degree) of attached or affixed powder 
on the surface of the tablet by wearing or abrasion was evaluated upon the 
following criteria. Further, after taking out the tablets, the extent of 
cloudiness (hazing) of the inside bottom of the white bottle due to the 
powder developed by wearing or abrasion was determined with a 
spectrophotometer in absorptiometry (reflectance at a wavelength of 500 
nm). The values of absorbances were corrected by an absorbance of the 
white bottle by itself which was preliminary determined. 
As a result of a preliminary examination, it was observed a relationship 
between the criteria of the cloudiness by visual evaluation and the 
results of absorptiometry as follows: 
______________________________________ 
Absorptiometry 
Criteria of cloudiness 
(Reflectance at 500 nm) 
______________________________________ 
+: powder was produced 
0.25 or more 
in a large amount 
+/-: powder was produced 
0.15 to 0.25 
in a small amount 
-: powder was produced 
0.15 or less 
scarcely 
______________________________________ 
(2) Assay of the amount of the drug attached inside of the bottle 
Compound A was dissolved in acetonitrile, the solution was diluted to a 
predetermined concentration, and a calibration curve was obtained by 
determining the absorbency of the solution with a spectrophotometer at 208 
nm. 
For the tablets of Example 6 and the tablets of Comparative Example 1, the 
powder attached to the bottle and remained after the abrasion resistance 
test mentioned above (1) was dissolved in acetonitrile, and the solution 
was filtered. The absorbance of the filtrate was determined in the same 
manner as above and the content of the drug in the powder was calculated 
using the calibration curve. The determined value of the content of the 
drug was corrected by the absorbance of the additives other than the drug 
preliminary determined. 
The results of the abrasion resistance and the content of the drug in the 
powder of the uncoated tablets obtained in Examples and Comparative 
Examples are shown in Table 1. 
TABLE 1 
__________________________________________________________________________ 
Oily or fatty 
substance 
Amount Degree of 
Absorptiometry 
Amount of drug 
Species (% by weight) 
cloudiness 
(Reflectance) 
(.mu.g per tablet) 
__________________________________________________________________________ 
Ex. 1 PEG 6,000 
0.1 + 0.28 - 
Ex. 2 PEG 6,000 
0.2 +/- 0.16 - 
Ex. 3 PEG 6,000 
0.4 - 0.08 - 
Ex. 4 PEG 6,000 
0.6 - 0.08 - 
Ex. 5 PEG 6,000 
1.0 - 0.07 - 
Ex. 6 PEG 6,000 
3.0 - 0.06 0.068 
Comp. Ex. 1 
- - + 0.44 0.309 
Comp. Ex. 2 
- - + 0.43 - 
Ex. 7 PEG 6,000 
approx. 0.4 
- 0.08 - 
Comp. Ex. 3 
- - + 0.51 - 
Ex. 8 Stearic acid 
1.0 - 0.07 - 
Ex. 9 Carnauba wax 
1.0 - 0.07 - 
Ex. 10 PEP-101 1.0 - 0.07 - 
Ex. 11 Pullronic 
1.0 - 0.05 - 
Ex. 12 PEG 4,000 
approx. 0.4 
- 0.10 - 
Ex. 13 PEG 20,00 
approx. 0.4 
- 0.09 - 
Ex. 14 PEG 6,000 
2.0 - 0.08 - 
__________________________________________________________________________ 
Comparison of Examples 1 to 14 with Comparative Examples 1 to 3 in Table 1 
clearly indicates that, regardless of species of the drug, the occurrence 
of powder was significantly suppressed and remarkable improvements in the 
abrasion resistance by a small amount of the oily or fatty substance 
having a lower melting point were observed. Further, as apparent from the 
results of the Example 14, even when the comminuted powder prepared by wet 
granulation using the oily or fatty substance having a lower melting point 
was used, the abrasion resistance of the tablet was also specifically 
improved as other Examples. 
Regarding the amount of the drug attached to inside of the bottle by the 
abrasion resistance test, the amount of the drug of the tablets obtained 
in Example 6 was smaller than that of the tablets obtained in Comparative 
Example 1 by a factor of five. 
Test Example 
A tablet case (TK-50) of a compounding machine (automatic tablet packaging 
machine, ATC system, manufactured by Sanyo, Co., Ltd., Japan) was charged 
with the uncoated tablets of Example 3 and the uncoated tablets of 
Comparative Example 1 respectively, and the tablets were continuously 
discharged from the machine one by one at a rate of 150 tablets per 
minute. The abrasion extent (degree) of the surface of the tablets was 
evaluated in the following manner. 
Namely, a white bottle was disposed in the tablet discharging port of the 
tablet case, the uncoated tablets were discharged and powder developed by 
wearing or abrasion were recovered with the discharged tablets. Only the 
uncoated tablets were taken out from the bottle, and the content of 
Compound A in the remained powder was determined. The amount of the drug 
was determined during the time course and evaluated as an accumulated drug 
amount (.mu.g per tablet). The results are shown in Table 2. 
TABLE 2 
______________________________________ 
Accumulated amount of drug 
due to abrasion (.mu.g/tablet) 
Number of discharged 
tablet 2,000 4,000 6,000 
______________________________________ 
Example 3 0.02 0.23 0.45 
Comparative 0.15 0.58 1.25 
Example 1 
______________________________________ 
As clearly shown in Table 2, the abrasion or wearing amount of the uncoated 
tablet of Example 3 was, in spite of an extremely small amount of the oily 
or fatty substance having a lower melting point, significantly reduced and 
the abrasion resistance was improved two and a half times as much as the 
tablet of the Comparative Example 1.