U.S. patent application number 16/432091 was filed with the patent office on 2020-01-02 for solid preparation.
The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Wataru HOSHINA, Yutaka NISHIMOTO, Yukihiro NOMURA, Ikuro YAMANE.
Application Number | 20200000730 16/432091 |
Document ID | / |
Family ID | 56789547 |
Filed Date | 2020-01-02 |
United States Patent
Application |
20200000730 |
Kind Code |
A1 |
YAMANE; Ikuro ; et
al. |
January 2, 2020 |
SOLID PREPARATION
Abstract
Provided is a solid preparation showing improved stability of
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea and a salt thereof in the solid preparation, and a
method of stabilizing the compound in a solid preparation. A tablet
containing not less than 25 mass % of the compound; a solid
preparation containing (1) the compound, and (2) a fat and oil-like
substance having a low melting point, which is selected from
polyethylene glycol, glycerol monostearate and triethyl citrate; a
method of stabilizing the compound in a tablet, including adding
not less than 25 mass % of the compound; and a method of
stabilizing the compound, including adding a fat and oil-like
substance having a low melting point, which is selected from
polyethylene glycol, glycerol monostearate and triethyl citrate to
a solid preparation containing the compound.
Inventors: |
YAMANE; Ikuro; (Osaka,
JP) ; NOMURA; Yukihiro; (Osaka, JP) ;
NISHIMOTO; Yutaka; (Osaka, JP) ; HOSHINA; Wataru;
(Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Family ID: |
56789547 |
Appl. No.: |
16/432091 |
Filed: |
June 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15553852 |
Aug 25, 2017 |
10350170 |
|
|
PCT/JP2016/055540 |
Feb 25, 2016 |
|
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16432091 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 9/2018 20130101; A61K 31/519 20130101; A61K 47/10 20130101;
A61K 9/20 20130101; A61K 47/34 20130101; A61K 9/2054 20130101; A61K
9/2031 20130101; A61K 9/2886 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14; A61K 47/34 20060101 A61K047/34; A61K 31/519 20060101
A61K031/519; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2015 |
JP |
2015-037462 |
Claims
1-6. (canceled)
7. A tablet comprising (1)
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof and (2) a fat and oil-like
substance having a low melting point, which is selected from
polyethylene glycol and glycerol monostearate, wherein the tablet
comprises 0.1-10 mass % of the fat and oil-like substance having a
low melting point.
8-12. (canceled)
13. The tablet according to claim 7, wherein the tablet comprises
0.2-1.7 mass % of the fat and oil-like substance having a low
melting point, and wherein the fat and oil-like substance having a
low melting point is polyethylene glycol.
14. The tablet according to claim 13, wherein the tablet comprises
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in an amount of 80 mg measured
based on free form
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-met-
hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y-
l)phenyl)-N'-methoxyurea, 157.2 mg of D-mannitol, 20 mg of
crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg of
polyethylene glycol 6000, 12.7 mg of croscarmellose sodium, and 2.5
mg of magnesium stearate.
15. The tablet according to claim 13, wherein the tablet comprises
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in an amount of 80 mg measured
based on free form
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-met-
hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y-
l)phenyl)-N'-methoxyurea, 157.2 mg of D-mannitol, 20 mg of
crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg
polyethylene glycol with an average molecular weight of 100000,
12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium
stearate.
16. The tablet according to claim 7, wherein the tablet comprises
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in an amount of 80 mg measured
based on free form
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-met-
hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y-
l)phenyl)-N'-methoxyurea, 147.2 mg of D-mannitol, 20 mg of
crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 10 mg of
glycerol monostearate, 12.7 mg of croscarmellose sodium, and 2.5 mg
of magnesium stearate.
17. The tablet according to claim 16, further comprising a
film-coating, wherein the film-coating comprises hypromellose,
titanium oxide, red ferric oxide, and yellow ferric oxide.
18. The tablet according to claim 16, further comprising a
film-coating, wherein the film-coating comprises 9.06 mg of
hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric
oxide, and 0.077 mg yellow ferric oxide.
19. The tablet according to claim 13, wherein the tablet comprises
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in an amount of 80 mg measured
based on free form
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-met-
hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y-
l)phenyl)-N'-methoxyurea, 156 mg of D-mannitol, 20 mg of
crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 1.2 mg of
polyethylene glycol 6000, 12.7 mg of croscarmellose sodium, and 2.5
mg of magnesium stearate.
20. The tablet according to claim 19, further comprising a
film-coating, wherein the film-coating comprises hypromellose,
titanium oxide, red ferric oxide, and yellow ferric oxide.
21. The tablet according to claim 19, further comprising a
film-coating, wherein the film-coating comprises 9.06 mg of
hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric
oxide, and 0.077 mg yellow ferric oxide.
22. The tablet according to claim 13, wherein the tablet comprises
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in an amount of 80 mg measured
based on free form
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-met-
hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y-
l)phenyl)-N'-methoxyurea, 152.4 mg of D-mannitol, 20 mg of
crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg of
polyethylene glycol 400, 12.7 mg of croscarmellose sodium, and 2.5
mg of magnesium stearate.
23. The tablet according to claim 22, further comprising a
film-coating, wherein the film-coating comprises hypromellose,
titanium oxide, red ferric oxide, and yellow ferric oxide.
24. The tablet according to claim 22, further comprising a
film-coating, wherein the film-coating comprises 9.06 mg of
hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric
oxide, and 0.077 mg yellow ferric oxide.
Description
TECHNICAL FIELD
[0001] The present invention relates to a solid preparation (e.g.,
tablet) showing improved stability of
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea (to be also referred to as compound A in the present
specification) and a salt thereof in the solid preparation, and a
method of stabilizing compound A and a salt thereof in a solid
preparation.
BACKGROUND ART
[0002] Patent document 1 discloses that a compound represented by a
formula and a salt thereof, encompassing compound A and a salt
thereof, have a superior gonadotropic hormone-releasing hormone
antagonistic action and can be used, for example, as a prophylactic
or therapeutic agent for hormone dependent diseases, together with
the production method of the compound.
[0003] Patent document 2 discloses a preparation containing a
compound represented by the above-mentioned formula and a salt
thereof, which characteristically contains an organic acid and
shows improved oral absorbability.
DOCUMENT LIST
Patent Documents
[0004] [patent document 1] WO 2004/067535
[0005] [patent document 2] WO 2010/026993
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0006] While compound A and a salt thereof are stable to
temperature, humidity and the like when they are alone and in a
solid state, the present inventors have found a problem that a
decomposed product of compound A or a salt thereof increases
chronologically when compound A or a salt thereof is formulated as
a solid preparation (e.g., tablet) according to a preparation
formulation containing other components.
[0007] The present invention aims to solve such newly-found
problem, and the present invention aims to provide a solid
preparation (e.g., tablet) showing improved stability of compound A
and a salt thereof in the solid preparation, and a method of
stabilizing compound A and a salt thereof in a solid
preparation.
Means of Solving the Problems
[0008] As a result of intensive studies conducted in an attempt to
solve the aforementioned problems, the present inventors have found
that chronological decomposition of compound A and a salt thereof
in a tablet is suppressed by setting the content of compound A and
a salt thereof in the tablet to not less than 25 mass %; in other
word's, that compound A and a salt thereof in a tablet are
stabilized.
[0009] In addition, as a result of intensive studies conducted in
an attempt to solve the aforementioned problems, the present
inventors have found that chronological decomposition of compound A
and a salt thereof in a solid preparation is suppressed by adding a
fat and oil-like substance having a low melting point, which is
selected from polyethylene glycol, glycerol monostearate and
triethyl citrate, to a solid preparation (e.g., tablet); in other
words, that compound A and a salt thereof in a solid preparation
are stabilized.
[0010] Based on the above-mentioned finding, the present inventors
have further conducted intensive studies and completed the present
invention.
[0011] That is, the present invention provides the following.
[1] A tablet comprising not less than 25 mass % of N-(4-(1-(2,
6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyu-
rea or a salt thereof. [2] The tablet of the above-mentioned [1],
comprising D-mannitol particles having an average particle size of
60-500 .mu.m. [3] The tablet of the above-mentioned [1], comprising
D-mannitol particles having an average particle size of 60-250
.mu.m. [4] A method of stabilizing
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof in a tablet, comprising adding not
less than 25 mass % of
N-(4-(1-(2,6-difluorobonzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof. [5] The method of the
above-mentioned [4], further comprising adding D-mannitol particles
having an average particle size of 60-500.mu.m. [6] The method of
the above-mentioned [4], further comprising adding D-mannitol
particles having an average particle size of 60-250 .mu.m. [7] A
solid preparation comprising (1)
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof and (2) a fat and oil-like
substance having a low melting point, which is selected from
polyethylene glycol, glycerol monostearate and triethyl citrate.
[8] The solid preparation of the above-mentioned [7], wherein the
fat and oil-like substance having a low melting point, is
polyethylene glycol. [9] The solid preparation of the
above-mentioned [7], wherein the fat and oil-like substance having
a low melting point is polyethylene glycol having an average
molecular weight of about 6000 to about 120000. [10] A method of
stabilizing
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof, comprising adding a fat and
oil-like substance having a low melting point, which is selected
from polyethylene glycol, glycerol monostearate and triethyl
citrate to a solid preparation comprising
N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr-
idazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)--
N'-methoxyurea or a salt thereof. [11] The method of the
above-mentioned [10], wherein the fat and oil-like substance having
a low melting point is polyethylene glycol. [12] The method of the
above-mentioned [10], wherein the fat and oil-like substance having
a low melting point is polyethylene glycol having an average
molecular weight of about 6000 to about 120000.
Effect of the Invention
[0012] According to the present invention, a solid preparation
(e.g., tablet) showing improved stability of compound A and a salt
thereof in the solid preparation, and a method of stabilizing
compound A and a salt thereof in a solid preparation can be
provided.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention is explained in detail below.
[0014] As a salt of compound A, a physiologically acceptable acid
addition salt is preferable. As such salt, salt with inorganic acid
(e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, phosphoric acid), salt with organic acid (e.g., formic acid,
acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid)
and the like are used.
1. Tablet Containing Compound A or a Salt Thereof at a High
Content
[0015] In one embodiment, the present invention relates to a tablet
containing compound A or a salt thereof at a high content,
specifically, a tablet containing compound A or a salt thereof at
not less than 25 mass % (preferably not less than 35 mass %, more
preferably not less than 40 mass %) (hereinafter sometimes to be
abbreviated as the tablet of the present invention).
[0016] In the tablet of the present invention, the content of
compound A or a salt thereof is, for example, not more than 80 mass
% (preferably not more than 75 mass %).
[0017] Since the tablet of the present invention contains not less
than 25 mass % (preferably not less than 35 mass %, more preferably
not less than 40 mass %) of compound A or a salt thereof, it can
improve the stability of compound A and a salt thereof in the
tablet as compared to a tablet containing compound A or a salt
thereof at a low content e.g., less than 25 mass %). In addition,
since the tablet of the present invention contains compound A or a
salt thereof at a high content, the tablet can be downsized, which
in turn is expected to provide an improving effect on the dosing
compliance of the patients.
[0018] The present inventors have found that a tablet containing
compound A or a salt thereof at a high content (preferably not less
than 25 mass %, preferably not less than 30 mass %, More preferably
not less than 35 mass %, further preferably not less than 40 mass
%) can be obtained by adding D-mannitol particles having an average
particle size of 60-500 .mu.m (more preferably 60-250 .mu.m,
further preferably 70-200 .mu.m, particularly preferably 80-150
.mu.m) as an excipient to the tablet containing compound A or a
salt thereof. In the present specification, the average particle
size refers to a value generally called a median diameter, which
corresponds to 50% of the cumulative distribution (volume
distribution) of powder particles. The average particle size can be
measured by a particle laser diffraction particle size analyzer
(HELOS system and RODOS dispersing unit, Sympatech) at a dispersing
pressure of 2.0 bar.
[0019] D-mannitol particles having an average particle size within
the above-mentioned range can be produced by a method known per se,
and is not particularly limited. For example, it can be produced by
a spray dry production method. As a D-mannitol particles having an
average particle size within the above-mentioned range, a
commercially available product (e.g., PEARLITOL 100SD, PEARLITOL
200SD, PEARLITOL 300DC, PEARLITOL 400DC, all by ROQUETTE) can also
be used. As the above-mentioned D-mannitol particles, D-mannitol
particles having an average particle size of 75-150 .mu.m (e.g.,
PEARLITOL 100SD) are preferable.
[0020] In the tablet of the present invention, the content of
D-mannitol particles is preferably 10-75 mass %, more preferably
12-70 mass %, further preferably 15-65 mass %, further more
preferably 15-60 mass %.
[0021] The tablet of the present invention may further contain
additives conventionally used in the pharmaceutical field. Examples
of the additive include excipient, binder, disintegrant, lubricant,
colorant, pH adjuster, surfactant, sweetener, flavor, coating base,
and coating additive. Unless particularly indicated, these
additives are used in amounts conventionally employed in the
pharmaceutical field.
[0022] Examples of the excipient include mannitol (e.g., D-mannitol
{e.g., PEARLITOL 50C (trade name); ROQUETTE}); crystalline
cellulose; starches such as corn starch, potato starch, wheat
starch, rice starch, partly pregelatinized starch, pregelatinized
starch, porous starch and the like; anhydrous calcium phosphate;
precipitated calcium carbonate; and calcium silicate, with
preference given to D-mannitol and crystalline cellulose.
[0023] In the tablet of the present invention, the content of the
excipient is preferably 10-75 mass %, more preferably 20-65 mass
%.
[0024] As the excipient in the present invention, D-mannitol
particle or mannitol (e.g., D-mannitol) is preferable, and
D-mannitol particle is more preferable. D-mannitol and D-mannitol
particle may be used alone or in combination.
[0025] When the aforementioned D-mannitol particles are used as an
excipient in the present invention, the total amount of the
excipient only needs to fall within the above-mentioned range.
[0026] When the aforementioned mannitol is used as the excipient in
the present invention, the total amount of the excipient is
preferably 10-75 mass %, more preferably 12-70 mass %, further
preferably 15-65 mass %, further more preferably 15-60 mass %.
[0027] Examples of the binder include crystalline cellulose [e.g.,
crystalline cellulose {e.g., CEOLUS KG-802 (grade: KG-802) (trade
name); CEOLUS PH-302 (grade: PH-302) (trade name); Asahi Kasei
Chemicals Corporation}, crystalline cellulose (particles),
crystalline cellulose (fine particles)], hydroxypropylcellulose
[e.g., grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.],
hydroxypropylmethylcellulose [e.g., hypromellose 2910, TC-5 (grade:
MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.],
povidone (polyvinylpyrrolidone), and copolyvidone, with preference
given to hydroxypropylcellulose.
[0028] In the tablet of the present invention, the content of the
binder is preferably 0.5-20 mass %, more preferably 1-10 mass
%.
[0029] Examples of the disintegrant include corn starch,
carboxymethylcellulose, calcium carboxymethylcellulose, sodium
carboxymethyl starch, croscarmellose sodium (e.g., Ac-Di-Sol),
crospovidone, low-substituted hydroxypropylcellulose (L-HPC),
hydroxypropylstarch, sodium starch glycolate, and magnesium alumino
metasilicate, with preference given to croscarmellose sodium and
sodium starch glycolate.
[0030] In the tablet of the present invention, the content of the
disintegrant is preferably 1-20 mass %, more preferably 2-10 mass
%.
[0031] Examples of the lubricant include magnesium stearate,
calcium stearate, talc, sucrose esters of fatty acids, and sodium
stearyl fumarate, with preference given to magnesium stearate.
[0032] In the tablet of the present invention, the content of the
lubricant is preferably 0.1-5 mass %, more preferably 0.2-3 mass
%.
[0033] Examples of the colorant include food colors such as Food
Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 and
the like, food lake colors, red ferric oxide, and yellow ferric
oxide.
[0034] Examples of the pH adjuster include citric acid or a salt
thereof, phosphoric acid or a salt thereof, carbonic acid or a salt
thereof, tartaric acid or a salt thereof, fumaric acid or a salt
thereof, acetid acid or a salt thereof, and amino acid or a salt
thereof.
[0035] Examples of the surfactant include sodium lauryl sulfate,
polysorbate 80, and
polyoxyethylene(160)polyoxypropylene(30)glycol.
[0036] Examples of the sweetener include aspartame (trade name),
acesulfame potassium, sucralose, thaumatin, saccharin sodium, and
dipotassium glycyrrhizinate.
[0037] Examples of the flavor include menthol, peppermint oil,
lemon oil, and vanillin.
[0038] Examples of the coating base include sugar coating base,
water-soluble film coating base, enteric film coating base, and
sustained-release film coating base.
[0039] Examples of the sugar coating base include sucrose, and one
or more kinds selected from talc, precipitated calcium carbonate,
gelatin, gum arabic, pullulan, carnauba wax and the like may be
used in combination.
[0040] Examples of the water-soluble film coating base include
cellulose polymers such as hydroxypropylcellulose [e.g., grade: L,
SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.],
hydroxypropylmethylcellulose [e.g., hypromellose 2910, TC-5 (grade:
MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.],
hydroxyethylcellulose, methylhydroxyethylcellulose and the like;
synthetic polymers such as polyvinyl acetaldiethylaminoacetate,
aminoalkylmethacrylate copolymer E [Eudragit E (trade name)],
polyvinylpyrrolidone and the like; and polysaccharides such as
pullulan and the like.
[0041] Examples of the enteric film coating base include cellulose
polymers such as hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate,
carboxymethylethylcellulose, cellulose acetate phthalate and the
like; acrylic acid polymers such as methacrylic acid copolymer L
[Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit
L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S
(trade name)] and the like; and naturally-occurring substances such
as shellac and the like.
[0042] Examples of the sustained-release film coating base include
cellulose polymers such as ethylcellulose and the like; acrylic
acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit
RS (trade name)], ethyl acrylate-methyl methatrylate copolymer
suspension [Eudragit NE (trade name)] and the like.
[0043] Examples of the coating additive include light shielding
agents such as titanium oxide and the like; fluidizers such as talc
and the like; colorants such as red ferric oxide, yellow ferric
oxide and the like; plasticizers such as polyethylene glycol (e.g.,
macrogol 6000), triethyl citrate, castor oil, polysorbates and the
like; organic acids such as citric acid, tartaric acid, malic acid,
ascorbic acid and the like.
[0044] Two or more kinds of the above-mentioned additives may be
used as a mixture at an appropriate ratio.
[0045] The tablet of the present invention may be film coated for
the purpose of improving easy administrability, hardness and the
like. Examples of the coating base and coating additive to be used
for the film coating include those similar to the ones used for the
aforementioned additive.
[0046] When the tablet of the present invention is film-coated, the
film coating layer is formed in a proportion of generally 1-10
parts by mass, preferably 2-6, parts by mass, per 100 parts by mass
of the tablet.
[0047] When the tablet of the present invention a film-coated
tablet, the contents of compound A or a salt thereof and an
additive in a core tablet before applying film coating are
preferably within the aforementioned ranges.
[0048] The tablet of the present invention is preferably a tablet
containing compound A or a salt thereof, an excipient (e.g.,
D-mannitol particles, D-mannitol, preferably D-mannitol particles),
a disintegrant (e.g., sodium starch glycolate), a binder (e.g.,
hydroxypropylcellulose), and a lubricant (e.g., magnesium
stearate), wherein the content of compound A or a salt thereof is
not less than 25 mass % (preferably not less than 30 mass %, more
preferably not less than 35 mass %, further preferably not less
than 40 mass %).
[0049] In addition, the tablet of the present invention is
preferably a film-coated tablet wherein a tablet (core tablet)
containing compound A or a salt thereof, an excipient (e.g.,
D-mannitol particles), a disintegrant (e.g., sodium starch
glycolate), a binder (e.g., hydroxypropylcellulose), and a
lubricant (e.g., magnesium stearate) is coated with a coating base
(e.g., hydroxypropylmethylcellulose) and a coating additive (e.g.,
titanium oxide, red ferric oxide), and the content of compound A or
a salt thereof is not less than 25 mass % (preferably not less than
30 mass %, more preferably not less than 35 mass %, further
preferably not less than 40 mass %) relative to the core
tablet.
[0050] The tablet of the present invention preferably further
contains a fat and oil-like substance having a low melting point,
which is selected from polyethylene glycol, glycerol monostearate
and triethyl citrate. When a fat and oil-like substance having a
low melting point is added to the tablet of the present invention,
the content etc. thereof are the same as those described below in
"2. Solid preparation containing compound A or a salt thereof and a
fat and oil-like substance having a low melting point".
[0051] The tablet of the present invention is produced by
appropriately combining operations such as granulation, mixing,
tableting (compression molding), coating and the like.
[0052] Granulation is performed using, for example, a granulation
machine such as a high shear granulator, a fluid bed granulator, a
dry granulator or the like.
[0053] Mixing is performed using, for example, a mixer such as a
V-type mixer, a tumbler mixer or the like.
[0054] Tableting (compression molding) is performed by punching
using, for example, a single punch tableting machine or a rotary
tableting machine.
[0055] Coating is performed using, for example, a film coating
apparatus. As the coating base here, those exemplified as the
aforementioned additive can be mentioned.
[0056] Two or more kinds of the above-mentioned coating base may be
used as a mixture at an appropriate ratio. Also, a coating additive
may be used during coating.
[0057] The tablet of the present invention can be produced, for
example, according to the following production steps. Each starting
material in the following production steps is used in such amount
as to achieve the aforementioned content in the finally obtained
tablet.
1) Compound A or a salt thereof, and an excipient (e.g., D-mannitol
particles, D-mannitol, crystalline cellulose, preferably D-mannitol
particles) are mixed together with other additive (e.g.,
disintegrant (e.g., sodium starch glycolate)) as necessary, the
mixture is granulated while spraying a solution obtained by
dissolving or dispersing a binder (e.g., hydroxypropylcellulose) in
a solvent or dispersing medium (e.g., water), dried and sieved as
necessary to give a granulated powder (or a sieved powder). 2) An
additive (e.g., lubricant (e.g., magnesium stearate)) is added to
the obtained granulated powder (or sieved powder) as necessary, and
they are mixed to give granules for tableting. 3) The granules are
tableted to give a core tablet. 4) A film coating solution is
sprayed on the obtained core tablet, when desired, to give a
film-coated tablet.
[0058] The present invention also relates to a stabilizing method
of the following compound A or a salt thereof.
[0059] One embodiment of the present invention relates to method of
stabilizing compound A or a salt thereof in a tablet, comprising
adding not less than 25 mass % (preferably not less than 30 mass %,
more preferably not less than 40 mass %) of compound A or a salt
thereof (hereinafter sometimes to be abbreviated as the method of
the present invention).
[0060] In the present specification, addition and containing mean
the same and, for example, adding not less than 25 mass % of
compound A or a salt thereof to a tablet means that the tablet
contains not less than 25 mass % of compound A or a salt
thereof.
[0061] In the method of the present invention, further addition of
(1) D-mannitol particles having an average particle size of 60-500
.mu.m (preferably 60-250 .mu.m, more preferably 70-200 .mu.m,
particularly preferably 80-150 .mu.m) or (2) D-mannitol having an
average particle size of 30-60 .mu.m (e.g., PEARLITOL 50C (trade
name); ROQUETTE)) is preferable, and addition of the
above-mentioned D-mannitol particles is more preferable. D-mannitol
and D-mannitol particles may be used alone or in combination.
[0062] The tablet by the method of the present invention is
prepared in the same manner as in the aforementioned formulation of
the tablet of the present invention. For example, the amount of the
D-mannitol particles or D-mannitol is analogous to that in the
tablet of the present invention.
[0063] The method of the present invention may include a step of
confirming the stabilizing effect (e.g., step of measuring the
content of a decomposed product (U-2) of compound A or a salt
thereof in the tablet etc.). The step of measuring the content of
the decomposed product can be performed according to, for example,
the below-mentioned Experimental Example 1.
2. Solid Preparation Containing Compound A or a Salt Thereof and A
Fat and Oil-Like Substance Having A Low Melting Point
[0064] Another embodiment of the present invention relates to a
solid preparation containing (1) compound A or a salt thereof, and
(2) a fat and oil-like substance having a low melting point, which
is selected from polyethylene glycol, glycerol monostearate and
triethyl citrate (hereinafter sometimes to be abbreviated as the
solid preparation of the present invention).
[0065] In the solid preparation of the present invention, the
content of compound A or a salt thereof is preferably not less than
4 mass % and less than 100 mass %, more preferably 4-80 mass %,
further preferably 18-50 mass %.
[0066] Since the solid preparation of the present invention
contains a fat and oil-like substance having a low melting point,
which is selected from polyethylene glycol, glycerol monostearate
and triethyl citrate, it can improve the stability of compound A
and a salt thereof in the solid preparation. These fat and oil-like
substances having a low melting point may be used alone or two or
more kinds thereof may be used in combination.
[0067] In the solid preparation of the present invention, the
content of a fat and oil-like substance having a low melting point,
which is selected from polyethylene glycol, glycerol monostearate
and triethyl citrate is, for example, 0.1-10 mass %.
[0068] While the preferable range of the above-mentioned content
varies depending on the kind of the fat and oil-like substance
having low melting point to be added to a solid preparation, for
example, when the-above-mentioned fat and oil-like substance having
a low melting point is polyethylene glycol (e.g., polyethylene
glycol 6000), it is, for example, 0.1-4.0 mass % (preferably
0.2-2.0 mass %, more preferably 0.2-1.7 mass %, further preferably
0.2-0.4 mass %). When, for example, the above-mentioned fat and
oil-like substance having a low melting point is glycerol
monostearate or triethyl citrate, it is 0.1-10 mass % (preferably,
1.0-4.0 mass %).
[0069] In the present invention, a fat and oil-like substance
having a low melting point is particularly preferably polyethylene
glycol.
[0070] Examples of the polyethylene glycol include polyethylene,
glycol haying an average molecular weight of 200-7000000
(preferably bout 6000--about 120000, more preferably about
8000--about 100000) (e.g., polyethylene glycol 400 (the Japanese
Pharmacopoeia), and polyethylene glycol 6000 (the Japanese
Pharmacopoeia)), POLYOX WSR N-10 (trade name), POLYOX WSR
N-205-(trade name), POLYOX WSR N-12K (trade name), POLYOX WSR 303
(trade name), preferably POLYOX WSR N-10 (trade name), polyethylene
glycol 6000, more preferably polyethylene glycol 6000) is
preferable. As used herein, polyethylene glycol is a generic term
of compounds represented by the formula
H(OCH.sub.2CH.sub.2).sub.nOH wherein n is a natural number
(compound wherein n is not less than 2000 is sometimes referred to
is polyethylene oxide).
[0071] Here, polyethylene glycol 6000 is also referred to as
macrogol 6000 in the Japanese Pharmacopoeia (an average molecular
weight thereof is generally said to be 7300-9300). In addition,
polyethylene glycol 6000 is referred to as polyethylene glycol 8000
in the NATIONAL FORMULARY.
[0072] In the present specification, the "average molecular weight"
in the explanation of polyethylene glycol means "number average
molecular weight".
[0073] These fat and oil-like substances having a low melting
point, which are in a solid form or a liquid form, are added to an
active ingredient (compound A or a salt thereof). The present
invention is more advantageously applied to a solid preparation
(granule, tablet and the like, preferably tablet) produced by
molding (granulation, compression molding and the like).
[0074] The solid preparation of the present invention is generally
produced by adding the above-mentioned fat and oil-like substance
having a low melting point to an active ingredient (compound A or a
salt thereof) and molding the mixture.
[0075] The addition is performed by an addition method generally
used for preparations, for example, mixing, kneading, screening,
stirring and the like. For example, a fat and oil-like substance
having a low melting point may be directly added to the active
ingredient and mixed, and a solvent may be further added and mixed
therewith, and the mixture can be kneaded, granulated and dried by
conventional methods.
[0076] It is also possible to dissolve a fat and oil-like substance
having a low melting point in suitable solvent, mix same with an
active ingredient, and knead, granulate and dry same by
conventional methods. Furthermore, a solution containing a fat and
oil-like substance having a low melting point and a solution
containing an active ingredient may be separately sprayed on a
powder of excipient and the like.
[0077] As the above-mentioned suitable solvent, a solvent that does
not adversely influence the active ingredient, for example, water,
dimethyl formamide, acetone, ethanol, propyl alcohol, isopropyl
alcohol, butyl alcohol, methylene chloride, and trichloroethane are
used.
[0078] After the completion of addition, a tablet can be produced
by a known compression molding means. Compression molding means
compressing under pressurization to give a desired form, which most
generally refers to, for example, tableting and the like.
[0079] The solid preparation of the present invention may further
contain an additive, conventionally used in the pharmaceutical
field. Example of the additive include excipient, binder,
disintegrant, lubricant, colorant, pH adjuster, surfactant,
sweetener, flavor, coating base, coating additive and the like.
Unless particularly indicated, these additives are used in amounts
conventionally employed in the pharmaceutical field.
[0080] Examples of these additives include those similar to the
additives, exemplified for the aforementioned tablet of the present
invention.
[0081] In the solid preparation of the present invention, the
excipient is preferably D-mannitol, D-mannitol particle or
crystalline cellulose, more preferably D-mannitol or crystalline
cellulose. The content of the excipient is preferably 10-70 mass %,
more preferably 16-64 mass %.
[0082] In the solid preparation of the present invention, the
binder is preferably hydroxypropylcellulose. The content of the
binder is preferably 0.5-20 mass %, more preferably 1-10 mass
%.
[0083] In the solid preparation of the-present invention, the
disintegrant is preferably croscarmellose sodium. The content of
the disintegrant is preferably 1-20 mass %, more preferably 2-10
mass %.
[0084] In the solid preparation of the present invention, the is
preferably magnesium stearate. The content of the lubricant is
preferably 0.1-3 mass %, more preferably 0.2-2 mass %.
[0085] The solid preparation of the present invention may be film
coated for the purpose of improving easy administrability, hardness
and the like. Examples of the coating base and coating additive to
be used for the film coating include those exemplified as the
aforementioned additive.
[0086] When the solid preparation of the present invention is
film-coated/ the film coating layer is formed in a proportion of
generally 1-10 parts by mass, preferably 2-6 parts by mass, per 100
parts by mass of the solid preparation.
[0087] When the solid preparation of the present invention is a
film-coated tablet, the contents of compound A or a salt thereof, a
fat and oil-like substance having a low melting point and an
additive in the core tablet before application of film coating are
preferably within the aforementioned ranges.
[0088] The solid preparation of the present invention is preferably
a tablet containing compound A or a salt thereof; a fat and
oil-like substance having a low melting point, which is selected
from polyethylene glycol, glycerol monostearate and triethyl
citrate; excipient (e.g., D-mannitol, crystalline cellulose); a
disintegrant (e.g., croscarmellose sodium); a binder (e.g.,
hydroxypropylcellulose); and a lubricant (e.g., magnesium
stearate).
[0089] The solid preparation of the present invention is preferably
a film-coated, tablet wherein a tablet (core tablet) containing
compound A or a salt thereof; a fat and oil-like substance having a
low melting point, which is selected from polyethylene glycol,
glycerol monostearate and triethyl citrate; an excipient (e.g.,
D-mannitol, crystalline cellulose); a disintegrant (e.g.,
croscarmellose sodium); a binder (e.g., hydroxypropylcellulose);
and a lubricant (e.g., magnesium stearate) is coated with a coating
base (e.g., hydroxypropylmethylcellulose) and a coating additive
(e.g., titanium oxide, red ferric oxide, yellow ferric oxide).
[0090] The solid preparation of the present invention is produced
by appropriately combining operations such as granulation, mixing,
tableting (compression molding), coating and the like. Granulation,
mixing, tableting (compression molding) and coating can be
performed according to the method and steps exemplified for the
aforementioned tablet of the present invention.
[0091] The solid preparation of the present invention can be
produced, for example, according to the following production steps.
Each starting material in the following production steps is used in
such amount as to achieve the aforementioned content in the finally
obtained solid preparation.
1) Compound A or a salt thereof, and an excipient (e.g.,
D-mannitol, crystalline cellulose) are mixed together with other
additives as necessary, the mixture is granulated while spraying a
solution obtained by dissolving or dispersing a binder (e.g.,
hydroxypropylcellulose) and a fat and oil-like substance having a
low melting point, which is selected from polyethylene glycol,
glycerol monostearate and triethyl citrate, in a solvent or
dispersing medium (e.g., water), dried and sieved as necessary to
give a granulated powder (or a sieved powder). 2) An additive
(e.g., lubricant (e.g., magnesium stearate), disintegrant (e.g.,
croscarmellose sodium)) is added to the obtained granulated powder
(or sieved powder) as necessary, and the mixture is mixed to give
granules for tableting. 3) The granules are tableted to give a core
tablet. 4) A film coating solution is sprayed on the obtained core
tablet, when desired, to give a film-coated tablet.
[0092] The aforementioned tablet of the present invention and the
solid preparation of the present invention (hereinafter these are
collectively referred to the solid preparation of the present
invention) have low toxicity and can be safely administered orally
to mammals (e.g., mouse, rat, rabbit, cat, dog, bovine, horse,
monkey, human).
[0093] The solid preparation of the present invention is, for
example, useful for the prophylaxis or treatment of
hormone-dependent diseases (e.g., prostate cancer) and the
like.
[0094] The dose of the solid preparation of the present invention
varies depending on the severity of symptoms; age, sex, body weight
and sensitivity of the administration subject; and timing,
frequency and the like of administration, and is not particularly
limited as long as the object of the present invention is achieved.
For example, when it is used as an oral preparation for the
treatment of the aforementioned hormone dependency diseases (e.g.,
prostate cancer), about 0.01-30 mg, preferably about 0.02-10 mg,
more preferably 0.1-10 mg, most preferably 0.5-10 mg, per 1 kg body
weight based on a free form of compound A, can be administered to a
mammal (e.g., human) in 1 to 4 portions per day.
[0095] The solid preparation of the present invention is preferably
a tablet and the size thereof varies depending on the shape of the
tablet (e.g., round, caplet, oblong etc.). It only needs to be a
size that can be easily taken by the patients.
[0096] As the solid preparation of the present invention, a tablet
containing 40-120 mg, preferably 80 mg or 120 mg, of compound A or
a salt thereof based on compound A (free form) per tablet can be
mentioned.
[0097] In the solid preparation of the present invention, compound
A or a salt thereof can also be used in combination with one or
more different kinds of medicaments.
[0098] In addition, the solid preparation of the present invention
preferably contains D-mannitol particles as an excipient. The
content etc. of the D-mannitol particles in the solid preparation
of the present invention are the same as those detailedly described
in "1. Tablet containing compound A or a salt thereof at a high
content".
[0099] Another embodiment of the present invention relates to a
method of stabilizing compound A or a salt thereof, comprising
adding a fat and oil-like substance having a low melting point,
which is selected from polyethylene glycol, glycerol monostearate
and triethyl citrate to a solid preparation containing compound A
or a salt thereof.
[0100] The order of addition of each component is not particularly
limited and, for example, as mentioned above, a fat and oil-like
substance having a low melting point may be directly added to an
active ingredient (compound A or a salt thereof) and mixed, and a
solvent may be further added and mixed therewith, and the mixture
can be kneaded, granulated and dried by conventional methods; a fat
and oil-like substance having a low melting point may be dissolved
in a suitable solvent, uniformly mixed with an active ingredient,
and kneaded, granulated and dried by conventional methods; or a
solution containing a fat and oil-like substance having a low
melting point and a solution containing an active ingredient may be
separately sprayed on a powder of excipient and the like. After the
completion of addition, a tablet can be produced by a known
compression molding means.
[0101] Specifically, for example, when the solid preparation is a
tablet, compound A or a salt thereof is granulated while spraying a
solution obtained by dissolving or dispersing a fat and oil-like
substance having a low melting point in a solvent or dispersion
medium (e.g., water), and dried to give a granulated powder, and
the obtained granulated powder is punched to give a tablet.
[0102] The solid preparation by the method is prepared in the same
manner as in the aforementioned formulation of the solid
preparation of the present invention. For example, the amounts of
the fat and oil-like substance having a low melting point, which is
selected from polyethylene glycol, glycerol monostearate and
triethyl citrate are analogous to those in the solid preparation of
the present invention.
[0103] This method may include a step of confirming a stabilizing
effect (e.g., step of measuring the content of decomposed product
(U-2) of compound A or a salt thereof in the solid preparation
etc.). The step of measuring the content of the decomposed product
can be performed, for example, according to the below-mentioned
Experimental Example 1.
EXAMPLES
[0104] The present invention is explained in more detail in the
following by referring to Examples, Comparative Examples,
Reference, Examples, and Experimental Examples, which are not to be
construed as limitative.
[0105] D-mannitol (PEARLITOL 50C (trade name), manufactured by
ROQUETTE), D-mannitol particles (PEARLITOL 100SD (trade name),
PEARLITOL 200SD (trade name), PEARLITOL 300DC (trade name) or
PEARLITOL 400DC (trade name), all manufactured by ROQUETTE),
crystalline cellulose (CEOLUS PH-101 or KG-802 (trade name),
manufactured by Asahi Kasei Chemicals Corporation),
hydroxypropylcellulose (HPC-L (trade name), manufactured by NIPPON
SODA CO., LTD.), croscarmellose sodium (Ac-Di-Sol(trade name)
manufactured by FMC), sodium starch glycolate (Primojel (trade
name), manufactured by DMV), magnesium stearate (Magnesium Stearate
(trade name), manufactured by Taihei Chemical Industrial Co.,
Ltd.), polysorbate 80 (POLYSORBATE 80 (trade name), manufactured by
Sanyo Chemical Industries, Ltd.), hydroxypropylmethylcellulose 2910
(TC-5 (trade name), manufactured by Shin-Etsu Chemical Co., Ltd.)
(hereinafter sometimes to be abbreviated as hypromellose),
polyethylene glycol 6000 (MACROGOL 6000 (trade name), manufactured
by Sanyo Chemical Industries, Ltd.), titanium oxide (titanium oxide
(trade name) manufactured by Freund Corporation), glycerol
monostearate (manufactured by RIKEN VITAMIN CO., LTD.) (sometimes
referred to as GMS in the present specification) were the Japanese
Pharmacopoeia, 15th Edition, compatible products, red ferric oxide
(red ferric oxide (trade name) manufactured by LCW), and triethyl
citrate (CITROFLEX 2 (trade name), manufactured by CBC) were
Japanese Pharmaceutical Excipients 2003 compatible products,
magnesium alumino metasilicate (Neusilin FL2 (trade name),
manufactured by Fuji Chemical Industries Co., Ltd.) was the
Japanese Pharmaceutical Codex 2002 compatible product, polyethylene
glycol 400 (Polyethylene Glycol 400 (trade name), manufactured by
Wako Pure Chemical Industries, Ltd.) was a reagent grade product,
POLYOX (POLYOX WSR N-10 (trade name), POLYOX WSR N-205 (trade
name), POLYOX WSR N-12K (trade name), POLYOX WSR 303 (trade name),
all manufactured by Dow Chemical) was the National Formulary
compatible product, all of which were used in the following
Examples, Comparative Examples Reference Examples, and Experimental
Examples.
Comparative Example 1
[0106] A core tablet containing compound A at a composition ratio
shown in Table 1-1 was produced as follows.
[0107] That is, in a fluid bed granulator/dryer (LAB-1, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. Croscarmellose sodium and magnesium
stearate were added to the obtained granulated powder and they were
mixed in a bag to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (compact tableting machine,
Kikusui Seisakusho Ltd.) with a 6.0 mm.phi. punch to give core
tablets (110 mg per tablet).
[0108] The core tablet was placed in a film coating machine
(DRC-200, Powrex Corporation), a film coating solution with a
composition ratio shown in Table 1-2 was sprayed to give film
coated tablets (about 114.0 mg per tablet). The obtained film
coated tablets were placed in a glass bottle, which was tightly
sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00001 TABLE 1-1 additive formulation amount (mg/tablet)
compound A 5 D-mannitol 76 crystalline cellulose 20
hydroxypropylcellulose 3 croscarmellose sodium 5 magnesium stearate
1 Total 110
TABLE-US-00002 TABLE 1-2 additive formulation amount (mg/tablet)
hypromellose 3.56 titanium oxide 0.40 red ferric oxide 0.04 Total
4.00
Comparative Example 2
[0109] A core tablet containing compound A at a composition ratio
shown in Table 2-1 was produced as follows.
[0110] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, U-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. The granulated powder was milled by a
milling machine (Power mill P-3, SHOWA KAGAKUKIKAI CO., LTD.) to
give a milled powder. Croscarmellose sodium and magnesium stearate
were added to the obtained milled powder and they were mixed in a
blending machine (Tumbler 15 L, SHOWA KAGAKUKIKAI Co., LTD.) to
give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (Correct 12HUK, Kikusui Seisakusho Ltd.) with a
13.0X7.0 mm punch to give core tablets (440 mg per tablet).
[0111] The core tablets were placed in a film coating machine
(Doria coater DRC500, Powrex Corporation), a film coating solution
with a composition ratio shown in Table 2-2 was sprayed to give
film coated tablets (about 456.0 mg per tablet). The obtained film
coated tablets were placed in a glass bottle, which was tightly
sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00003 TABLE 2-1 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 244 crystalline cellulose 80
hydroxypropylcellulose 12 croscarmellose sodium 20 magnesium
stearate 4 Total 440
TABLE-US-00004 TABLE 2-2 additive formulation amount (mg/tablet)
hypromellose 14.24 titanium oxide 1.60 red ferric oxide 0.16 Total
16.00
Reference Example 1
[0112] A core tablet containing compound A at a composition ratio
shown in Table 3-1 was produced as follows.
[0113] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. The granulated powder was milled by a
milling machine (Power mill P-3, SHOWA KAGAKUKIKAI Co., LTD.) to
give a milled powder. Crystalline cellulose, croscarmellose sodium
and magnesium stearate were added to the obtained milled powder and
they were mixed in a blending machine (Tumbler 15 L, SHOWA
KAGAKUKIKAI Co., LTD.) to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (Correct 12HUK, Kikusui
Seisakusho Ltd.) with a 8.0 mm.phi. punch, to give core tablets
(220 mg per tablet).
[0114] The core tablets were placed in a film coating machine
(Doria coater DRC500, Powrex Corporation), a film coating solution
with a composition ratio shown in Table 3-2 was sprayed to give
film coated tablets (about 228.0 mg per tablet).
TABLE-US-00005 TABLE 3-1 additive formulation amount (mg/tablet)
compound A 40 D-mannitol 122 crystalline cellulose 40
hydroxypropylcellulose 6 croscarmellose sodium 10 magnesium
stearate 2 Total 220
TABLE-US-00006 TABLE 3-2 additive formulation amount (mg/tablet)
hypromellose 7.12 titanium oxide 0.80 red ferric oxide 0.02 yellow
ferric oxide 0.06 Total 8.00
Example 1
[0115] A core tablet containing compound A at a composition ratio
shown in Table 4-1 was produced as follows.
[0116] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. The granulated powder was milled by a
milling machine (Power mill P-3, SHOWA KAGAKUKIKAI Co., LTD.) to
give a milled powder. Croscarmellose sodium and magnesium stearate
were added to the obtained milled powder and they were mixed in a
blending machine (Tumbler 15 L, SHOWA KAGAKUKIKAI Co., LTD.) to
give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (Correct 12HUK, Kikusui Seisakusho Ltd.) with a
9.0 mm.phi. punch to give core tablets (280 mg per tablet).
[0117] The core tablets were placed in a film coating machine
(Doria coater DRC500, Powrex Corporation), a film coating solution
with a composition ratio shown in Table 4-2 was sprayed to give
film coated tablets (about 290.2 mg per tablet). The obtained film
coated tablets were placed in a glass bottle, which was tightly
sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00007 TABLE 4-1 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 126.2 crystalline cellulose 51
hydroxypropylcellulose 7.6 croscarmellose sodium 12.7 magnesium
stearate 2.5 Total 280
TABLE-US-00008 TABLE 4-2 additive formulation amount (mg/tablet)
hypromellose 9.06 titanium oxide 1.02 red ferric oxide 0.10 Total
10.2
Example 2
[0118] A core tablet containing compound A at a composition ratio
shown in Table 5-1 was produced as follows.
[0119] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol particles (PEARLITOL 100SD,
ROQUETTE) and sodium starch glycolate were preheated and mixed, an
aqueous solution of hydroxypropylcellulose was sprayed and the
mixture was dried to give a granulated powder. The granulated
powder was milled by a milling machine (Power mill P-3, SHOWA
KAGAKUKIKAI Co., LTD.) to give a milled powder. Magnesium stearate
was added to the obtained milled powder and they were mixed in a
blending machine (Tumbler 15 L, SHOWA KAGAKUKIKAI Co., LTD.) to
give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (Correct 12HUK, Kikusui Seisakusho Ltd.) with a
8.0 mm.phi. punch to give core tablets (200 mg per tablet).
[0120] The core tablets were placed in a film coating machine
(Doria coater DRC500, Powrex Corporation), a film coating solution
with a composition ratio shown in Table 5-2 was sprayed to give
film coated tablets (about 208 mg per tablet). The obtained film
coated tablets were placed in a glass bottle, which was tightly
sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00009 TABLE 5-1 additive formulation amount (mg/tablet)
compound A 80 D-mannitol particles 102 sodium starch glycolate 10
hydroxypropylcellulose 6 magnesium stearate 2 Total 200
TABLE-US-00010 TABLE 5-2 additive formulation amount (mg/tablet)
hypromellose 7.12 titanium oxide 0.80 red ferric oxide 0.08 Total
8.00
Example 3
[0121] A core tablet containing compound A at a composition ratio
shown in Table 6-1 was produced as follows.
[0122] That is, in a fluid bed granulator/dryer (LAB-1, Powrex
Corporation), compound A, D-mannitol particles (PEARLITOL 100SD,
ROQUETTE), magnesium alumino metasilicate and sodium starch
glycolate were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. Magnesium stearate was added to the
obtained granulated powder and they were mixed in a bag to give a
mixed powder. The mixed powder was tableted by a rotary tableting
machine (compact tableting machine, Kikusui Seisakusho Ltd.) with a
6.0 mm.phi. punch to give core tablets (110 mg per tablet).
[0123] The core tablets were placed in a film coating machine
(Doria coater DRC500, Powrex Corporation), a film coating solution
with a composition ratio shown in Table 6-2 was sprayed to give
film coated tablets (about 114.0 mg per tablet). The obtained film
coated tablets were placed in a glass bottle, which was tightly
sealed and preserved at 60 .degree. C. for 2 weeks.
TABLE-US-00011 TABLE 6-1 additive formulation amount (mg/tablet)
compound A 80 D-mannitol particles 18.8 sodium starch glycolate 5
hydroxypropylcellulose 3 magnesium alumino metasilicate 2.2
magnesium stearate 1 Total 110
TABLE-US-00012 TABLE 6-2 additive formulation amount (mg/tablet)
hypromellose 3.56 titanium oxide 0.40 red ferric oxide 0.04 Total
4.00
Example 4
[0124] A core tablet containing compound A at a composition ratio
shown in Table 7-1 was produced as follows.
[0125] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and the mixture was dried to
give a granulated powder. Croscarmellose sodium and magnesium
stearate were added to the obtained granulated powder, and they
were mixed in a bag to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (Kikusui Seisakusho Ltd.,
compact tableting machine) with a 9 mm.phi. punch to give core
tablets (280 mg per tablet).
[0126] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in Table 7-2 was sprayed to give film
coated tablets (about 290 mg per tablet). The obtained film coated
tablets were placed in a glass bottle, which was tightly sealed and
preserved at 60.degree. C. for 2 weeks.
TABLE-US-00013 TABLE 7-1 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 157.2 crystalline cellulose 20
hydroxypropylcellulose 7.6 croscarmellose sodium 12.7 magnesium
stearate 2.5 Total 280
TABLE-US-00014 TABLE 7-2 additive formulation amount (mg/tablet)
hypromellose 9.06 titanium oxide 1.02 red ferric oxide 0.026 yellow
ferric oxide 0.077 Total 10.183
Example 5
[0127] A core tablet containing compound A at a composition
ratio-shown in Table 8 was produced as follows.
[0128] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose and polyethylene glycol 6000 was sprayed and
the mixture was dried to give a granulated powder. Croscarmellose
sodium and magnesium stearate were added to the obtained granulated
powder and they were mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give tore tablets (280 mg per tablet).
[0129] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets (about 290 mg per tablet). The obtained
film coated tablets were plated in a glass bottle, which was
tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00015 TABLE 8 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 156 crystalline cellulose 20
hydroxypropylcellulose 7.6 polyethylene glycol 6000 1.2
croscarmellose sodium 12.7 magnesium stearate 2.5 Total 280
Example 6
[0130] A core tablet containing compound A at a composition ratio
shown in Table 9 was produced as follows.
[0131] That is, in, a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, a dispersion obtained by dispersing
glycerol monostearate (hereinafter to be referred to as GMS) in
aqueous hydroxypropylcellulose solution was sprayed and the mixture
was dried to give a granulated powder. Croscarmellose sodium and
magnesium stearate were added to the obtained granulated powder and
they were mixed in a bag to give a mixed powder. The mixed powder
was tableted by a rotary tableting machine (Kikusui Seisakusho
Ltd., compact tableting machine) with a 9 mm.phi. punch to give
core tablets (280 mg per tablet).
[0132] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets (about 290 mg per tablet). The obtained
film coated tablets were placed in a glass bottle, which was
tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00016 TABLE 9 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 156 crystalline cellulose 20
hydroxypropylcellulose 7.6 GMS 1.2 croscarmellose sodium 12.7
magnesium stearate 2.5 Total 280
Example 7
[0133] A core tablet containing compound A at a composition ratio
shown in Table 10 was produced as follows.
[0134] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose and polyethylene glycol 400 was sprayed and
the mixture was dried to give a granulated powder. Croscarmellose
sodium and magnesium stearate were added to the obtained granulated
powder and they were mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give core tablets (280 mg per tablet).
[0135] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets (about 290 mg per tablet). The obtained
film coated tablets were placed in a glass bottle, which was
tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00017 TABLE 10 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 152.4 crystalline cellulose 20
hydroxypropylcellulose 7.6 polyethylene glycol 400 4.8
croscarmellose sodium 12.7 magnesium stearate 2.5 Total 280
Example 8
[0136] A core tablet containing compound A at a composition ratio
shown in Table 11 was produced as follows.
[0137] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose and triethyl citrate was sprayed and the
mixture was dried to give a granulated powder. Croscarmellose
sodium and magnesium stearate were added to the obtained granulated
powder and they were mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give core tablets (280 mg per tablet).
[0138] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets (about 290 mg per tablet). The obtained
film coated tablets were placed in a glass bottle, which was
tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00018 TABLE 11 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 152.4 crystalline cellulose 20
hydroxypropylcellulose 7.6 triethyl citrate 4.8 croscarmellose
sodium 12.7 magnesium stearate 2.5 Total 280
Example 9
[0139] A core tablet containing compound A at a composition ratio
shown in Table 12 was produced as follows.
[0140] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, a dispersion obtained by dispersing GMS
in aqueous hydroxypropylcellulose solution was sprayed and the
mixture was dried to give a granulated powder. Croscarmellose
sodium and magnesium stearate were added to the obtained granulated
powder and they were mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give core tablets (280 mg per tablet).
[0141] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20), a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets (about 290 mg per tablet). The obtained
film coated tablets were placed in a glass bottle, which was
tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00019 TABLE 12 additive formulation amount (mg/tablet)
compound A 80 D-mannitol 147.2 crystalline cellulose 20
hydroxypropylcellulose 7.6 GMS 10 croscarmellose sodium 12.7
magnesium stearate 2.5 Total 280
Experimental Example 1
[0142] The film coated tablets obtained in Comparative Examples 1,
2, Examples 1-3, 5, 7-9 were examined for the amount of a
decomposed product of compound A (U-2
(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-meth-
oxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione):
relative retention time about 19 min) and the total amount of the
decomposed product. The decomposed product was measured by
extracting tablets with 0.05 mol/L sodium phosphate buffer (pH
2.0)/acetonitrile mixed solution (4:1) by the HPLC method. The test
conditions of HPLC are shown below.
HPLC Test Conditions
[0143] detector: ultraviolet absorptiometer (measurement
wavelength: 230 nm) column: Intersil ODS-4, 3 .mu.m, 4.6 mm i.d.X15
cm (GL Sciences Inc.) column temperature: constant temperature near
40.degree. C. mobile phase A: 0.05 mol/L sodium phosphate buffer
(pH 2.0)/acetonitrile mixed solution (4:1) mobile phase B:
acetonitrile/0.5 mol/L sodium phosphate buffer (pH 2.0) (3:2)
mobile phase feed: The mixing ratio of mobile phase A and mobile
phase B was controlled as shown in Table 13.
TABLE-US-00020 TABLE 13 time (min) SOLUTION A (%) SOLUTION B (%) 0
(injecting) 90 10 45 90 10 90 20 80 90.1 90 10 100 90 10 Time span
of measurement: 90 min
Test Results 1
[0144] The film coated tablets of Comparative Examples 1, 2,
Examples 1-3 were measured for a decomposed product before
preservation and after preservation at 60.degree. C. for 2 weeks,
and the results of total decomposed product and U-2 are shown in
Table 14.
TABLE-US-00021 TABLE 14 Test results of stability over days content
percentage total of compound A decomposed formulation in core
tablet preservation U-2 (%) product (%) Comparative 4.5 Initial
0.06 0.23 Example 1 60.degree. C. 2 w 0.37 0.97 Comparative 18.2
Initial 0.09 0.41 Example 2 60.degree. C. 2 w 0.26 0.81 Example 1
28.6 Initial 0.10 0.40 60.degree. C. 2 w 0.22 0.65 Example 2 40.0
Initial 0.09 0.38 60.degree. C. 2 w 0.16 0.56 Example 3 72.7
Initial 0.04 0.26 60.degree. C. 2 w 0.11 0.49
[0145] The production of the total decomposed product and
decomposed product U-2 was suppressed by increasing the content
percentage of compound A in the tablets.
Test Results 2
[0146] The film coated tablet of Example 5 was measured for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, and the results of total decomposed
product and U-2 are shown in Table 15.
TABLE-US-00022 TABLE 15 Test results of stability over days total
decomposed formulation preservation U-2 (%) product (%) Example 5
Initial 0.04 0.21 60.degree. C. 2 w 0.06 0.21
[0147] The production of the total decomposed product and
decomposed product U-2 was suppressed by adding a fat and oil-like
substance having a low melting point. Particularly, the production
of decomposed product U-2, which increases markedly when a fat and
oil-like substance having a low melting point is not added, was
remarkably suppressed.
Test Results 3
[0148] The film coated tablets of Examples 7-9 were measured for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, and the results of total decomposed
product and U-2 are shown in Table 16.
TABLE-US-00023 TABLE 16 Test results of stability over days total
decomposed formulation preservation U-2 (%) product (%) Example 7
Initial 0.04 0.22 60.degree. C. 2 w 0.06 0.23 Example 8 Initial
0.04 0.27 60.degree. C. 2 w 0.06 0.28 Example 9 Initial 0.04 0.23
60.degree. C. 2 w 0.06 0.20
[0149] The production of the total decomposed product and
decomposed product U-2 was suppressed by adding a different fat and
oil-like substance having a low melting point. Particularly, the
production of decomposed product U-2, which increases markedly when
a fat and oil-like substance having a low melting point is not
added, was remarkably suppressed.
Examples 10-12
[0150] According to the formulation of Table 17, compound, A,
D-mannitol (PEARLITOL 50C, ROQUETTE), hydroxypropylcellulose,
sodium starch glycolate and magnesium stearate were mixed in a
bottle to give a mixed powder for tableting. The mixed powder was
tableted by a tabletop tablet molding machine (HANDTAB200,
ICHIHASHI SEIKI) with a 9.0 mm.phi. punch to give core tablets (300
mg per tablet). The obtained core tablets were placed in a glass
bottle, which was tightly sealed and preserved at 60.degree. C. for
2 weeks.
TABLE-US-00024 TABLE 17 formulation amount (mg/tablet) additive
Example 10 Example 11 Example 12 compound A 80 120 220 D-mannitol
193 153 53 hydroxypropylcellulose 9 9 9 sodium starch glycolate 15
15 15 magnesium stearate 3 3 3 Total 300 300 300
Experimental Example 2
[0151] The core tablets of Examples 10-12 were measured for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, by the test method of Experimental
Example 1, and the results of total decomposed product and U-2 are
shown in Table 18.
TABLE-US-00025 TABLE 18 Test results of stability over days percent
content total of compound A decomposed formulation in core tablet
preservation U-2 (%) product (%) Example 10 26.7 Initial 0.06 0.23
60.degree. C. 2 w 0.16 0.47 Example 11 40.0 Initial 0.06 0.25
60.degree. C. 2 w 0.15 0.45 Example 12 73.3 Initial 0.06 0.21
60.degree. C. 2 w 0.13 0.37
[0152] The production of the total decomposed product and
decomposed product U-2 was suppressed by setting the percent
content of compound A in the tablets to not less than 26.7%.
Reference Examples 2 and 3
[0153] According to the formulation of Table 19, compound A,
D-mannitol (PEARLITOL 50C, ROQUETTE), hydroxypropylcellulose,
sodium starch glycolate and magnesium stearate were mixed in a
bottle to give a mixed powder for tableting. The mixed powder was
tableted by a tabletop tablet molding machine (HANDTAB200,
ICHIHASHI SEIKI) with a 9.0 mm.phi. punch.
TABLE-US-00026 TABLE 19 formulation amount (mg/tablet) Reference
Reference additive Example 2 Example 3 compound A 5 20 D-mannitol
268 253 hydroxypropylcellulose 9 9 sodium starch glycolate 15 15
magnesium stearate 3 3 Total 300 300
[0154] In Reference, Examples 2 and 3 having a percent content of
compound A of 1.7% and 6.7%, respectively, a tablet having a
sufficient hardness as a preparation could not be obtained.
Comparative Example 3, Examples 13-15
[0155] According to the formulation of Table 20, compound A,
D-mannitol particles (PEARLITOL 100SD, ROQUETTE),
hydroxypropylcellulose, sodium starch glycolate and magnesium
stearate were mixed in a bottle to give a mixed powder for
tableting. The mixed powder was tableted by a tabletop tablet
molding machine (HANDTAB200, ICHIHASHI SEIKI) with a 9.0 mm.phi.
punch to give core tablets (300 mg per tablet). The obtained core
tablets were placed in a glass bottle, which was tightly sealed and
preserved at 60.degree. C. for 2 weeks.
TABLE-US-00027 TABLE 20 formulation amount (mg/tablet) Comparative
Exam- Exam- Exam- additive Example 3 ple 13 ple 14 ple 15 compound
A 5 80 120 220 D-mannitol particles 268 193 153 53
hydroxypropylcellulose 9 9 9 9 sodium starch glycolate 15 15 15 15
magnesium stearate 3 3 3 3 Total 300 300 300 300
Experimental Example 3
[0156] The core tablets of Comparative Example 3 and Examples 13-15
were measured for a decomposed product before preservation and
after preservation at 60.degree. C. for 2 weeks, by the test method
of Experimental Example 1, and the results of total decomposed
product and U-2 are shown in Table 21.
TABLE-US-00028 TABLE 21 Test results of stability over days percent
content total of compound A decomposed formulation in core tablet
preservation U-2 (%) product (%) Comparative 1.7 Initial 0.09 0.43
Example 3 60.degree. C. 2 w 0.41 1.56 Example 13 26.7 Initial 0.06
0.26 60.degree. C. 2 w 0.14 0.40 Example 14 40.0 Initial 0.06 0.25
60.degree. C. 2 w 0.11 0.39 Example 15 73.3 Initial 0.06 0.20
60.degree. C. 2 w 0.11 0.31
[0157] The production of the total decomposed product and
decomposed product U-2 was suppressed by using D-mannitol particles
(PEARLITOL 100SD, ROQUETTE) and setting the percent content of
compound A in the tablet to not less than 26.7%.
Examples 16-18
[0158] The core tablets of Examples 16-18 containing compound A at
composition ratios shown in Table 22 were produced as follows.
[0159] That is, compound A, D-mannitol particles,
hydroxypropylcellulose, sodium starch glycolate and magnesium
stearate were mixed in a bottle to give a mixed powder for
tableting. The mixed powder was tableted by a tabletop tablet
molding machine (HANDTAB200, ICHIHASHI SEIKI) with a 9.0 mm.phi.
punch to give core tablets (300 mg per tablet). The obtained core
tablets were placed in a glass bottle, which was tightly sealed and
preserved at 60.degree. C. for 2 weeks.
TABLE-US-00029 TABLE 22 formulation amount (mg/tablet) Exam- Exam-
Exam- Exam- Exam- additive ple 10 ple 13 ple 16 ple 17 ple 18
compound A 80 80 80 80 80 D-mannitol 193 -- -- -- -- (PEARLITOL
50C; average diameter 30-60 .mu.m) D-mannitol particles -- 193 --
-- -- (PEARLITOL 100SD; average particle size 75-150 .mu.m)
D-mannitol particles -- -- 193 -- -- (PEARLITOL 200SD; average
particle size 100-200 .mu.m) D-mannitol particles -- -- -- 193 --
(PEARLITOL 300DC; average particle size 270-370 .mu.m) D-mannitol
particles -- -- -- -- 193 (PEARLITOL 400DC; average particle size
350-450 .mu.m) hydroxypropylcellulose 9 9 9 9 9 sodium starch
glycolate 15 15 15 15 15 magnesium stearate 3 3 3 3 3 Total 300 300
300 300 300
Experimental Example 4
[0160] The core tablets of Examples 16-18 were measured, for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, by the test method of Experimental
Example 1, and the results of total decomposed product and U-2 are
shown in Table 23. The test results of the stability over days of
the core tablets of the aforementioned Examples 10 and 13 are also
shown in Table 23.
TABLE-US-00030 TABLE 23 Test results of stability over days percent
content total of compound A decomposed formulation in core tablet
preservation U-2 (%) product (%) Example 10 26.7 Initial 0.06 0.23
60.degree. C. 2 w 0.16 0.47 Example 13 26.7 Initial 0.06 0.26
60.degree. C. 2 w 0.14 0.40 Example 16 26.7 Initial 0.06 0.24
60.degree. C. 2 w 0.14 0.41 Example 17 26.7 Initial 0.06 0.26
60.degree. C. 2 w 0.20 0.57 Example 18 26.7 Initial 0.06 0.28
60.degree. C. 2 w 0.18 0.53
[0161] When mannitol particles having various average particle
sizes were used and the percent content of compound A in the tablet
was set to 26.7%, the production of the total decomposed product
and decomposed product U-2 was extremely suppressed when mannitol
particles having an average particle size of 60-250 .mu.m were
used.
Examples 19-21
[0162] The core tablets of Examples 19-21 containing compound A at
composition ratios shown in Table 24 were produced as follows.
[0163] That is, compound A, D-mannitol particles,
hydroxypropylcellulose, sodium starch glycolate and magnesium
stearate were mixed in a bottle to give a mixed powder for
tableting. The mixed powder was tableted by a tabletop tablet
molding machine (HANDTAB200, ICHIHASHI SEIKI) with a 9.0 mm.phi.
punch to give core tablets (300 mg per tablet). The obtained core
tablets were placed in a glass bottle, which was tightly sealed and
preserved at 60.degree. C. for 2 weeks.
TABLE-US-00031 TABLE 24 formulation amount (mg/tablet) Exam- Exam-
Exam- Exam- Exam- additive ple 11 ple 14 ple 19 ple 20 ple 21
compound A 120 120 120 120 120 D-mannitol 153 -- -- -- --
(PEARLITOL 50C) D-mannitol particles -- 153 -- -- -- (PEARLITOL
100SD) D-mannitol particles -- -- 153 -- -- (PEARLITOL 200SD)
D-mannitol particles -- -- -- 153 -- (PEARLITOL 300DC) D-mannitol
particles -- -- -- -- 153 (PEARLITOL 400DC) hydroxypropylcellulose
9 9 9 9 9 sodium starch 15 15 15 15 15 glycolate magnesium stearate
3 3 3 3 3 Total 300 300 300 300 300
Experimental Example 5
[0164] The core tablets of Examples 19-21were measured for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks; and the results of total decomposed
product and U-2 ate shown in Table 25. The test results of the
stability over days of the core tablets of the aforementioned
Examples 11 and 14 are also shown in Table 25.
TABLE-US-00032 TABLE 25 Test results of stability over days percent
content total of compound A decomposed formulation in core tablet
preservation U-2 (%) product (%) Example 11 40.0 Initial 0.06 0.25
60.degree. C. 2 w 0.15 0.45 Example 14 40.0 Initial 0.06 0.25
60.degree. C. 2 w 0.11 0.39 Example 19 40.0 Initial 0.06 0.26
60.degree. C. 2 w 0.13 0.40 Example 20 40.0 Initial 0.07 0.41
60.degree. C. 2 w 0.19 0.61 Example 21 40.0 Initial 0.07 0.41
60.degree. C. 2 w 0.16 0.56
[0165] When mannitol particles having various diameters were used
and the percent content of compound A in the tablet was set to
40.0%, the production of the total decomposed product and
decomposed product U-2 was extremely suppressed when mannitol
particles having an average particle size of 60-250 .mu.m were
used.
Example 22
[0166] A core tablet containing compound A at a composition ratio
shown in Table 26-1 was produced as follows.
[0167] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol particles (PEARLITOL 100SD,
ROQUETTE) and sodium starch glycolate were preheated and mixed, an
aqueous solution of hydroxypropylcellulose was sprayed and the
mixture was dried to give a granulated powder. The granulated
powder was milled by a milling machine (Power mill P-3, SHOWA
KAGAKUKIKAI Co., LTD.) to give a milled powder. Magnesium stearate
was added to the obtained milled powder and they were mixed in a
blending machine (Tumbler 15 L, SHOWA KAGAKUKIKAI Co., LTD.) to
give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (compact tableting machine, Kikusui Seisakusho
Ltd.) with a 6.0 mm.phi. punch to give core, tablets (100 mg per
tablet).
[0168] The core tablets were placed in a film coating machine
(Doria coater DRC200,Powrex Corporation), a film coating solution
with a composition ratio shown in Table 26-2 was sprayed to give
film coated tablets (about 104.0 mg per tablet).
TABLE-US-00033 TABLE 26-1 additive formulation amount (mg/tablet)
compound A 40 D-mannitol particles 51 sodium starch glycolate 5
hydroxypropylcellulose 3 magnesium stearate 1 Total 100
TABLE-US-00034 TABLE 26-2 additive formulation amount (mg/tablet)
hypromellose 3.56 titanium oxide 0.4 red ferric oxide 0.04 Total
4.00
Example 23
[0169] A core tablet containing compound A at a composition ratio
shown in Table 27 is produced as follows.
[0170] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol particles (PEARLITOL 100SD,
ROQUETTE), and sodium starch glycolate are preheated and mixed, an
aqueous solution of hydroxypropylcellulose is sprayed and the
mixture is dried to give a granulated powder. The granulated powder
is milled by a milling machine (Power mill P-3, SHOWA KAGAKUKIKAI
Co., LTD.) to give a milled powder. Magnesium stearate is added to
the obtained milled powder and they are mixed in a blending machine
(Tumbler 15 L, SHOWA KAGAKUKIKAI Co., LTD.) to give a mixed powder.
The mixed powder is tableted by a rotary tableting machine (compact
tableting Machine, Kikusui Seisakusho Ltd.) with a 7.0 mm.phi.
punch to give core tablets (125 mg per tablet).
TABLE-US-00035 TABLE 27 additive formulation amount (mg/tablet)
compound A 50 D-mannitol particles 63.75 sodium starch glycolate
6.25 hydroxypropylcellulose 3.75 magnesium stearate 1.25 Total
125
Examples 24-29
[0171] The core tablets of Examples 24-29 containing compound A at
composition ratios shown in Tables 28-1 and 28-2 were produced as
follows.
[0172] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose and polyethyleneglycol 6000 was sprayed and
the mixture was dried to give a granulated powder. Croscarmellose
sodium and magnesium stearate were added to the obtained granulated
powder and they were mixed in a bag to give a mixed powder. The
mixed, powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give core tablets (280 mg per tablet).
[0173] The core tablets were placed in a film coating machine
(Freund Corporation, HC-LABO-20) a film coating solution with a
composition ratio shown in the aforementioned Table 7-2 was sprayed
to give film coated tablets of Examples 24-29 (about 290 mg per
tablet). The obtained film coated tablets were placed in a glass
bottle, which was tightly sealed and preserved at 60.degree. C. for
2 weeks.
TABLE-US-00036 TABLE 28-1 formulation amount (mg/tablet) Exam-
Exam- Exam- Exam- additive ple 4 ple 24 ple 25 ple 5 compound A 80
80 80 80 D-mannitol 157.2 156.9 156.6 156 crystalline cellulose 20
20 20 20 hydroxypropylcellulose 7.6 7.6 7.6 7.6 polyethylene glycol
6000 0 0.3 0.6 1.2 croscarmellose sodium 12.7 12.7 12.7 12.7
magnesium stearate 2.5 2.5 2.5 2.5 Total 280 280 280 280
TABLE-US-00037 TABLE 28-2 formulation amount (mg/tablet) Exam-
Exam- Exam- Exam- additive ple 26 ple 27 ple 28 ple 29 compound A
80 80 80 80 D-mannitol 154.4 152.4 148.8 143.2 crystalline
cellulose 20 20 20 20 hydroxypropylcellulose 7.6 7.6 7.6 7.6
polyethylene glycol 6000 2.8 4.8 8.4 14.0 croscarmellose sodium
12.7 12.7 12.7 12.7 magnesium stearate 2.5 2.5 2.5 2.5 Total 280
280 280 280
Experimental Example 6
[0174] The film coated tablets of Examples 24-29 were measured for
a decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, by the test method described in
Experimental Example 1, and the results of total decomposed product
and U-2 are shown in Table 29. In addition, the aforementioned film
coated tablet of Example 4 was measured for a decomposed product
before preservation and after preservation at 60.degree. C. for 2
weeks, by a similar method, and the results of total decomposed
product and U-2 are shown in Table 29. The test results of the
stability over days of the film-coated tablet of the aforementioned
Example 5 are also shown in Table 29.
TABLE-US-00038 TABLE 29 Test results of stability over days total
Example (content (wt %) decomposed of PEG in core tablet)
preservation U-2 (%) product (%) Example 4 (0%) Initial 0.04 0.23
60.degree. C. 2 w 0.16 0.43 Example 24 (0.1 wt %) Initial 0.04 0.24
60.degree. C. 2 w 0.12 0.33 Example 25 (0.2 wt %) Initial 0.04 0.25
60.degree. C. 2 w 0.08 0.27 Example 5 (0.4 wt %) Initial 0.04 0.21
60.degree. C. 2 w 0.06 0.21 Example 26 (1 wt %) Initial 0.07 0.26
60.degree. C. 2 w 0.11 0.32 Example 27 (1.7 wt %) Initial 0.04 0.27
60.degree. C. 2 w 0.06 0.33 Example 28 (3 wt %) Initial 0.07 0.31
60.degree. C. 2 w 0.12 0.39 Example 29 (5 wt %) Initial 0.07 0.35
60.degree. C. 2 w 0.15 0.54
[0175] The production of the total decomposed product and
decomposed product U-2 was markedly suppressed in a tablet setting
a percent content of PEG, which is a fat and oil-like substance
having a low melting point, (particularly, PEG 6000) to 0.2-1.7 wt
% (preferably 0.2-0.4 wt %) relative to the core tablet.
Reference Example 4, Examples 30-34
[0176] Core tablets containing compound A at composition ratios
shown in Tables 30-1 and 30-2 were produced as follows.
[0177] That is, in a fluid bed granulator/dryer (MP-01, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose was sprayed and dried to give a granulated
powder. Croscarmellose sodium, magnesium stearate and, in Examples
30-34, polyethylene glycol having various average-molecular weights
(specifically, polyethylene glycol 6000 (average molecular weight:
7300-9300), POLYOX WSR N-10 (average molecular weight: 100000),
POLYOX WSR N-205 (average molecular weight: 600000), POLYOX WSR
N-12K (average molecular weight: 1000000); POLYOX WSR 303 (average
molecular weight: 7000000)) were added to the obtained granulated
powder, and they were mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (Kikusui
Seisakusho Ltd., compact tableting machine) with a 9 mm.phi. punch
to give core tablets (280 mg per tablet, Reference Example 4) and
(284.8 mg, Examples 30-34).
[0178] The obtained core tablets were placed in a glass bottle,
which was tightly sealed and preserved at 60.degree. C. for 2
weeks.
TABLE-US-00039 TABLE 30-1 formulation amount (mg/tablet) Reference
additive Example 4 Example 30 Example 31 compound A 80 80 80
D-mannitol 157.2 157.2 157.2 crystalline cellulose 20 20 20
hydroxypropylcellulose 7.6 7.6 7.6 croscarmellose sodium 12.7 12.7
12.7 polyethylene glycol 6000 -- 4.8 -- POLYOX WSR N-10 -- -- 4.8
POLYOX WSR N-205 -- -- -- POLYOX WSR N-12K -- -- -- POLYOX WSR 303
-- -- -- magnesium stearate 2.5 2.5 2.5 Total 280 284.8 284.8
TABLE-US-00040 TABLE 30-2 formulation amount (mg/tablet) additive
Example 32 Example 33 Example 34 compound A 80 80 80 D-mannitol
157.2 157.2 157.2 crystalline cellulose 20 20 20
hydroxypropylcellulose 7.6 7.6 7.6 croscarmellose sodium 12.7 12.7
12.7 polyethylene glycol 6000 -- -- -- POLYOX WSR N-10 -- -- --
POLYOX WSR N-205 4.8 -- -- POLYOX WSR N-12K -- 4.8 -- POLYOX WSR
303 -- -- 4.8 magnesium stearate 2.5 2.5 2.5 Total 284.8 284.8
284.8
Experimental Example 7
[0179] The core tablets obtained in Tables 30-1 and 30-2:were
measured for a decomposed product before preservation and after
preservation at 60.degree. C. for 2 weeks, and the results of total
decomposed product and U-2 are shown in Table 31.
TABLE-US-00041 TABLE 31 Test results of stability over days total
decomposed Example preservation U-2 (%) product (%) Reference
Example 4 (tablet Initial 0.06 0.24 not containing PEG) 60.degree.
C. 2 w 0.20 0.50 Example 30 (average Initial 0.05 0.26 molecular
weight of PEG: 60.degree. C. 2 w 0.09 0.37 7300-9300) Example 31
(average Initial 0.05 0.24 molecular weight of PEG: 60.degree. C. 2
w 0.12 0.31 100000) Example 32 (average Initial 0.05 0.19 molecular
weight of PEG: 60.degree. C. 2 w 0.17 0.40 600000) Example 33
(average Initial 0.05 0.19 molecular weight of PEG: 60.degree. C. 2
w 0.17 0.40 1000000) Example 34 (average Initial 0.05 0.18
molecular weight of PEG: 60.degree. C. 2 w 0.17 0.41 700000)
[0180] In a tablet containing PEG, the production of the total
decomposed product and decomposed product U-2, each derived from
compound A, was suppressed. In particular, in a tablet containing
PEG having an average, molecular weight of 7300-9300, or 100000,
the production of the total decomposed product and decomposed
product U-2was markedly suppressed.
Example 35
[0181] A core tablet containing compound A at a composition ratio
shown in Table 32-1 was produced as follows.
[0182] That is, in a fluid bed granulator/dryer (FD-5S, Powrex
Corporation), compound A, D-mannitol, and crystalline cellulose
were preheated and mixed, an aqueous solution of
hydroxypropylcellulose and polyethylene glycol 6000 was sprayed and
the mixture was dried to give a granulated powder. The granulated
powder was milled by a milling machine (Power mill P-3, SHOWA
KAGAKUKIKAI Co., LTD.) to give a milled powder. Croscarmellose
sodium and magnesium stearate were added to the obtained milled
powder and they were mixed in a blending machine (Tumbler 15 L,
SHOWA KAGAKUKIKAI Co., LTD.) to give a mixed powder. The mixed
powder was tableted by a rotary tableting machine (AQUARIUS,
Kikusui SeisakuSho Ltd.) with a 12.0X8.4 mm.phi. punch to give core
tablets (420 mg per tablet).
[0183] The core tablet was placed in a film coating machine (Doria
coater DRC500, Powrex Corporation), a film coating solution with a
composition ratio shown in Table 32-2 was sprayed and the tablet
was coated with a trace amount of Carnauba wax (0.012 mg per
tablet) to give a film coated tablet (about 435 mg per tablet). The
obtained film-coated tablets were placed in a glass bottle, which
was tightly sealed and preserved at 60.degree. C. for 2 weeks.
TABLE-US-00042 TABLE 32-1 additive formulation amount (mg/tablet)
compound A 120 D-mannitol 234 crystalline cellulose 30
hydroxypropylcellulose 11.4 polyethylene glycol 6000 1.8
croscarmellose sodium 19.05 magnesium stearate 3.75 Total 420
TABLE-US-00043 TABLE 32-2 additive formulation amount (mg/tablet)
hypromellose 13.5 titanium oxide 1.5 red ferric oxide 0.15 Total
15.15
Experimental Example 8
[0184] The film coated tablet of Example 35 was measured for a
decomposed product before preservation and after preservation at
60.degree. C. for 2 weeks, and the results of total decomposed
product and U-2 are shown in Table 33.
TABLE-US-00044 TABLE 33 Test results of stability over days total
decomposed formulation preservation U-2 (%) product (%) Example 35
Initial 0.06 0.25 60.degree. C. 2 w 0.07 0.23
[0185] From the results of this test, it was clarified that, even
when the total amount of the core tablet is 420 mg, the production
of the total decomposed product and decomposed product U-2 was
suppressed by adding a fat and oil-like substance having a low
melting point (particularly, polyethylene glycol) to the core
tablet.
[0186] This application is based on patent application No.
2015-037462 filed in Japan, the contents of which are encompassed
in full herein.
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