U.S. patent application number 13/322961 was filed with the patent office on 2012-03-29 for quinoline derivative-containing pharmaceutical composition.
This patent application is currently assigned to EISAI R&D MANAGEMENT CO., LTD.. Invention is credited to Masashi Bando.
Application Number | 20120077842 13/322961 |
Document ID | / |
Family ID | 43607048 |
Filed Date | 2012-03-29 |
United States Patent
Application |
20120077842 |
Kind Code |
A1 |
Bando; Masashi |
March 29, 2012 |
QUINOLINE DERIVATIVE-CONTAINING PHARMACEUTICAL COMPOSITION
Abstract
A pharmaceutical composition comprising a compound represented
by the formula (I) or pharmaceutically acceptable salt thereof or
solvate thereof; and a basic substance is excellent in dissolution,
is stable even after a long term storage, and is useful as a
preventive or therapeutic agent against a tumor: ##STR00001##
wherein, R.sup.1 is a hydrogen atom, a C.sub.1-6 alkyl group or a
C.sub.3-8 cycloalkyl group; and R.sup.2 is a hydrogen atom or a
methoxy group.
Inventors: |
Bando; Masashi;
(Kakamigahara, JP) |
Assignee: |
EISAI R&D MANAGEMENT CO.,
LTD.
Tokyo
JP
|
Family ID: |
43607048 |
Appl. No.: |
13/322961 |
Filed: |
August 16, 2010 |
PCT Filed: |
August 16, 2010 |
PCT NO: |
PCT/JP10/63804 |
371 Date: |
November 29, 2011 |
Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 9/485 20130101;
A61K 9/1652 20130101; A61K 9/4866 20130101; A61K 9/1611 20130101;
A61P 43/00 20180101; A61P 35/00 20180101; A61K 47/02 20130101; C07D
215/48 20130101; A61P 35/04 20180101; A61K 31/47 20130101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 19, 2009 |
JP |
2009-190145 |
Claims
1. A pharmaceutical composition comprising (1) a compound
represented by the formula (I) or pharmaceutically acceptable salt
thereof or solvate thereof: ##STR00004## wherein R.sup.1 is a
hydrogen atom, a C.sub.1-6 alkyl group or a C.sub.3-8 cycloalkyl
group; and R.sup.2 represents a hydrogen atom or a methoxy group;
and (2) a basic substance.
2. The composition according to claim 1, wherein the basic
substance is a carbonate.
3. The composition according to claim 2, wherein the salt is an
alkaline earth metal salt.
4. The composition according to claim 3, wherein the alkaline earth
metal salt is a magnesium salt or a calcium salt.
5. The composition according to claim 1, further comprising a
disintegrating agent.
6. The composition according to claim 5, wherein the disintegrating
agent is carmellose sodium, carmellose calcium, carboxymethyl
starch sodium, croscarmellose sodium, low-substituted
hydroxypropylcellulose or crospovidone.
7. The composition according to claim 1, wherein R.sup.1 is a
hydrogen atom, a methyl group, an ethyl group, an n-propyl group or
a cyclopropyl group.
8. The composition according to claim 1, wherein R.sup.1 is a
cyclopropyl group.
9. The composition according to claim 1, wherein R.sup.2 is a
hydrogen atom, a methoxy group or an ethoxy group.
10. The composition according to claim 1, wherein R.sup.2 is a
hydrogen atom.
11. The composition according to claim 1, wherein the
pharmaceutically acceptable salt is hydrochloride, hydrobromide,
p-toluenesulfonate, sulfate, methanesulfonate or
ethanesulfonate.
12. The composition according to claim 1, wherein the compound
represented by the formula (I) is
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide methanesulfonate.
Description
TECHNICAL FIELD
[0001] The present invention relates to a pharmaceutical
composition comprising a quinoline derivative, useful as a
medicament. More specifically, the present invention relates to a
pharmaceutical composition improved in dissolution of a quinoline
derivative or a pharmaceutically acceptable salt thereof or a
solvate thereof.
BACKGROUND ART
[0002] A quinoline derivative represented by the formula (I) or a
pharmaceutically acceptable salt thereof or a solvate thereof
(hereinafter referred to as quinoline derivative (I)) has been
known to have a potent angiogenesis inhibitory effect (Patent
Literature 1) and a c-Kit kinase inhibitory effect (Patent
Literature 2) and to be useful as a preventive or therapeutic agent
against various tumors such as thyroid cancer, lung cancer,
melanoma and pancreatic cancer, and as an metastatic inhibitor
against these tumors:
##STR00002##
wherein, R.sup.1 is a hydrogen atom, a C.sub.1-6 alkyl group or a
C.sub.3-8 cycloalkyl group; and R.sup.2 is a hydrogen atom or a
methoxy group.
[0003] However, the quinoline derivative (I) has been found to
degrade under humidifying and warming storage conditions when
formulated into a pharmaceutical composition. In addition, when the
pharmaceutical composition absorbs moisture, dissolution of the
quinoline derivative (I) from the pharmaceutical composition that
is an active ingredient may delay because of gelation on the
surface of the composition. In order to overcome these problems, a
pharmaceutical composition which includes the quinoline derivative
(I), (1) a compound, a 5% (w/w) aqueous solution or suspension of
which has a pH of 8 or more, and/or (2) silicic acid, salt thereof
or solvate thereof has been developed (Patent Literature 3).
CITATION LIST
Patent Literature
[0004] Patent Literature 1: WO 2002/32872 [0005] Patent Literature
2: WO 2004/080462 [0006] Patent Literature 3: WO 2006/030826
SUMMARY OF INVENTION
Technical Problem
[0007] However, development of a pharmaceutical composition further
excellent in the dissolution of the quinoline derivative (I) has
been desired. Thus, the present invention is aimed at providing a
pharmaceutical composition that is excellent in dissolution of the
quinoline derivative (I) that is maintained even after long term
storage.
Solution to Problem
[0008] The present inventors have intensively studied in order to
solve the problems above and surprisingly have discovered the
configuration below could solve the problems and have completed the
present invention.
[0009] Specifically, the present invention provides the following
<1> to <12>.
[1] A pharmaceutical composition comprising:
[0010] (1) a compound represented by the formula (I) or
pharmaceutically acceptable salt thereof or solvate thereof:
##STR00003##
wherein R.sup.1 is a hydrogen atom, a C.sub.1-6 alkyl group or a
C.sub.3-8 cycloalkyl group; and R.sup.2 represents a hydrogen atom
or a methoxy group; and
[0011] (2) a basic substance.
[2] The composition according to [1], wherein the basic substance
is a carbonate. [3] The composition according to [2], wherein the
salt is an alkaline earth metal salt [4] The composition according
to [3], wherein the alkaline earth metal salt is a magnesium salt
or a calcium salt. [5] The composition according to any one of [1]
to [4], further comprising a disintegrating agent. [6] The
composition according to [5], wherein the disintegrating agent is
carmellose sodium, carmellose calcium, carboxymethyl starch sodium,
croscarmellose sodium, low-substituted hydroxypropylcellulose or
crospovidone. [7] The composition according to any one of [1] to
[6], wherein R.sup.1 is a hydrogen atom, a methyl group, an ethyl
group, an n-propyl group or a cyclopropyl group. [8] The
composition according to any one of [1] to [7], wherein R.sup.1 is
a cyclopropyl group. [9] The composition according to any one of
[1] to [8], wherein R.sup.2 is a hydrogen atom, a methoxy group or
an ethoxy group. [10] The composition according to any one of [1]
to [9], wherein R.sup.2 is a hydrogen atom. [11] The composition
according to any one of [1] to [10], wherein the pharmaceutically
acceptable salt is hydrochloride, hydrobromide, p-toluenesulfonate,
sulfate, methanesulfonate or ethanesulfonate. [12] The composition
according to any one of [1] to [11], wherein the compound
represented by the formula (I) is
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6--
quinolinecarboxamide methanesulfonate.
Advantageous Effects of Invention
[0012] The pharmaceutical composition of the present invention is
excellent in dissolution of the quinoline derivative (I), which is
a principal agent, and is also excellent in absorption into a
living body. The pharmaceutical composition is also a
pharmaceutical composition that is maintained even after long term
storage.
BRIEF DESCRIPTION OF DRAWINGS
[0013] FIG. 1 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Examples 4 to 6 and
Comparative Example 1.
[0014] FIG. 2 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Examples 7 to 9 and
Comparative Example 2.
[0015] FIG. 3 shows the dissolution patterns of the compound A from
the pharmaceutical compositions obtained in Examples 10 to 12 and
Comparative Example 3.
[0016] FIG. 4 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Examples 13 to 15 and
Comparative Example 4.
[0017] FIG. 5 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Examples 16 to 17 and
Comparative Example 5.
[0018] FIG. 6 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Example 18 and
Comparative Examples 7 to 8.
[0019] FIG. 7 shows the dissolution profiles of the compound A from
the pharmaceutical compositions obtained in Example 19 and
Comparative Examples 9 to 10.
DESCRIPTION OF EMBODIMENTS
[0020] The pharmaceutical composition of the present invention
means a composition comprising the quinoline derivative (I) and a
basic substance as essential ingredients. A mixing ratio of the
quinoline derivative (I) and the basic substance is, but is not
limited to, normally 1:0.5 to 50, preferably 1:1 to 25, further
preferably 1:2 to 12.5.
[0021] In addition, a mixing rate of the quinoline derivative (I)
with respect to the total weight of the pharmaceutical composition
(excluding a capsule shell) is normally 0.25 to 50 weight %,
preferably 0.5 to 25 weight %, further preferably 1 to 12.5 weight
%.
[0022] A mixing rate of the basic substance with respect to the
total weight of the pharmaceutical composition is normally 1 to 60
weight %, preferably 5 to 50 weight %, further preferably 10 to 40
weight %. At least one basic substance of the present invention may
be included in the pharmaceutical composition, or two or more basic
substances may also be included.
[0023] A dosage form of the pharmaceutical composition specifically
means a solid preparation such as granules, fine granules, tablets
or capsules and so on. It is preferably fine granules, granules or
capsules filled with fine granules or granules.
[0024] The quinoline derivative (I) is a compound disclosed in WO
2002/32872. A preferable quinoline derivative (I) is a quinoline
derivative or pharmacologically acceptable salt thereof or solvate
thereof selected from the group consisting of
4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-
-6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-
-6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-
-6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydro-
xypropyl)oxy-6-quinolinecarboxamide,
4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecar-
boxamide,
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quin-
olinecarboxamide,
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy--
6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)--
6-quinolinecarboxamide,
4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quin-
olinecarboxamide,
N-(2-fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N'-cycloprop-
ylurea,
N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)ami-
no)phenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinec-
arboxamide,
4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-meth-
oxy-6-quinolinecarboxamide,
N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2--
methoxyethoxy)-6-quinolinecarboxamide and
N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-
-quinolinecarboxamide.
[0025] A more preferable quinoline derivative (I) is a quinoline
derivative or pharmacologically acceptable salt thereof or solvate
thereof selected from the group consisting of
4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecar-
boxamide,
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quin-
olinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide,
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-me-
thoxy-6-quinolinecarboxamide and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy--
6-quinolinecarboxamide.
[0026] A particularly preferable quinoline derivative (I) is
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide or pharmacologically acceptable salt thereof or
solvate thereof.
[0027] The pharmaceutically acceptable salt of the present
invention means hydrochloride, hydrobromide, p-toluenesulfonate,
sulfate, methanesulfonate or ethanesulfonate. It is preferably the
methanesulfonate.
[0028] The solvate of the present invention means hydrate, dimethyl
sulfoxide solvate or acetic acid solvate.
[0029] The quinoline derivative (I) is preferably a crystal of a
salt of
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide, or a solvate thereof disclosed in WO 2005/063713. A
particularly preferred quinoline derivative (I) is the C Form
crystal of
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide methanesulfonate.
[0030] The quinoline derivative (I) is useful as a preventive or
therapeutic agent against various tumors and as a metastasis
inhibitor against tumors. Examples of the tumors against which the
quinoline derivative (I) is effective include thyroid cancer,
non-small-cell lung cancer, melanoma, laryngopharyngeal cancer,
esophageal cancer, gastric cancer, colorectal cancer,
hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer,
bladder cancer, breast cancer, uterine cancer, ovarian cancer,
prostate cancer, testicular cancer, gastrointestinal stromal tumor,
sarcoma, osteogenic sarcoma, angioma, malignant lymphoma, myeloid
leukemia, neuroma and neuroglioma.
[0031] The basic substance of the present invention means a basic
inorganic salt. Such basic inorganic salts include beryllium
carbonate, magnesium carbonate, calcium carbonate, strontium
carbonate, barium carbonate, potassium carbonate, calcium
hydrogenphosphate and titanium oxide. It is preferably an alkaline
earth metal salt of carbonic acid, further preferably magnesium
carbonate or calcium carbonate.
[0032] It is also acceptable to further include a disintegrating
agent in the pharmaceutical composition of the present invention.
Such a disintegrating agent include corn starch, partially
pregelatinized starch, hydroxypropyl starch, carmellose, carmellose
sodium, carmellose calcium, carboxymethyl starch sodium,
croscarmellose sodium, low-substituted hydroxypropylcellulose and
crospovidone. It is preferably the croscarmellose sodium, the
low-substituted hydroxypropylcellulose or the crospovidone.
[0033] The pharmaceutical composition of the present invention may
be prepared by a known method such as a method described in the
General Rules for Preparations in the Japanese Pharmacopoeia
Fifteenth Edition.
[0034] For example, in the case of the granule, it is possible to
add an excipient, a binder, a disintegrating agent, a solvent, or
the like to the quinoline derivative (I) as needed, to perform
agitation granulation, extruding granulation, tumbling granulation,
fluidized-bed granulation, spray granulation, or the like, and to
prepare it. It is also acceptable to be coated with an atomizing
agent containing the quinoline derivative (I) and an additive such
as corn starch, microcrystalline cellulose, hydroxypropylcellulose,
methylcellulose or polyvinylpyrrolidone while spraying water or a
solution of a binder such as saccharose, hydroxypropylcellulose or
hydroxypropylmethylcellulose on a core material such as a purified
sucrose spherical granule, a lactose/crystalline cellulose
spherical granule, a saccharose/starch spherical granule or a
granular crystalline cellulose. It is also acceptable to perform
sizing and milling as needed.
[0035] It is also possible to further, as needed, add an excipient,
a binder, a disintegrating agent, a lubricant, an anti-oxidizing
agent, a corrigent, a coloring agent, a flavoring agent, or the
like to the granule prepared in this way and to compress it to be a
tablet. A required excipient may be added to the quinoline
derivative (I) to directly compress the mixture into a tablet. It
is also possible to fill a capsule with the quinoline derivative
(I) added/mixed with an excipient such as lactose, saccharose,
glucose, starch, microcrystalline cellulose, powdered glycyrrhiza,
mannitol, calcium phosphate or calcium sulfate, or with the
granule.
[0036] Examples of the excipient include lactose, saccharose,
glucose, fructose, starch, potato starch, corn starch, wheat
starch, rice starch, crystalline cellulose, microcrystalline
cellulose, powdered glycyrrhiza, mannitol, erythritol, maltitol,
sorbitol, trehalose, silicic anhydride, calcium silicate, sodium
hydrogencarbonate, calcium phosphate, anhydrous calcium phosphate
and calcium sulfate.
[0037] Examples of the binder include gelatin, starch, gum arabic,
tragacanth, carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone,
methylcellulose, partially pregelatinized starch, pregelatinized
starch, polyvinyl alcohol, sodium arginine, pullulan and
glycerin.
[0038] Examples of the disintegrating agent include corn starch,
partially pregelatinized starch, hydroxypropyl starch, carmellose,
carmellose sodium, carmellose calcium, carboxymethyl starch sodium,
croscarmellose sodium, low-substituted hydroxypropylcellulose and
crospovidone.
[0039] Examples of the lubricant include magnesium stearate,
stearic acid, calcium stearate, sodium stearyl fumarate, talc and
macrogol.
[0040] Examples of the anti-oxidizing agent include sodium
ascorbate, L-cysteine, sodium sulfite, tocopherol and soybean
lecithin.
[0041] Examples of the corrigent include citric acid, ascorbic
acid, tartaric acid, malic acid, aspartame, acesulfame potassium,
thaumatin, saccharin sodium, dipotassium glycyrrhizinate, sodium
glutamate, sodium 5'-inosinate and sodium 5'-guanylate.
[0042] Examples of the coloring agent include titanium oxide, iron
sesquioxide, iron sesquioxide yellow, cochineal, carmine,
riboflavin, food yellow No. 5 and food blue No. 2.
[0043] Examples of the flavoring agent include lemon oil, orange
oil, menthol, peppermint oil, borneol and vanilla flavor.
EXAMPLES
[0044] The present invention will be described in more detail below
with reference to Examples, but is not limited to the Examples.
Examples 1 to 3
[0045] Wet granulation was performed with purified water as a
solvent using a high-shear granulator (apparatus name: FM-VG-10,
manufactured by Powrex Corporation) with the C form crystal of
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli-
necarboxamide methanesulfonate (hereinafter referred to as compound
A), D-mannitol (trade name: Mannitol, Merck), precipitated calcium
carbonate (trade name: Whiton F, Shiraishi Calcium),
hydroxypropylcellulose (HPC-L, Nippon Soda), low-substituted
hydroxypropylcellulose (trade name: L-HPC (LH-21), Shin-Etsu
Chemical) and microcrystalline cellulose (trade name: Ceolus
PH-101, Asahi Kasei Chemicals) according to the formulation
proportions in Table 1. The granules of which a moisture content
was reduced to be less than 2% by further drying were sized using a
screen mill (apparatus name: Power Mill P-04S, manufactured by
Showa Giken KK) so that their granule diameters were less than 1
mm. Then, microcrystalline cellulose (trade name: Ceolus PH-102,
Asahi Kasei Chemicals) and talc (trade name: Hi-Filler 17, Iwai
Chemicals Company) were added to the sized granules according to
the formulation proportions in Table 1, and the mixture was
thoroughly mixed using a diffusion (tumbler-type) mixer (trade
name: 10L/20L Exchange-type Tumbler Mixer, manufactured by Toyo
Packing Corporation). Hard capsules size #4 were filled with 100 mg
of the resultant granules to prepare capsules containing the
compound A.
TABLE-US-00001 TABLE 1 Ex. 1 Ex. 2 Ex. 3 Compound A 1.25 5 12.5
Precipitated calcium carbonate 33 33 33 D-Mannitol 19.75 16 8.5
Hydroxypropylcellulose 3 3 3 Low-substituted 25 25 25
hydroxypropylcellulose Microcrystalline cellulose (PH-101) 10 10 10
Microcrystalline cellulose (PH-102) 5 5 5 Talc 3 3 3 Total 100 100
100 Unit: weight %
Examples 4 to 9, Comparative Examples 1 to 2
[0046] The compound A, precipitated calcium carbonate,
low-substituted hydroxypropylcellulose, D-mannitol and talc were
thoroughly mixed using a mortar and a pestle according to the
formulation proportions in Table 2 and Table 3. Hard capsules size
#3 were filled with 100 mg of the resultant mixtures to prepare
capsules in Examples 4 to 9. Capsules in Comparative Examples 1 to
2, which contained no precipitated calcium carbonate, were also
prepared by the same method.
TABLE-US-00002 TABLE 2 Com. Ex. 1 Ex. 4 Ex. 5 Ex. 6 Compound A 5 5
5 5 Precipitated calcium carbonate 0 5 10 20 Low-substituted 30 25
20 10 hydroxypropylcellulose D-Mannitol 62 62 62 62 Talc 3 3 3 3
Total 100 100 100 100 Unit: weight %
TABLE-US-00003 TABLE 3 Com. Ex. 2 Ex. 7 Ex. 8 Ex. 9 Compound A 20
20 20 20 Precipitated calcium carbonate 0 5 10 20 Low-substituted
30 25 20 10 hydroxypropylcellulose D-Mannitol 47 47 47 47 Talc 3 3
3 3 Total 100 100 100 100 Unit: weight %
Test Example 1
[0047] The dissolutions of the compound A in the capsules in
Examples 4 to 9 and Comparative Examples 1 to 2 were examined
according to the Dissolution Test (the Paddle method, test medium:
JP1 solution) described in the Japanese Pharmacopoeia Fifteenth
Edition. As a result, the dissolutions of the compound A in the
capsules in Comparative Examples 1 to 2, in which no calcium
carbonate was mixed, were insufficient. In contrast, the
dissolutions of the compound A in the capsules in Examples 4 to 9,
in which calcium carbonate was mixed, were good (FIG. 1 and FIG.
2).
Examples 10 to 15, Comparative Examples 3 to 4
[0048] The compound A, magnesium carbonate (Kyowa Chemical
Industry), low-substituted hydroxypropylcellulose, D-mannitol and
talc were thoroughly mixed using a mortar and a pestle according to
the formulation proportions in Table 4 and Table 5. Hard capsules
size #3 were filled with 100 mg of the resultant mixtures to
prepare capsules in Examples 10 to 15. Capsules in Comparative
Examples 3 to 4, which contained no magnesium carbonate, were also
prepared by the same method.
TABLE-US-00004 TABLE 4 Com. Ex. 3 Ex. 10 Ex. 11 Ex. 12 Compound A 5
5 5 5 Magnesium carbonate 0 5 10 20 Low-substituted 30 25 20 10
hydroxypropylcellulose D-Mannitol 62 62 62 62 Talc 3 3 3 3 Total
100 100 100 100 Unit: weight %
TABLE-US-00005 TABLE 5 Com. Ex. 4 Ex. 13 Ex. 14 Ex. 15 Compound A
20 20 20 20 Magnesium carbonate 0 5 10 20 Low-substituted 30 25 20
10 hydroxypropylcellulose D-Mannitol 47 47 47 47 Talc 3 3 3 3 Total
100 100 100 100 Unit: weight %
Test Example 2
[0049] The dissolutions of the compound A in the capsules in
Examples 10 to 15 and Comparative Examples 3 to 4 were examined by
the same method as in Test Example 1. The dissolutions of the
compound A in the capsules in Comparative Examples 3 to 4, in which
no magnesium carbonate was mixed, were insufficient. In contrast,
the dissolutions of the compound A in the capsules in Examples 10
to 15, in which the magnesium carbonate was mixed, were good (FIG.
3 and FIG. 4).
Examples 16 to 17, Comparative Examples 5 to 6
[0050] Purified water was added to the compound A, precipitated
calcium carbonate or magnesium carbonate, hydroxypropylcellulose
and croscarmellose sodium (trade name: Ac-Di-Sol, Asahi Kasei
Chemicals) to perform granulation using a mortar and a pestle,
followed by sizing of the dried granules so that their granule
diameters were less than 1 mm. Then, microcrystalline cellulose
(trade name: Ceolus PH-102, Asahi Kasei Chemicals), low-substituted
hydroxypropylcellulose and talc (trade name: Hi-Filler 17, Iwai
Chemicals Company) were added to the sized granules according to
the formulation proportions in Table 6, and the mixture was mixed
thoroughly. Hard capsules size #4 were filled with 100 mg of the
resultant mixtures to prepare capsules in Examples 16 to 17.
Capsules in Comparative Examples 5 to 6, which contained neither
precipitated calcium carbonate nor magnesium carbonate but
contained mannitol or talc as a substitute, were also similarly
prepared according to the formulation proportions in Table 7.
TABLE-US-00006 TABLE 6 Ex. 16 Ex. 17 Compound A 10 10 Precipitated
calcium carbonate 15 0 Magnesium carbonate 0 15
Hydroxypropylcellulose 2 2 Croscarmellose sodium 10 10
Low-substituted 20 20 hydroxypropylcellulose Microcrystalline
cellulose (PH-102) 41 41 Talc 2 2 Total 100 100 Unit: weight %
TABLE-US-00007 TABLE 7 Com. Com. Ex. 5 Ex. 6 Compound A 10 10
Mannitol 15 0 Talc 0 15 Hydroxypropylcellulose 2 2 Croscarmellose
sodium 10 10 Low-substituted 20 20 hydroxypropylcellulose
Microcrystalline cellulose (PH-102) 41 41 Talc 2 2 Total 100 100
Unit: weight %
Test Example 3
[0051] The dissolutions of the compound A in the capsules in
Examples 16 to 17 and Comparative Example 5 were examined by the
same method as in Test Example 1. The dissolution of the compound A
in the capsule in Comparative Example 5, in which neither calcium
carbonate nor magnesium carbonate was mixed, was insufficient. In
contrast, the dissolutions of the compound A in the capsules in
Examples 16 to 17, in which calcium carbonate or magnesium
carbonate was mixed, were good (FIG. 5).
Test Example 4
[0052] The capsules in Examples 16 to 17 and Comparative Example 6
were stored for 1 week in an open system under an environment at a
temperature of 60.degree. C. and a relative humidity of 75%,
followed by determining the production of the degradants with
high-performance liquid chromatography. In the capsule formulation
in Comparative Example 6, in which neither calcium carbonate nor
magnesium carbonate was mixed, an amount of the degradants was
increased. In contrast, in the capsules in Examples 16 to 17, in
which calcium carbonate or magnesium carbonate was mixed, no
increase in amount of the degradants was observed (Table 8).
TABLE-US-00008 TABLE 8 Quantitated Degradants (%) compound A(%)
Compound A (Initial) 1.61% 98.38% Com. Ex. 6 1.92% 98.08% Ex. 16
1.50% 98.50% Ex. 17 1.57% 98.44%
Examples 18 to 19, Comparative Examples 7 to 10
[0053] The respective ingredients were mixed according to the
formulations of Tables 9 and 10 by the same method as in Examples 4
to 9 and Comparative Examples 1 to 2. Hard capsules size #3 were
filled with 100 mg of the resultant mixtures to prepare capsules in
Examples 18 to 19 and Comparative Examples 7 to 10.
TABLE-US-00009 TABLE 9 Com. Com. Ex. 18 Ex. 7 Ex. 8 Compound A 20
20 20 Precipitated calcium carbonate 10 0 0 Calcium oxide 0 10 0
Calcium hydroxide 0 0 10 Low-substituted 20 20 20
hydroxypropylcellulose D-Mannitol 47 47 47 Talc 3 3 3 Total 100 100
100 Unit: weight %
TABLE-US-00010 TABLE 10 Com. Com. Ex. 19 Ex. 9 Ex. 10 Compound A 20
20 20 Magnesium carbonate 10 0 0 Magnesium oxide 0 10 0 Magnesium
hydroxide 0 0 10 Low-substituted 20 20 20 hydroxypropylcellulose
D-Mannitol 47 47 47 Talc 3 3 3 Total 100 100 100 Unit: weight %
Test Example 5
[0054] The dissolutions of the compound A in the capsules in
Examples 18 to 19 and Comparative Examples 7 to 10 were examined by
the same method as in Test Example 1. As a result, the dissolutions
of the compound A in the capsules in Comparative Examples 7 to 10,
in which calcium oxide, calcium hydroxide, magnesium oxide or
magnesium hydroxide was mixed, were insufficient. In contrast, the
dissolutions of the compound A in the capsules in Examples 18 to
19, in which calcium carbonate or magnesium carbonate was mixed,
were good (FIG. 6 and FIG. 7).
INDUSTRIAL APPLICABILITY
[0055] The pharmaceutical composition of the present invention is
excellent in dissolution of the quinoline derivative and also in
stability, and is therefore useful as a medicament for prevention
or treatment of a tumor.
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