U.S. patent application number 10/834002 was filed with the patent office on 2004-10-14 for intraoral quickly disintegrating tablets.
This patent application is currently assigned to EISAI CO., LTD.. Invention is credited to Furitsu, Hisao, Kato, Akira, Ohwaki, Takayuki, Yasui, Masanobu.
Application Number | 20040202715 10/834002 |
Document ID | / |
Family ID | 26554584 |
Filed Date | 2004-10-14 |
United States Patent
Application |
20040202715 |
Kind Code |
A1 |
Furitsu, Hisao ; et
al. |
October 14, 2004 |
Intraoral quickly disintegrating tablets
Abstract
The present invention provides an intraoral quickly
disintegrating tablet containing a phosphodiesterase inhibitor
having an effect of improving the erectile dysfunction and a method
for manufacturing the tablet. The present invention also provides
an intraoral quickly disintegrating tablet containing a slightly
soluble pharmaceutical agent having an improved solubility and a
method for manufacturing the tablet. That is, it is an intraoral
quickly disintegrating tablet containing a cyclic GMP
phosphodiesterase inhibitor and a saccharide, and a method for
manufacturing the tablet. Further, it is a method for manufacturing
an intraoral quickly disintegrating tablet, which comprises
dissolving a slightly soluble pharmaceutical agent in an organic
solvent or an aqueous organic solvent together with a surfactant
and/or a water-soluble polymer, coating the solution on a filler or
granulating it with a filler to obtain molded products, mixing a
saccharide with them, adding an organic solvent, water or an
aqueous organic solvent thereto, followed by kneading, and
subjecting it to a compression-molding.
Inventors: |
Furitsu, Hisao; (Ibaraki,
JP) ; Kato, Akira; (Ibaraki, JP) ; Ohwaki,
Takayuki; (Aichi, JP) ; Yasui, Masanobu;
(Saitama, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
EISAI CO., LTD.
|
Family ID: |
26554584 |
Appl. No.: |
10/834002 |
Filed: |
April 29, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10834002 |
Apr 29, 2004 |
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09806823 |
Apr 5, 2001 |
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6743443 |
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09806823 |
Apr 5, 2001 |
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PCT/JP99/05298 |
Sep 28, 1999 |
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Current U.S.
Class: |
424/465 |
Current CPC
Class: |
A61K 31/4985 20130101;
A61K 31/502 20130101; A61K 9/0056 20130101; A61K 31/517 20130101;
A61K 31/519 20130101; A61K 9/2095 20130101 |
Class at
Publication: |
424/465 |
International
Class: |
A61K 009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 5, 1998 |
JP |
10-282378 |
Oct 19, 1998 |
JP |
10-295947 |
Claims
1. An intraoral quickly disintegrating tablet comprising a
difficultly soluble pharmaceutical agent and a saccharide and
further comprising at least one selected from surfactant and a
water-soluble polymer.
2. A method for manufacturing the tablet as claimed in claim 1,
which comprises dissolving a difficultly soluble pharmaceutical
agent in an organic solvent or an aqueous organic solvent together
with at least one selected from a surfactant and a water-soluble
polymer, coating the solution on a filler or granulating it with a
filler to obtain molded products, mixing a saccharide with them,
adding an organic solvent, water or an aqueous organic solvent
thereto, followed by kneading, and subjecting it to a
compression-molding.
3. A method for manufacturing the tablet as claimed in claim 1,
which comprises adding at least one selected from a surfactant and
a water-soluble polymer and a saccharide to a difficultly soluble
pharmaceutical agent, followed by mixing, adding an organic
solvent, water or an aqueous organic solvent thereto, followed by
kneading, and subjecting it to a compression-molding.
4. The method for manufacturing as claimed in claim 2, wherein the
molded products are granules, fine granules or powder.
5. The method for manufacturing as claimed in claim 2, in which the
granulation-molding is carried out, using a fluidized bed
granulator, a tumbling granulator, an extrusion granulator or a
spray-drying granulator.
6. The method for manufacturing as claimed in claim 2 or 3, which
comprises filling the powder kneaded with the organic solvent,
water or the aqueous organic solvent in a mold and subjecting it to
compression-molding with a film in the compression-molding
stage.
7. The tablet as claimed in claim 1, wherein the slightly soluble
pharmaceutical agent is a cyclic GMP phosphodiesterase
inhibitor.
8. The method for manufacturing as claimed in claim 2 or 3, wherein
the slightly soluble pharmaceutical agent is a cyclic GMP
phosphodiesterase inhibitor.
9. The tablet as claimed in claim 7, wherein the cyclic GMP
phosphodiesterase inhibitor is selected from the group consisting
of:
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one represented the
formula (I)
11,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazo-
lo[3,4-d]pyrimidin-4-one represented by the formula (II)
22-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinaz-
oline represented by the formula (III)
3(6R,12aR)-2,3,6,7,12,12a-hexahydr-
o-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-i-
ndol-1,4-dione represented by the formula (IV)
4(3S,6R,12aR)-2,3,6,7,12,1-
2a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-
pyrido[3,4-b]-indol-1,4-dione shown by the formula (V) 5or a
pharmacologically acceptable salt thereof.
10. The method as claimed in claim 7, which comprises filling the
kneaded mixture in a mold and subjecting it to a
compression-molding with a film.
11. The tablet as claimed in claim 10, wherein the cyclic GMP
phosphodiesterase inhibitor is a compound selected from the group
consisting of:
4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypipe- ridino)
phthalazine hydrochloride represented by the formula (IX)
64-(3-chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxypiperidino)phth-
alazine hydrochloride represented by the formula (X)
74-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3,5]non-7-yl-
)-6-phthalazine carbonitrile hydrochloride represented by the
formula (XI)
81-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-4-[(4-methoxy-3-methylbenzyl)amin-
o]-6-phthalazine carbonitrile hydrochloride represented by the
formula (XII)
91-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbe-
nzyl)amino]-6-phthalazine carbonitrile hydrochloride represented by
the formula (XIII)
104-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-a-
zaspiro[3,5]non-7-yl)-6-phthalazine carbonitrile hydrochloride
shown by the formula (XIV)
114-[(3-chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-
-azaspiro[4,5]decen-8-yl)-6-phthalazine carbonitrile represented by
the formula (XV) 12
12. The tablet as claimed in claim 1, wherein the saccharide is at
least one selected from mannitol, sucrose, lactose, trehalose,
xylitol, erythritol, glucose, starch and dextrin.
13. The method for manufacturing as claimed in claim 12, wherein
the cyclic GMP phosphodiesterase inhibitor is selected from the
group consisting of:
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-me-
thyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
represented by the formula (I), and a compound represented by the
formula (VI), or pharmacologically acceptable salts thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to an intraoral quickly
disintegrating tablet containing a phosphodiesterase inhibitor
having an effect of improving the erectile dysfunction and to a
method for manufacturing the tablet.
[0002] The present invention also relates to an intraoral quickly
disintegrating tablet containing a slightly soluble pharmaceutical
agent such as a phosphodiesterase inhibitor having an improved
solubility and to a method for manufacturing the tablet.
PRIOR ART
[0003] It is reported in JP-B 9-503996 that pyrazonopyrimidinone
compounds having an inhibitory action to a cyclic GMP
phosphodiesterase type V are useful for the therapy of erectile
dysfunction by means of oral administration. Further,
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-p-
henyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(general name: sildenafil) belonging to the same classification and
being represented by the formula (I) surely shows duration of its
pharmaceutical effect at least for two hours when it is orally
administered (British J. Urology, 78, 257-261, 1996.) and,
therefore, there is a high possibility that they are used for a
highly practical drug therapy for erectile dysfunction as a
substitute for an injection therapy of papaverine hydrochloride or
prostaglandin E1 into corpus cavernosum penis which has been
carried out in an urological field. In addition, with regard to a
compound having an inhibitory action to a cyclic GMP
phosphodiesterase type V, there is disclosed a pyrazolopyrimidinone
derivative represented by the formula (II)
{1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazol-
o[3,4-d]-pyrimidin-4-one} in JP-A 7-70128 while, in WO 97/03675,
there are mentioned a compound represented by the formula (IV)
{(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-
-pyrazino[2',1':6,1]pyrido[3,4-b]-indol-1,4-dione)} and a compound
represented by the formula (V)
{(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-
-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]ind-
ol-1,4-dione}.
[0004] Further, in WO 93/07124, there is mentioned a compound
represented by the formula (III)
{2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl-
)amino-6-chloroquinazoline}. Furthermore, the compounds of a fused
pyridazine type represented by the formula (VI) mentioned in JP-A
10-114657 have an inhibitory action to a cyclic GMP
phosphodiesterase type V and are useful as therapeutic agents for
erectile dysfunction.
[0005] It has been said that the number of the latent patients of
erectile dysfunction are about 3,000,000 in Japan and are about
20,000,000 in U.S.A. It has been also reported that, while the
number of the patients of erectile dysfunction in U.S.A. are only
2-7% of the male population of younger than 50 years age, the rate
increases together with aging and 15% of males of fifties and a
little over 30% of males of sixties are suffering from this
disease. Most of them are derived from organic disorder and, taking
the advent of an aging society in near future into consideration,
it may be concluded that oral preparations of cyclic GMP
phosphodiesterase inhibitors will play a very big role in improving
the quality of life (QOL) of the patients suffering from erectile
dysfunction.
[0006] However, when the conventional oral preparations containing
a cyclic GMP phosphodiesterase inhibitor are administered, there is
a possibility that, for example, administration of tablets is
difficult or that powdery or granular agent adheres in the mouth or
comes into artificial teeth whereby a part of the preparation is
dropped out since aged people have a low swallowing ability.
[0007] When a consideration is made on the standpoint of the aged
people as such, there is a very high demand for "therapeutic
preparations for erectile dysfunction which can be easily taken,
easily swollen and easily handled" which is able to be "one of the
means whereby control of the carnal desire which is the fundamental
desire of human being can be embodied". Even in ordinary and
healthy adults, therapeutic preparations for erectile dysfunction
which can be taken at any place without water greatly contribute to
their QOL.
[0008] On the other hand, intraoral quickly disintegrating tablets
have been known as the tablets which are quickly disintegrated in
the mouth and, since they can be easily taken without water, they
are recently receiving public attention as a dosage form which is
suitable for the people having insufficient swallowing functions
such as aged people and small children.
[0009] It has been known that the intraoral quickly disintegrating
tablets can be prepared, for example, by the use of wet powder.
With regard to a method where wet powder is dried without a
tableting step whereupon the intraoral quickly disintegrating
tablets are prepared, there is disclosed for example in JP-A
5-511543 for "a solid preparation which is quickly disintegrated in
the mouth comprising an active ingredient, a saccharide selected
from lactose and/or mannitol and agar".
[0010] On the other hand, with regard to an intraoral quickly
disintegrating tablet prepared by a compression-molding of wet
powder filled in a molding machine, there are disclosed, for
example, "a method for the manufacture of an intraoral quickly
disintegrating tablet where a mixture containing a pharmaceutical
ingredient, a saccharide and water which is in an amount of
moisturizing the particle surface of the saccharide is made into a
tablet" in JP-A 5-271054; "an intraoral quickly disintegrating
tablet comprising a pharmaceutical agent, a saccharide, a sugar
alcohol and a water-soluble polymer and being prepared by
moisturizing and molding" in JP-A 9-48726; and "a wet-process
tablet where a pharmaceutical agent is mixed with a saccharide, a
filler, etc., kneaded after addition of water and/or organic
solvent, filled in a mold and subjected to a compression-molding
and a method for manufacturing the same" in JP-A 6-218028. Further,
with regard to a method for the molding of an intraoral quickly
disintegrating tablet, there is disclosed in JP-A 8-19589 for an
invention concerning "a method for the manufacture of a tablet
where wet powder is filled in a hole for molding the tablet and at
least one side of the wet powder in the hole is made into a shape
of a tablet by means of a metal mold for molding with a film for
prevention of adhesion and an apparatus for manufacturing the
tablet".
[0011] However, there has been no report yet for a preparation
containing a cyclic GMP phosphodiesterase inhibitor and being able
to greatly contribute in such a QOL improvement and for a method of
manufacturing such a preparation.
[0012] Incidentally, in the case of a slightly soluble
pharmaceutical agent, it is not preferred to directly apply the
intraoral quickly disintegrating tablet using the above-mentioned
known means and the method for manufacturing the tablet. That is
because the low solubility of the slightly soluble pharmaceutical
agent delays the time for reaching the effective blood level by
oral administration and long time is required for achieving the
pharmaceutical effect and also because there is a risk that a
sufficient pharmaceutical effect is not achieved due to a low
bioavailability.
[0013] In general, one of the most important factors among various
factors affecting the absorption of a pharmaceutical agent via
digestive tracts is its solubility and, especially in the case of a
slightly soluble pharmaceutical agent, it is quite often that its
dissolving rate determines the rate of absorption. Various methods
have been known for promoting the solubility of a pharmaceutical
agent and they may be roughly classified into the following three.
Thus, (1) to increase the surface area of the pharmaceutical
particles; (2) to use amorphous or metastable crystals; and (3) to
utilize various types of salt or to add a solubilizer. As to the
specific means therefor, making the pharmaceutical agent into fine
powder, formation of a solvate and adsorption on the surface of a
carrier have been known for (1); selection of crystal polymorphism,
mixing/pulverization and preparation of a solid dispersion have
been known for (2); and preparation of an acidic salt or an
alkaline salt, addition of various pH buffers and/or surfactants,
etc. have been known for (3) and they are disclosed, for example,
in JP-A 59-14446 and JP-A 58-183615.
[0014] However, there has been no report yet for an intraoral
quickly disintegrating tablet containing a slightly soluble
pharmaceutical agent having an improved solubility as such and for
a method of manufacturing the tablet. One of the reasons therefor
is that it is difficult for satisfying all of the requirements for
improving the solubility of the slightly soluble pharmaceutical
agent, for a quick disintegration in the mouth and for ensuring a
good touch on the tongue upon disintegration. Many of the
pharmaceutical ingredients acting as a cyclic GMP phosphodiesterase
inhibitor are the compounds having a relatively low solubility and
are within a category of the slightly soluble pharmaceutical
agents. Especially in the weakly acidic to neutral regions which
are the pH of the stomach of the persons of an acidity and the pH
ranging from duodenum to small intestine which are the main sites
for absorption of the pharmaceutical agent, the solubility
significantly lowers. Solubilities at 37.degree. C. in the first
disintegration test solution (pH 1.2) and the second disintegration
test solution (pH 6.8) according to the Japanese Pharmacopoeia are
2.52 mg/ml and 0.11 mg/ml, respectively for sildenafil (citrate);
0.13 mg/ml and 0.0063 mg/ml, respectively, for
4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxyp-
iperidino)-phthalazine hydrochloride which is represented by the
formula (IX) among the phthalazine compounds of the formula (VI);
and 0.028 mg/ml and 0.0012 mg/ml, respectively, for
4-(3-chloro-4-methoxyphenethyl)-amino-
-6-cyano-1-(4-hydroxypiperidino)phthalazine hydrochloride
represented by the formula (X).
[0015] It is worried about that the slight solubility of the cyclic
GMP phosphodiesterase inhibitor agent as such may result in a delay
of the time reaching the effective blood level, a lowering of the
bioavailability and an expansion of the dispersion thereof.
[0016] Accordingly, in a cyclic GMP phosphodiesterase inhibitor
having such a low solubility, it is desired that the solubility of
the effective ingredient in the intraoral quickly disintegrating
tablet is improved so that the time for reaching the effective
blood level is made shorter and that the absorption is improved so
that the bioavailability is improved.
DISCLOSURE OF THE INVENTION
[0017] With regard to a preparation containing a cyclic GMP
phosphodiesterase inhibitor, there has been a brisk demand for the
development of an oral preparation which is able to contribute in
the QOL of the patients suffering from erectile dysfunction or, in
other words, an oral preparation which can be easily taken by aged
people and can be taken without water even by adults having a
swallowing ability and a method for manufacturing the
preparation.
[0018] To be more specific, there has been a demand for the
development of an intraoral quickly disintegrating tablet
containing a cyclic GMP phosphodiesterase inhibitor having quick
disintegrating property and solubility in the mouth and also having
a strength for retaining its shape during preservation and a method
of manufacturing the tablet.
[0019] There has been also a demand for the development of an
intraoral quickly disintegrating tablet containing a slightly
soluble pharmaceutical agent having quick disintegrating property
and solubility in the mouth, showing a good touch on the tongue
upon disintegration in the mouth and having a strength for
retaining its shape during preservation and a method of
manufacturing the tablet. Thus, it is expected that the solubility
of the pharmaceutical ingredient in the intraoral quickly
disintegrating tablet is improved whereby the time for reaching the
effective blood level is made short, the time until expressing the
pharmaceutical effect is made short and absorption is improved so
that the bioavailability is improved.
[0020] However, although there are many aged people among the
patients suffering from erectile dysfunction and there have been so
many demands for an intraoral quickly disintegrating tablet
containing a cyclic GMP phosphodiesterase inhibitor and to a method
for manufacturing the tablet, such tablet and method have not been
developed yet. Such a situation is the same for an intraoral
quickly disintegrating tablet containing a slightly soluble
pharmaceutical agent with an improved solubility and a method for
manufacturing the tablet as well.
[0021] Under such circumstances, the present inventors have carried
out an intensive study for investigating an intraoral quickly
disintegrating tablet with an excellent disintegrating property
containing a cyclic GMP phosphodiesterase inhibitor and a
saccharide and a method for manufacturing the tablet and also for
an intraoral quickly disintegrating tablet with an excellent
solubility containing a slightly soluble pharmaceutical agent and a
saccharide and a method for manufacturing the tablet. As a result,
it has been found that the aimed object can be achieved by the
constitutions as mentioned below whereupon the present invention
has been accomplished.
[0022] The present invention is an intraoral quickly disintegrating
tablet containing a cyclic GMP phosphodiesterase inhibitor and a
saccharide.
[0023] Further, the present invention is an intraoral quickly
disintegrating tablet containing a cyclic GMP phosphodiesterase
inhibitor, a saccharide and a binder.
[0024] Furthermore, the present invention is an intraoral quickly
disintegrating tablet where a cyclic GMP phosphodiesterase
inhibitor and a saccharide are mixed, kneaded with an organic
solvent, water or an aqueous organic solvent and subjected to a
compression-molding and also a method for manufacturing the
tablet.
[0025] Still further, the present invention is an intraoral quickly
disintegrating tablet where a cyclic GMP phosphodiesterase
inhibitor and a saccharide are mixed, kneaded with an organic
solvent, water or an aqueous organic solvent, filled in a mold and
subjected to a compression-molding with a film and also a method
for manufacturing the tablet.
[0026] The cyclic GMP phosphodiesterase inhibitor covers both that
which is slightly soluble and that which is not slightly
soluble.
[0027] Still furthermore, the present invention is a method for the
manufacture of an intraoral quickly disintegrating tablet where a
slightly soluble pharmaceutical agent is dissolved in an organic
solvent or an aqueous organic solvent together with a surfactant
and/or a water-soluble polymer, then a saccharide is mixed with a
molded product prepared by a coating of a filler or by a
granulation together with a filler, an organic solvent, water or an
aqueous organic solvent is added thereto and the mixture is kneaded
and subjected to a compression-molding. Here, the term "molded
product" means granules, fine granules, powder or the like and the
molded product may be manufactured using, for example, a fluidized
bed granulator, a tumbling granulator, an extrusion granulator or a
spray-drying granulator.
[0028] Further, the present invention is a method for the
manufacture of an intraoral quickly disintegrating tablet where a
surfactant and/or a water-soluble polymer are/is added to a
slightly soluble pharmaceutical agent followed by mixing, an
organic solvent, water or an aqueous organic solvent is added
thereto and the mixture is kneaded and subjected to a
compression-molding.
[0029] The term "slightly soluble" means that the substance is
slightly soluble in water, saliva, gastric juice, intestinal juice,
etc., and that can be measured by common tests.
[0030] Here, the surfactant and/or the water-soluble polymer
play(s) a role of improving the solubility whereby wetting of the
slightly soluble pharmaceutical ingredient per se with water is
improved. A method for improving the solubility of the
pharmaceutical agent in accordance with the present invention is
not only able to improve the solubility of the intraoral quickly
disintegrating tablet containing the slightly soluble
pharmaceutical agent and to ensure its quick disintegration in the
mouth but also able to ensure the good touch on the tongue during
the disintegration in the mouth.
[0031] During the course of the compression-molding in the present
invention, it is preferred for keeping the good molding property of
the tablet that the powder kneaded with an organic solvent, water
or an aqueous organic solvent is filled in a mold and subjected to
a compression-molding with a film.
[0032] Furthermore, the present invention is an intraoral quickly
disintegrating tablet with an improved solubility containing a
cyclic GMP phosphodiesterase inhibitor which is a slightly soluble
pharmaceutical agent and also is a method for manufacturing the
tablet.
[0033] Examples of the slightly soluble pharmaceutical agent in the
present invention are nifedipine, phenytoin, nitrofurantoin,
benoxaprofen, griseofulvin, sulfathiazole, tacrolimus, piroxicam,
carbamazepine, phenacetin and cyclic GMP phosphodiesterase
inhibitor although the present invention is not limited
thereto.
[0034] Examples of the cyclic GMP phosphodiesterase inhibitor in
the present invention are pyrazonopyrimidinone compounds (JP-B
9-50396) represented by
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-me-
thyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(general name: sildenafil) of the formula (I); pyrazolopyrimidinone
compounds represented by
1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5--
dihydropyrazolo[3,4-d]pyrimidin-4-one of the formula (II) (JP-A
7-70128);
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)--
pyrazino[2',1':6,1]-pyrido[3,4-b]indol-1,4-dione) represented by
the formula (IV) and
(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,-
4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indol-1,4-dione
represented by the formula (V) (WO 97/03675);
2-(4-carboxypiperidino)-4-(-
3,4-methylenedioxybenzyl)amino-6-chloroquinazoline represented by
the formula (III) (WO 93/07124); a fused pyridazine compound
represented by the formula (VI); and a pharmacologically acceptable
salt thereof.
[0035] Examples of the compound shown by the formula (VI) are
4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalaz-
ine hydrochloride represented by the formula (IX) (JP-A 8-225541),
4-(3-chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxypiperidino)-phth-
alazine hydrochloride represented by the formula (X),
4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3,5]-non-7-yl-
)-6-phthalazine carbonitrile hydrochloride represented by the
formula (XI),
1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-4-[(4-methoxy-3-methylbenzyl)-
amino]-6-phthalazine carbonitrile hydrochloride represented by the
formula (XII),
1-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylben-
zyl)amino]-6-phthalazine carbonitrile hydrochloride shown by the
formula (XIII),
4-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-azaspiro[3,-
5]non-7-yl)-6-phthalazine carbonitrile hydrochloride represented by
the formula (XIV) and
4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-az-
aspiro[4,5]dece-8-yl)-6-phthalazine carbonitrile represented by the
formula (XV).
[0036] However, the cyclic GMP phosphodiesterase inhibitor of the
present invention is not limited to those compounds only.
[0037] Usually, the compounding ratio of the cyclic GMP
phosphodiesterase inhibitor or the slightly soluble pharmaceutical
agent in the present invention to 1 part by weight of the tablet is
0.0001-0.4 part by weight, preferably 0.005-0.3 part by weight or,
more preferably, 0.01-0.25 part by weight.
[0038] An average particle diameter of the cyclic GMP
phosphodiesterase inhibitor or the slightly soluble pharmaceutical
agent per se is 1-100 .mu.m, preferably 5-70 .mu.m and more
preferably, 5-50 .mu.m.
[0039] With regard to the saccharide in the present invention, any
saccharide may be used so far as it is soluble in water and is
stable and its examples are mannitol, sucrose, lactose, trehalose,
xylitol, erythritol, glucose, starch and dextrin. In the present
invention, each of them may be used solely or two or more thereof
may be used jointly.
[0040] The compounding ratio of the saccharide in the present
invention varies depending upon the type of the cyclic GMP
phosphodiesterase inhibitor or the slightly soluble pharmaceutical
agent but, usually, it is 2-50 parts by weight, preferably 3-40
parts by weight or, more preferably, 4-30 parts by weight to 1 part
by weight of the cyclic GMP phosphodiesterase inhibitor or the
slightly soluble pharmaceutical agent.
[0041] An average particle size of the saccharide is 1-100 .mu.m,
preferably 5-70 .mu.m or, more preferably, 5-50 .mu.m.
[0042] The intraoral quickly disintegrating tablet of the present
invention may be compounded with a binder if necessary.
[0043] Examples of the binder are polyvinylpyrrolidone, Macrogol,
hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, carboxymethycellulose sodium,
cellulose acetate phthalate, gum arabic, gelatin, methacrylic acid
copolymer, carboxyvinyl polymer, polyvinyl alcohol, alpha-starch
and pullulan. In the present invention, each of them may be used
solely or two or more thereof may be used jointly and the use of
polyvinylpyrrolidone is particularly preferred.
[0044] The compounding ratio of the binder in the present invention
to 1 part by weight of the tablet is usually 0.001-0.1 part by
weight or, preferably, 0.005-0.05 part by weight, and that may be
appropriately increased or decreased so as to give desired
disintegrating degree and hardness. Incidentally, the binder may be
added in its powdery form to a mixture of the cyclic GMP
phosphodiesterase inhibitor and the saccharide or may be added
after dissolving in the organic solvent, pure water or the aqueous
organic solvent.
[0045] The intraoral quickly disintegrating tablet according to the
present invention is a tablet which is quickly disintegrated in the
mouth after administration and is able to be easily taken even
without water. In addition to the above-mentioned saccharide and
binder, the intraoral quickly disintegrating tablet may be
compounded with conventionally used filler, lubricant,
disintegrating agent, sweetener and/or coloring agent if
necessary.
[0046] The intraoral quickly disintegrating tablet may be prepared
in such a manner that a saccharide and a binder are mixed with a
cyclic GMP phosphodiesterase inhibitor, then conventionally used
filler, lubricant, sweetener, coloring agent, disintegrating agent,
etc. are added thereto if necessary, kneaded with an organic
solvent, water or an aqueous organic solvent, filled in a mold and
subjected to a compression-molding. The kneading and granulating
operations carried out by adding such auxiliary agents for making
the preparation and by adding such a solvent may be conducted using
the conventionally used apparatus. For example, a fluidized bed
granulator, a tumbling granulator, an extrusion granulator or a
spray-drying drier may be used.
[0047] Examples of the filler are crystalline cellulose,
ethylcellulose, dextrin, various kinds of cyclodextrin
(.alpha.-cyclodextrin, .beta.-cyclodextrin and
.gamma.-cyclodextrin) as well as derivatives thereof and
pullulan.
[0048] Examples of the lubricant are magnesium stearate, calcium
stearate, stearic acid and talc; examples of the sweetener are
aspartame, dipotassium glycyrrhizinate, white sugar, licorice,
saccharin and sodium saccharinate; and examples of the coloring
agent are yellow iron sesquioxide, yellow iron oxide, Yellow #4 dye
for food, Yellow #5 dye for food, (Yellow #4 dye for food aluminum
lake), red iron oxide, iron sesquioxide, Red #2 dye for food, Red
#3 dye for food and Red #102 dye for food. In the present
invention, each of them may be used solely or two or more thereof
may be used jointly.
[0049] Examples of the disintegrating agent are light silicic
anhydride, crystalline cellulose, cross povidone, lowly substituted
hydroxypropyl cellulose, cross carmellose sodium, calcium silicate,
magnesium metasilicate aluminate, carboxymethyl cellulose,
carboxymethyl cellulose calcium, hydroxypropyl starch,
carboxymethyl starch sodium, partially .alpha.-starch and sodium
alginate. In the present invention, each of them may be used solely
or two or more thereof may be used jointly.
[0050] In the present invention, an intraoral quickly
disintegrating tablet may be manufactured in such a manner that a
cyclic GMP phosphodiesterase inhibitor is mixed with a saccharide,
a binder is further added thereto if necessary, the mixture is
kneaded with an organic solvent, water or an aqueous organic
solvent and the resulting wet powder is made into a form of a
tablet followed by drying.
[0051] In the present invention, an intraoral quickly
disintegrating tablet may be manufactured in such a manner that 1)
a slightly soluble pharmaceutical agent is dissolved in an organic
solvent together with a surfactant and/or a water-soluble polymer,
coated on a filler or granulated together with a filler, a
saccharide is mixed with the resulting granules, fine granules or
powder or that 2) a slightly soluble pharmaceutical agent is mixed
with a saccharide and a surfactant and/or a water-soluble polymer,
then a binder, a disintegrating agent, a lubricant, a sweetener or
a coloring agent is added thereto if necessary and the mixture is
kneaded with an organic solvent, water or an aqueous organic
solvent and, after that, any of the above-mentioned mixture is
filled in a mold followed by subjecting to a compression
molding.
[0052] Examples of the surfactant used here are sodium lauryl
sulfate, sorbitan fatty acid ester, polyethylene glycol fatty acid
ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
alkyl ether, polyoxyethylene polyoxypropylene alkyl ether,
polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene
alkyl phenyl ether, polyoxyethylene castor oil, polyoxyethylene
hydrogenated castor oil, polyoxyethylene sorbitol fatty acid ester
and polyoxyethylene glycerol fatty acid ester. In the present
invention, each of them may be used solely or two or more thereof
may be used jointly.
[0053] The compounding ratio of the surfactant in the present
invention to 1 part by weight of the slightly soluble
pharmaceutical agent is usually 0.0005-0.1 part by weight,
preferably 0.001-0.08 parts by weight or, more preferably,
0.001-0.05 parts by weight.
[0054] Examples of the water-soluble polymer are hydroxypropyl
methylcellulose, methylcellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, carboxymethyl cellulose sodium,
cellulose acetate phthalate, gum arabic, agar, gelatin, sodium
alginate, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer,
methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol
and Macrogol and, in the present invention, each of them may be
used solely or two or more thereof may be used jointly.
[0055] The compounding ratio of the slightly soluble pharmaceutical
agent to the water soluble polymer in the present invention is
usually 0.001-0.6 parts by weight or, preferably, 0.005-0.1 part by
weight of the water-soluble polymer to 1 part by weight of the
slightly soluble pharmaceutical agent.
[0056] Further, the concentration of the water soluble polymer in
the solution of the water soluble polymer is usually 0.1-40% by
weight or, preferably, 1-20% by weight.
[0057] The solution of the water soluble polymer may be any of an
aqueous solution, an organic solvent solution and an aqueous
organic solvent solution containing the above-mentioned water
soluble polymer.
[0058] The solvent which is used for the kneading stage in the
manufacturing process for the intraoral quickly disintegrating
tablet may be any of an organic solvent, pure water and an aqueous
organic solvent. Examples of the organic solvent or of that used
for the aqueous organic solvent are ethanol, methanol, propanol and
isopropanol and, preferably, ethanol. In the present invention, one
of them may be used solely or two or more of them may be used
jointly. The preferred compounding ratio of the organic solvent in
the aqueous organic solvent is usually 0.05-0.99 parts by weight,
more preferably 0.2-0.98 parts by weight or, further preferably,
0.25-0.98 parts by weight to 1 part by weight of the aqueous
organic solvent.
[0059] In the molding of the wet powder, a lubricant may be
applied, if necessary, on upper and lower sides of the kneaded
mixture filled therein whereby an adhesion during the compressing
step can be prevented but, for the manufacture in a more efficient
and easier manner, it is preferred to use a tablet manufacturing
apparatus which is disclosed in JP-A 8-19589. Thus, a wet powder is
filled in a mold for the tablet molding of the tablet manufacturing
apparatus and at least one surface of the wet powder in the mold is
molded via an adhesion-preventing film whereby an adhesion of the
wet powder to the metal mold for molding can be prevented and a
quickly disintegrating tablets are able to be manufactured in an
efficient manner.
[0060] The pressure applied upon the compression-molding of the wet
powder after kneading the mixture or upon tableting via an
adhesion-preventing film after filling in a mold in the present
invention is usually 2-150 kg/cm.sup.2, preferably 2-100
kg/cm.sup.2 or, more preferably, 3-50 kg/cm.sup.2.
[0061] The drying temperature after the compression-molding or the
tableting in the present invention is usually 15-80.degree. C.,
preferably 20-75.degree. C. or, more preferably, 30-70.degree.
C.
[0062] The tablet hardness of the intraoral quickly disintegrating
tablet prepared by the manufacturing method in accordance with the
present invention is usually 1-15 kg/cm.sup.2, preferably 1.5-10
kg/cm.sup.2 or, more preferably, 2-6 kg/cm.sup.2. Time for
disintegration in the mouth of the intraoral quickly disintegrating
tablet is usually 0.05-3 minute(s), preferably 0.05-1 minute or,
more preferably, 0.1-0.5 minute.
[0063] The water content in the wet powder which is kneaded in the
present invention is 0.01-25% by weight, preferably 0.1-20% by
weight or, more preferably, 0.1-15% by weight of the kneaded
mixture.
[0064] The intraoral quickly disintegrating tablet according to the
present invention may, for example, be manufactured as follows.
Thus, 75 g of sildenafil having the formula (I) which is a cyclic
GMP phosphodiesterase inhibitor and 340.8 g of mannitol were well
mixed in a mixer. To this mixture was added an aqueous ethanol
solution where 4.2 g of polyvinylpyrrolidone K 30 were dissolved in
58.8 g of a 55% ethanol solution followed by kneading for about 3
minutes. After that, the kneaded mixture was subjected to a
compression-molding using, for example, a tablet manufacturing
apparatus disclosed in JP-A 8-19589 by filling in a mold via a film
with a pestle having a diameter of 9.5 mm with a compressing
pressure of 35 kg/cm.sup.2. The molded product was dried in a drier
of 50.degree. C. for about 2 hours to manufacture intraoral quickly
disintegrating tablets where each tablet (280 mg) contains 50 mg of
sildenafil.
[0065] Alternatively, 1.5 g of
4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-
-(4-hydroxypiperazino)-phthalazine hydrochloride having the formula
(IX) which is a slightly soluble cyclic GMP phosphodiesterase
inhibitor and 0.015 g of sodium lauryl sulfate were dissolved in
100 g of a 70% ethanol solution heated at 70.degree. C. After that,
40.08 g of mannitol were added thereto and the mixture was well
mixed in a mixer, followed by drying to give a powder. To this
powder is added an aqueous ethanol solution where 0.42 g of
polyvinylpyrrolidone K30 is dissolved in 5.88 g of a 55% ethanol
solution, and the mixture is kneaded for about 1 minute. Then the
kneaded mixture is subjected to a compression-molding using a
compression tester (Shimadzu Autograph) with a compressing pressure
of 35 kg/cm.sup.2 using a pestle having a diameter of 9.5 mm. The
molded product is dried in a drier of 50.degree. C. for about 2
hours to manufacture the tablets where each tablet (280 mg)
contains 10 mg of the phthalazine compound having the formula
(IX).
[0066] In accordance with the present invention, it is possible to
manufacture an intraoral quickly disintegrating tablet which
contains a cyclic GMP phosphodiesterase inhibitor having an
improving effect for erectile dysfunction and has quick
disintegrating property, solubility and appropriate strength in the
mouth.
[0067] In accordance with the present invention, it is also
possible to manufacture an intraoral quickly disintegrating tablet
containing a slightly soluble pharmaceutical agent, being
characterized in a quick dissolving in the mouth and having an
appropriate strength.
[0068] Examples of the such effects will be shown as hereunder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0069] FIG. 1 is a graph showing the changes of the eluting rate in
the first solution as regulated by the Japanese Pharmacopoeia
concerning the phthalazine compound per se having the formula (IX)
and the intraoral quickly disintegrating tablet containing the
phthalazine compound.
[0070] FIG. 2 is a graph showing the changes of the eluting rate in
the second solution as regulated by the Japanese Pharmacopoeia
concerning the phthalazine compound per se having the formula (IX)
and the intraoral quickly disintegrating tablet containing the
phthalazine compound.
[0071] FIG. 3 is a graph showing the changes of the eluting rate in
pure water concerning the phthalazine compound per se having the
formula (IX) and the intraoral quickly disintegrating tablet
containing the phthalazine compound.
[0072] FIG. 4 is a graph showing the changes of the eluting rate in
pure water concerning the intraoral quickly disintegrating tablet
containing the phthalazine compound having the formula (X) and the
tablet which is prepared by the conventional manufacturing
method.
EXPERIMENTAL EXAMPLES
[0073] 1) Good Physical Property of the Tablets Concerning the
Present Invention
[0074] In a mixer, 1.5 g of a phthalazine compound having the
formula (IX)
{4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)-phthal-
azine hydrochloride} and 40.08 g of mannitol were well mixed, an
aqueous ethanol solution where 0.42 g of polyvinylpyrrolidone K 30
was dissolved in 5.88 g of a 55% ethanol solution was added and the
mixture was kneaded for about 1 minute. The kneaded mixture was
molded using a compression tester (Shimadzu Autograph) with a
compressing pressure of 50 kg/cm.sup.2 using a pestle having a
diameter of 9.5 mm which was previously covered with a small amount
of magnesium stearate. The molded product was dried in a drier of
60.degree. C. for about 3 hours to manufacture the tablets where
each tablet (280 mg) contained 10 mg of the phthalazine compound
having the formula (IX).
[0075] When the physical property of the tablets was evaluated, the
tablet hardness was 5.59 kg/cm.sup.2 (mean value of five tablets)
and the disintegrating time of the tablet was within 15 seconds
and, therefore, it is apparent that the tablets have a good
physical property as intraoral quickly disintegrating tablets.
[0076] Each one of the above tablets was subjected to an eluting
test in each 900 ml of the first liquid (pH 1.2), the second liquid
(pH 6.8) and pure water as regulated by the Disintegration Test
Method of the Japanese Pharmacopoeia according to a puddle method
(50 r.p.m.) of the Disintegration Test Method of the Japanese
Pharmacopoeia using 10 mg of the phthalazine compound per se having
the formula (IX) as a control. Incidentally, the eluted amount of
the phthalazine compound having the formula (IX) was measured by
means of a high-performance liquid chromatography using an
ultraviolet absorptiometer (measured wave length=215 nm). Results
of the eluting test are shown in FIGS. 1-3.
[0077] From FIGS. 1-3, it is apparent that the intraoral quickly
disintegrating tablet containing a cyclic GMP phosphodiesterase
inhibitor according to the present invention shows quicker and
better eluting characteristic as compared with the sole use of the
agent per se.
[0078] 2) Good Solubility of the Tablet According to the Present
Invention Containing a Slightly Soluble Pharmaceutical Agent
[0079]
4-(3-Chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxypiperidino-
)phthalazine hydrochloride having the formula (X) has a very slight
solubility and its absorption in vivo is worried about.
[0080] Therefore, a pharmaceutical preparation where the solubility
of the phthalazine compound having the formula (X) was improved was
manufactured.
[0081] Thus, 16 g of the phthalazine compound having the formula
(X) and 1.6 g of sodium lauryl sulfate were dissolved in 1000 g of
a 55% ethanol solution heated at 60.degree. C. (step A).
Separately, a mixture of 198.4 g of mannitol and 8 g of light
silicic anhydride was subjected to a disintegration mixing using a
sample mill (step B). Then the mixed powder obtained in the step B
was subjected to a fluidized bed granulation using the solution
obtained in the step A to prepare granules, fine granules or
powder. Incidentally, temperatures of the sucking and exhausting
air during the fluidized bed granulation were set at 70.degree. C.
and 50.degree. C., respectively.
[0082] After that, 21 g of the granules, fine granules or powder
containing the phthalazine compound having the formula (X) were/was
well mixed with 20.6 g of mannitol in a mixer, an aqueous ethanol
solution where 0.42 g of polyvinylpyrrolidone K 30 was dissolved in
5.88 g of a 25% ethanol solution was added and the mixture was
kneaded for about 1 minute. The kneaded mixture was molded using a
compression tester (Shimadzu Autograph) with a compressing pressure
of 28.5 kg/cm.sup.2 using a pestle having a diameter of 9.5 mm
which was previously covered with a small amount of magnesium
stearate.
[0083] The molded product was dried in a drier of 60.degree. C. for
about 3 hours to manufacture the tablets where each tablet (280 mg)
contained 10 mg of the phthalazine compound having the formula
(X).
[0084] When the physical property of the tablets was evaluated, the
tablet hardness was 5.53 kg/cm.sup.2 (mean value of six tablets)
and the disintegrating time of the tablet was 18.2 seconds (mean
value of six tablets) and, therefore, it is apparent that the
tablets have a good physical property as intraoral quickly
disintegrating tablets.
[0085] One of the above tablets was subjected to an eluting test in
900 ml of the first solution (pH 1.2) as regulated by the
Disintegration Test Method of the Japanese Pharmacopoeia using a
tablet containing 10 mg of the phthalazine compound per se having
the formula (X) as a control and the eluting rate was evaluated
using an ultraviolet absorptiometer (measured wave length=240 nm).
Result of the eluting test is shown in FIG. 4.
[0086] Incidentally, the preparation which was prepared by the
conventional manufacturing method and used as a control was
prepared according to the following method.
[0087] Thus, 10 g of the phthalazine compound having the formula
(x), 85.3 g of lactose and 20 g of corn starch were mixed and
subjected to a granulation by a tumbling granulator together with a
gradual addition of a 7% aqueous solution of polyvinylpyrrolidone K
30 where 7 g of polyvinylpyrrolidone K 30 were dissolved whereupon
a granulated product was obtained. This granulated product was
dried at 60.degree. C. for 20 hours and sieved through a sieve of
24 mesh where 122 g of a sieved product was obtained, 7 g of cross
carmellose sodium and 0.7 g of magnesium stearate were added
thereto and the mixture was made into tablets using a pelletizer by
a pestle having a diameter of 7 mm with a compressing pressure of
600 kg/cm.sup.2 to manufacture the conventional tablets where each
tablet (130 mg) contained 10 mg of the phthalazine compound having
the formula (X).
[0088] As shown in FIG. 4, the intraoral quickly disintegrating
tablet containing the phthalazine compound having the formula (X)
showed a significantly quicker eluting characteristic as compared
with the preparation which was prepared by the conventional
manufacturing method. In general, preparations having a good
solubility show little dispersion in an absorbing property and, in
addition, a higher bioavailability is often achieved. It is
apparent that the intraoral quickly disintegrating tablet in
accordance with the present invention shows a better solubility
than the preparation which was prepared by the conventional
manufacturing methods.
EXAMPLES
[0089] The present invention will now be further illustrated by way
of the following Examples although the present invention is not
limited thereto.
Example 1
[0090] In a mixer, 50 g of sildenafil which is a cyclic GMP
phosphodiesterase inhibitor having a formula (III) and 228 g of
mannitol were well mixed. To this mixture was added an aqueous
ethanol solution where 2 g of polyvinylpyrrolidone K 30 was
dissolved in 15 g of a 5% ethanol solution, followed by kneading
for about 3 minutes. The resulting kneaded wet powder was subjected
to a compression-molding by a method mentioned in JP-A 8-19589 (the
kneaded mixture was filled in a mold for the tablet molding of the
pelletizer and at least one surface of the wet powder in the
above-mentioned mold was molded into a tablet by a metal mold for
the molding via an adhesion preventing film), to manufacture
tablets where each tablet contained 50 mg of sildenafil.
[0091] Hardness of the tablet was about 5 kg/cm.sup.2 and the
disintegrating time thereof in pure water was within 15
seconds.
Example 2
[0092] To 280 g of the kneaded mixture obtained in Example 1 were
added 1.4 g of a lowly-substituted hydroxypropyl cellulose and 0.1
g of magnesium stearate, followed by mixing. The mixture was
subjected to tableting by the same method as in Example 1, to give
tablets where each tablet contained 50 mg of sildenafil.
Example 3
[0093] In a mixer, 10 g of a phthalazine compound having the
formula (IX)
{4-(3-chloro-4-methoxybenzyl)-amino-6-cyano-1-(4-hydroxypiperidino)phthal-
azine hydrochloride}, 267 g of mannitol and 3 g of
polyvinylpyrrolidone K 30 were well mixed. To this mixture were
added 40 g of 25% ethanol, followed by kneading for about 1 minute.
The resulting kneaded mixture was subjected to the same operation
as in Example 1 via an adhesion preventing film, to manufacture
tablets where each tablet contained 10 mg of the phthalazine
compound having the formula (IX).
Example 4
[0094] Into 6000 g of a 25% ethanol solution heated at 50.degree.
C. were dissolved 100 g of the phthalazine compound having the
formula (X) and 15 g of polyoxyethylene hydrogenated castor oil
(step A). Separately, a mixture of 1240 g of mannitol and 100 g of
light silicic anhydride was disintegrated and mixed using a hammer
mill (step B). Next, the mixed powder obtained in the step B was
subjected to a tumbling granulation using a solution prepared in
the step A to prepare granules, fine granules or powder. In a
mixer, 147 g of the granules, the fine granules or the powder
prepared as such and 130 g of mannitol were well mixed, a 55%
ethanol solution where 3 g of hydroxypropyl methylcellulose were
dissolved therein was added and the mixture was kneaded for about 3
minutes. The kneaded mixture was molded by a means mentioned in
JP-A 8-19589 (the kneaded mixture was filled in a mold for the
tablet molding of the pelletizer and at least one surface of the
wet powder in the above-mentioned mold was molded into a tablet by
a metal mold for the molding via an adhesion preventing film) using
a pestle having a diameter of 9.5 mm and with a compressing
pressure of 45 kg/cm.sup.2.
* * * * *