U.S. patent application number 10/835442 was filed with the patent office on 2004-10-21 for stabilized pharmaceutical composition.
This patent application is currently assigned to TAKEDA CHEMICAL INDUSTRIES, LTD.. Invention is credited to Hirai, Shin-Ichiro, Makino, Tadashi, Tabata, Tetsuro.
Application Number | 20040209919 10/835442 |
Document ID | / |
Family ID | 29408288 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040209919 |
Kind Code |
A1 |
Makino, Tadashi ; et
al. |
October 21, 2004 |
Stabilized pharmaceutical composition
Abstract
The pharmaceutical composition of the invention, which comprises
a benzimidazole compound of the formula 1 wherein R.sup.1 is
hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,
carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy,
hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy,
aryl, aryloxy, alkylthio or alkylsulfinyl, R.sup.2 is hydrogen,
alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or
alkylsulfonyl, R.sup.3 and R.sup.5 are the same or different and
each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R.sup.4 is
hydrogen, alkyl, alkoxy which may optionally be fluorinated, or
alkoxyalkoxy, and m is an integer of 0 through 4, and a basic
inorganic salt stabilizing agent, is physically stable. Magnesium
and calcium basic inorganic salt stabilizing agents are
particularly useful.
Inventors: |
Makino, Tadashi; (Osaka,
JP) ; Tabata, Tetsuro; (Osaka, JP) ; Hirai,
Shin-Ichiro; (Kyoto, JP) |
Correspondence
Address: |
MERCHANT & GOULD PC
P.O. BOX 2903
MINNEAPOLIS
MN
55402-0903
US
|
Assignee: |
TAKEDA CHEMICAL INDUSTRIES,
LTD.
17-85, JUSOHONMACHI 2-CHOME
OSAKA
JP
532
|
Family ID: |
29408288 |
Appl. No.: |
10/835442 |
Filed: |
April 28, 2004 |
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10835442 |
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10335421 |
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6017560 |
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08810951 |
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5879708 |
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08810951 |
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08488152 |
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5639478 |
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08488152 |
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08120867 |
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5433959 |
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08120867 |
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07793091 |
Nov 15, 1991 |
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07793091 |
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07575897 |
Aug 31, 1990 |
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5093132 |
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07575897 |
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07014303 |
Feb 13, 1987 |
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5045321 |
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Current U.S.
Class: |
514/338 ;
424/717 |
Current CPC
Class: |
Y10S 514/951 20130101;
A61K 31/44 20130101; C07D 401/12 20130101; A61K 9/1611 20130101;
A61K 9/5026 20130101; A61K 47/02 20130101; A61K 31/4439 20130101;
A61K 9/5078 20130101; A61K 9/2009 20130101 |
Class at
Publication: |
514/338 ;
424/717 |
International
Class: |
A61K 031/4439; A61K
033/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 13, 1986 |
JP |
1986-29567 |
Feb 21, 1986 |
JP |
1986-38059 |
Claims
1-7. (Cancelled)
8. A stabilizing agent comprising a basic inorganic salt of at
least one selected from the group consisting of magnesium, calcium,
potassium, and sodium for a pharmaceutical composition for the
inhibition of gastric acid secretion, comprising an effective
amount of a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or
a derivative thereof or a pharmaceutically acceptable salt
thereof.
9. A stabilizing agent of claim 8, wherein the
2-[(2-pyridyl)methylsulfiny- l]benzimidazole compound is a
benzimidazole compound of the formula (I) 8wherein R.sup.1 is
hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,
carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy
hydroxyalkyl, trifluoromethyl, acyl carbamoyloxy, nitro, acyloxy,
aryl. aryloxy, alkylthio or alkylsulfinyl; R.sup.2 is hydrogen,
alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or
alkylsulfonyl; R.sup.3 and R.sup.5 are the same or different and
each is hydrogen, alkyl, alkoxy or alkoxyalkoxy; R.sup.4 is
hydrogen, alkyl, alkoxy which may optionally be fluorinated, or
alkoxyalkoxy; and m is an integer from 0 to 4, or a derivative
thereof or salt thereof having a gastric acid secretion inhibitory
property.
10. A stabilizing agent of claim 8, wherein the basic inorganic
salt is a basic inorganic salt of magnesium or calcium.
11. A stabilizing agent of claim 8, wherein the basic inorganic
salt is a basic inorganic salt of sodium.
12. A stabilizing agent of claim 8, wherein the basic inorganic
salt is a basic inorganic salt of potassium.
Description
[0001] This invention relates to a pharmaceutical composition which
comprises 2-[(2-pyridyl)methylsulphinyl]benzimidazole or a
derivative thereof (hereinafter sometimes referred to collectively
as "benzimidazole compounds"), particularly the derivatives
2-[[3-methyl-4-(2,2,2-trifluoro-
methoxy)-2-pyridyl]methylsulfinyl]benzimidazole and
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazo-
le, or a pharmaceutically acceptable salt thereof, which is useful
as an antiulcer agent. The composition is stabilized by
incorporation of an effective amount of a basic inorganic salt
stabilizing agent, with basic inorganic salts of magnesium,
calcium, potassium and sodium being useful, the magnesium can
calcium salts being preferred.
[0002] Certain benzimidazole compounds are recently under clinical
study as gastric acid secretion inhibitors. They serve as
therapeutic agents for digestive ulcer. Their principal
pharmacological effect consists in gastric acid secretion
suppression based on (H.sup.++K.sup.+)-ATPase inhibition and is
more potent and durable as compared with histamine H.sub.2 receptor
antagonists such as cimetidine and ranitidine. They also have
gastric mucosa protecting activity. Therefore, they have attracted
attention as next-generation potent therapeutic agents for
digestive ulcer.
[0003] Those benzimidazole compounds which are described in
Japanese Unexamined Patent laid open Nos. 62275/77, 141783/79,
53406/82, 135881/83, 192880/83 and 181277/84, corresponding to U.S.
Pat. No. 4,045,563, U.S. Pat. No. 4,255,431, European Patent
Publication No. 45,200, U.S. Patent No. No. 4,472,409, European
Patent Publication No. 5,129 and G.B. Patent Publication No.
2,134,523A, respectively, among others are known to have antiulcer
activity.
[0004] These compounds, however, are poor in stability. In solid
state, they are susceptible to heat, moisture and light and, in
aqueous solution or suspension, their stability decreases with
decreasing pH. In dosage forms, i.e. tablets, powders, fine
granules, granules and capsules, said compounds are apt to interact
with other components contained in said dosage forms and
accordingly are in less stable state as compared with the case
where they occur alone. Thus, the content decreases and the color
changes significantly in the manufacturing process of dosage form
and with the lapse of time. Microcrystalline cellulose,
polyvinylpyrrolidone (PVP), carboxymethylcellulose calcium,
polyethylene glycol 6000 and Pluronic F68
(polyoxyethylene-polyoxypropylene copolymer), for instance are
dosage form components adversely affecting the stability of said
compounds. Furthermore, in the case of coated tablets and coated
granules among the above dosage forms, enteric coating bases such
as cellulose acetate phthalate, hydroxy-propylmethylcellulose
acetate succinate and Eudragit (meth-acrylic acid-acrylic acid
copolymer) have poor compatibility with said compounds and cause
content decrease and color change. Nevertheless, one or more of
these components or ingredients, which, as mentioned above, can
produce adverse effects on the stability of said compounds, are
essential in the manufacture of oral preparations and therefore
difficulties are inevitably encountered in dosage form
manufacture.
[0005] The prior art avoids the above-mentioned stability problem
by using said benzimidazole compounds in a salt form, say in the
form of a lithium, sodium, potassium, magnesium, calcium or
titanium salt [Japanese Unexamined Patent laid open No. 167587/84
(European Patent Publication No. 124,495A)]
[0006] However, the above prior art method requires, for the
stabilization of the benzimidazole compounds, a step of converting
said compounds to such a salt form as mentioned above in
advance.
[0007] In view of the above, the present inventors made
investigations in an attempt to stabilize pharmaceutical
preparations containing benzimidazole compounds and, as a result,
have completed the present invention.
[0008] Thus, this invention relates to
[0009] (1) A pharmaceutical composition which comprises
2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof,
which has an antiulcer activity, and a basic inorganic salt of
magnesium and/or a basic inorganic salt of calcium, and
[0010] (2) A method of producing a stabilized pharmaceutical
composition which comprises incorporating a basic inorganic salt of
magnesium and/or a basic inorganic salt of calcium in a
pharmaceutical composition containing
2-[(2-pyridyl-methylsulfinyl]benzimidazole or a derivative thereof,
which has an antiulcer activity.
[0011] The benzimidazole compounds having an antiulcer activity
which are to be used in the practice of the invention are those
compounds which are described in the above-cited laid-open patent
specifications, for instance and are represented by the formula
2
[0012] wherein R.sup.1 is hydrogen, alkyl, halogen, cyano, carboxy,
carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy,
alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro,
acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R.sup.2 is
hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, alkylcarbonyl-methyl, alkoxycarbonylmethyl or
alkylsulfonyl, R.sup.3 and R.sup.5 are the same or different and
each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R.sup.4 is
hydrogen, alkyl, alkoxy which may optionally be fluorinated, or
alkoxyalkoxy, and m is an integer of 0 through 4.
[0013] The compounds of the formula(I) can be produced by the
methods described in the above-cited laid-open patent
specifications or modifications thereof.
[0014] In the following, brief mention is made of the substituents
in those compounds which have the formula (I) and are already
known.
[0015] Referring to R.sup.1 in the above formula, C alkyls 1-7 may
be mentioned as the alkyl represented by R.sup.1; C.sub.1-4 alkoxys
as the alkoxy moiety of the carboalkoxy; C.sub.1-4 alkoxys as the
alkoxy moiety of the carboalkoxyalkyl and C.sub.1-4 alkyls as the
alkyl moiety; C.sub.1-4 alkyls as the alkyl moiety of the
carbamoylalkyl; C.sub.1-5 alkoxys as the alkoxy; C.sub.1-7 alkyls
as the alkyl moiety of the hydroxy-alkyl; C.sub.1-4 alkanoyls as
the acyl; phenyl as the aryl; phenyl as the aryl moiety of the
aryloxy; C.sub.1-6 alkyls as the alkyl moiety of the alkylthio; and
C.sub.1-6 alkyls as the alkyl moiety of the alkylsulfinyl.
[0016] Referring to R.sup.2, C.sub.1-5 alkyls may be mentioned as
the alkyl represented by R.sup.2; C.sub.1-4alkanoyls as the acyl;
C.sub.1-4 alkoxys as the alkoxy moiety of the carboalkoxy;
C.sub.1-4 alkyls as the alkyl moiety of the alkylcarbamoyl;
C.sub.1-4 alkyls as each of the alkyl moieties of the
dialkyl-carbamoyl; C.sub.1-4 alkyls as the alkyl moiety of the
alkyl-carbonylmethyl; C.sub.1-4 alkoxys as the alkoxy moiety of the
alkoxycarbonylmethyl; and C.sub.1-4 alkyls as the alkyl moiety of
the alkylsulfonyl.
[0017] Referrring to R.sup.3, R.sup.4 and R.sup.5, C.sub.1-4 alkyls
may be mentioned as the alkyl represented by any of them; C.sub.1-8
alkoxys as the alkoxy; and C.sub.1-4 alkoxys as each of the alkoxy
moieties of the alkoxyalkoxy.
[0018] Referring to R.sup.4, C.sub.1-8 alkoxys may be mentioned as
the alkoxy, which may optionally be fluorinated.
[0019] Among those compounds of the above forumula (I), (1) the
compounds of which R.sup.1 is hydrogen, methoxy or trifluoromethyl,
R.sup.2 is hydrogen, R.sup.3 and R.sup.5 are the same or different
and each is hydrogen or methyl, R.sup.4 is fluorinated C.sub.2-5
alkoxy and m is 1, (2) the compounds of which R.sup.1 is hydrogen,
fluorine, methoxy or trifluoro-methyl, R.sup.2 is hydrogen, R.sup.3
is hydrogen or methyl, R.sup.4 is C.sub.3-8 alkoxy, R.sup.5 is
hydrogen and m is 1, and (3) the compounds of which R.sup.1 is
hydrogen, fluorine, methoxy or trifluoromethyl; R.sup.2 is
hydrogen, R.sup.3 is C.sub.1-8 alkoxy, R.sup.4 is C.sub.1-8 alkoxy
which may be fluorinated, R.sup.5 is hydrogen and m is 1.
[0020] Detailed mention is now made of the substituents in such
novel compounds.
[0021] Referring to R.sup.3, the lower alkyl represented thereby is
preferably C.sub.1-8 lower alkoxy such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, pentyloxy, hexyl-oxy, heptyloxy or
octyloxy and more preferably C.sub.1-4 lower alkoxy.
[0022] Referring to R.sup.4, C.sub.1-8 lower alkoxys may be
mentioned as the lower alkoxy, which may optionally be fluorinated,
and preferred examples are as mentioned above for R.sup.3. As the
fluorinated lower alkoxy, there may be mentioned, for example,
2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoro-propoxy,
1-(trifluoromethyl)-2,2,2-trifluoroethoxy,
2,2,3,3-tetrafluoropropoxy, 2,2,3,3,4,4,4-heptafluorobutoxy and
2,2,3,3,4,4,5,5-octafluoropentoxy, and fluorinated C.sub.2-4 lower
alkoxys are preferred.
[0023] The position of R.sup.1 is position 4 or position 5,
preferably position 5.
[0024] Some methods of producing the above novel compounds
[hereinafter referred to as "compounds of formula (I')"] are
described below.
[0025] Said compounds can be produced by subjecting a compound of
the formula 3
[0026] wherein R.sup.1-R.sup.5 are as defined above, to
oxidation.
[0027] The oxidizing agent to be used is, for example,
meta-chloroperbenzoic acid, peracetic acid, trifluoroper-acetic
acid, permaleic acid or the like peracid, sodium bromite or sodium
hypochlorite. Examples of the solvent to be used in carrying out
the reaction are halogenated hydrocarbons such as chloroform and
dichloromethane, ethers such as tetrahydrofuran and dioxane, amides
such as dimethylformamide, and water. These solvents may be used
either singly or in admixture. Said oxidizing agent is used
preferably in an amount approximately equivalent or slightly
excessive relative to the compound (II). Thus, said agent is used
in an amount of about 1-3 equivalents, more preferably about 1 to
1.5 equivalents. The reaction is carried out at a temperature from
about 0.degree. C. (ice cooling) to around the boiling point of the
solvent used, generally at a temperature from about 0.degree. C.
(ice cooling) to room temperature, preferably at a temperature of
about 0.degree. C. to 10.degree. C. The reaction time is generally
about 0.1 to 24 hours, preferably about 0.1 to 4 hours.
[0028] The desired novel compounds (I') produced by the above
reaction can be isolated and purified by conventional means such as
recrystallization, chromatography and so on.
[0029] Said compounds may be converted to pharmacologically
acceptable salts by conventional means. As such salts, there may be
mentioned hydrochloride, hydrobromide, hydro-iodide, phosphate,
nitrate, sulfate, acetate and citrate, among others.
[0030] The novel compounds (II) can be produced by reacting a
starting compound of the formula 4
[0031] wherein R.sup.1 and R.sup.2 are as defined above, with a
starting compound of the formula 5
[0032] wherein R.sup.3-R.sup.5 are as defined above and X is a
halogen atom.
[0033] The halogen atom represented by X is, for example, chlorine,
bromine or iodine.
[0034] The reaction is carried out advantageously in the presence
of a base. As said base, there may be mentioned alkali metal
hydrides such as sodium hydride and potassium hydride, alkali
metals such as metallic sodium, sodium alcoholates such as sodium
methoxide and sodium ethoxide, alkali metal carbonates such as
potassium carbonate and sodium carbonate, and organic amines such
as triethylamine, among others. As the solvent to be used in
carrying out the reaction, there may be mentioned, for example,
alcohols such as methanol and ethanol, and dimethylformamide. The
base is used generally in an amount slightly excessive relative to
the equivalent amount but may also be used in large excess. Thus,
it is used in an amount of about 2-10 equivalents, preferably about
2-4 equivalents. The above reaction is carried out generally at a
temperature of about 0.degree. C. to around the boiling point of
the solvent used, preferably at about 20.degree. C. to 80.degree.
C., for a period of about 0.2-24 hours, preferably about 0.5-2
hours.
[0035] Some methods of producing the starting compounds (IV) are
described below.
[0036] Among the compounds (IV), those compounds wherein R.sup.3
and R.sup.5 are the same or different and each is hydrogen or
methyl and R.sup.4 is fluorinated C.sub.2-5 alkoxy or C.sub.3-8
alkoxy can be produced by the following process: 6
[0037] A nitro compound of the formula (V), wherein R.sup.3 and
R.sup.5 are as defined above, is reacted with an alcohol derivative
of the formula R.sup.4'OH (VI) wherein R.sup.4' is fluorinated
C.sub.2-5 alkyl or C.sub.3-8 alkyl, in the presence of a base to
give an alkoxy derivative of the formula (VII) wherein R.sup.3,
R.sup.4 and R.sup.5 are as defined above. The base to be used in
carrying out the reaction includes, among others, alkali metals
such as lithium, sodium and potassium, alkali metal hydrides such
as sodium hydride and potassium hydride, alcoholates such as
potassium t-butoxide and sodium propoxide, alkali metal carbonates
and hydrogen carbonates such as potassium carbonate, lithium
carbonate, sodium carbonate, potassium hydrogen carbonate and
sodium hydrogen carbonate,
[0038] and alkali metal hydroxides such as
[0039] sodium hydroxide and potassium hydroxide. The alcohol
derivative to be submitted to the reaction includes, among others,
propanol, isopropanol, butanol, pentanol, hexanol,
2,2,2-trifluoroethanol, 2,2,3,3,3-pentafluoropropanol,
2,2,3,3-tetrafluoropropanol,
1-(trifluoromethyl)-2,2,2-trifluoroethanol,
2,2,3,3,4,4,4-heptafluorobuta- nol and
2,2,3,3,4,4,5,5-octafluoropentanol. While R.sup.4' OH itself may be
used as a solvent in carrying out the reaction, ethers such as
tetrahydrofuran and dioxane, ketones such as acetone and methyl
ethyl ketone, acetonitrile, dimethyl-formamide and
hexamethylphosphoric acid triamide, for instance, may also be used
as solvents. An appropriate reaction temperature may be selected
within the range of about 0.degree. C. (ice cooling) to around the
boiling point of the solvent used. The reaction time is about 1-48
hours.
[0040] Heating (about 80-120.degree. C.) of the thus-obtained
compound (VII) with acetic anhydride alone or in the presence of an
inorganic acid such as sulfuric acid or perchloric acid gives an
2-acetoxymethylpyridine derivative of the formula (VIII) wherein.
R.sup.3, R.sup.4 and R.sup.5 are as defined above. The reaction
period is generally about 0.1-10 hours.
[0041] The subsequent alkaline hydrolysis of the compound (VIII)
gives a 2-hydroxymethylpyridine derivative of the formula. (IX).
Sodium hydroxide, potassium hydroxide, potassium carbonate and
sodium carbonate, for instance, are usable as alkalis, and
methanol, ethanol and water, among others, are usable as solvents.
The reaction is generally conducted at about 20-60.degree. C. for
about 0.1-2 hours.
[0042] The compound (IX) is further halogenated with a chlorinating
agent such as thionyl chloride to give a 2-halomethylpyridine
derivative of the formula (IV) wherein R.sup.3, R.sup.4 and R.sup.5
are as defined above and X is chlorine, bromine or iodine. Usable
as solvents are, for example, chloroform, dichloromethane and
tetrachloro-ethane. The reaction is generally carried out at about
20-80.degree. C. for about 0.1-2 hours.
[0043] The compound (IV) thus produced occurs in the form of a salt
of hydrohalogenic acid corresponding to the halogenating agent used
and it is generally preferable to subject said compound to reaction
with the compound (III) immediately.
[0044] Among the compounds (V), those compounds wherein R.sup.3 is
C.sub.1-8 lower alkoxy, R.sup.4 is alkoxy which may optionally be
fluorinated, and R.sup.5 is hydrogen can be produced by the
following process: 7
[0045] Thus, maltol (X) is reacted with a alkyl halide of the
formula R.sup.3'X in the presence of silver oxide, for instance, to
give a compound of the formula (XI). Reaction of (XI) with aqueous
ammonia gives a pyridone derivative of the formula (XII). Direct
alkylation of the compound (XII) with an alkyl halide, or
halogenation of (XII) with a halogenating agent such as phosphorus
oxychloride followed by reaction of the resultant halo derivative
(XIV) with a lower alcohol of the formula R.sup.4"OH in the
presence of a base gives a compound of the formula (XIII). The
compound (XIII) can be converted to the compound (IV) by direct
halogenation with N-bromosuccinimide or chlorine, for instance. The
compound (XIII) may also be converted to the compound (IV) by
oxidizing the same with an oxidizing agent such as
m-chloroperbenzoic acid, reacting the resulting compound (XV) with
acetic anhydride, hydrolyzing the resulting compound (XVI) and
halogenating the resulting compound (XVII) with a halogenating
agent such as thionyl chloride.
[0046] The alkyl halide to be used in the production of the
compound (XI) includes, among others, methyl iodide, ethyl iodide,
propyl iodide, isopropyl iodide, butyl iodide, pentyl iodide and
hexyl iodide, and the alkyl halide to be used in the production of
the compound (XIII) further includes, in addition to those
mentioned above for use in the production of the compounds (XI),
2,2,2-trifluoroethyl iodide, 2,2,3,3,3-pentafluoropropyl iodide,
2,2,3,3-tetrafluoropropyl iodide,
1-(trifluoro-methyl)-2,2,2-trifluoroethyl iodide, 2,
2,3,3,4,4,4-hepta-fluorobutyl iodide and 2, 2,
3,3,4,4,5,5-octafluoropent- yl iodide, for instance. Such alkyl
iodides are used in an amount of about 1-10 equivalents. Silver
oxide, potassium carbonate, sodium carbonate or the like is used as
a deacidifying agent and dimethylformamide, dimethylacet-amide or
the like is used as a solvent. The reaction is generally carried
out at room temperature.
[0047] The halogenating agent to be used in the production of the
compound (XIV) includes, among others, phosphorus oxychloride,
phosphorus pentoxide and phosphorus tribromide and is used in an
amount of 1 equivalent to a large excess. The reaction is carried
out at a temperature of about 50-150.degree. C. The alcohol to be
used for the conversion of compound (XIV) to compound (XIII)
includes methanol and ethanol and further those alcohol derivaitves
mentioned for use in process 1) and is used in an amount of 1
equivalent to a large excess, and the base includes those sodium
alcoholates and potassium alcoholates which correspong to the
respective alcohols as well as potassium t-butoxide, sodium hydride
and so forth. An appropriate reaction temperature may be selected
within the range of room temperature to the boiling point of the
solvent used.
[0048] For direct bromination of the compound (XIII) with
N-bromosuccinimide, the reaction is preferably carried out under
light irradiation, and carbon tetrachloride, chloroform,
tetrachloroethane or the like is used as a solvent.
[0049] The oxidizing agent to be used for the conversion of
compound (XIII) to compound(XV) includes, among others, peracids
such as meta-chloroperbenzoic acid, peracetic acid,
trifluoroperacetic acid and permaleic acid as well as hydrogen
peroxide. Usable as solvents for the reaction are halogenated
hydrocarbons such as chloroform and dichloromethane, ethers such as
tetrahydrofuran and dioxane, amides such as dimethylformamide,
acetic acid and water, for instance, and these can be used either
singly or in admixture. Said oxidizing agent is preferably used in
an amount of about 1 equivalent to an excess relative to the
compound (XIII), more preferably about 1-10 equivalents. The
reaction is carried out at a temperature of about 0.degree. C. (ice
cooling) to around the boiling point of the solvent used generally
for a period of about 0.1-24 hours, preferably for about 0.1-4
hours.
[0050] The conversion of compound (XV) to compound (XVI) is
effected by heating (at about 80-120.degree. C.) the compound (XV)
with acetic anhydride alone or in the presence of an inorganic acid
such as sulfuric acid or perchloric acid and so on. The reaction
period is generally 0.1-10 hours.
[0051] The alkali to be used in the alkaline hydrolysis of compound
(XVI) to compound (XVII) includes, among others, sodium hydroxide,
potassium hydroxide, potassium carbonate and sodium carbonate.
Methanol, ethanol and water, for instance, may be mentioned as
usable solvents. The reaction is generally carried out at a
temperature of about 20-60.degree. C. for a period of about 0.1-2
hours.
[0052] For the production of compound (IV) from compound (XVII), a
chlorinating agent such as thionyl chloride or an organic sulfonic
or organic phosphoric acid chloride such as methanesulfonyl
chloride, p-toluenesulfonyl chloride or diphenylphosphoryl chloride
is used. When a chlorinating agent such as thionyl chloride is
used, it is used in an amount of 1 equivalent to a large excess
relative to the compound (XVII) and a solvent such as chloroform,
dichloromethane or tetrachloroethane is used, and the reaction is
generally carried out at a temperature of about 20-80.degree. C.
for a period of about 0.1-2 hours. When an organic sulfonic or
organic phosphoric acid chloride is used, it is used in an amount
of 1 equivalent to a slight excess relative to the compound (XVII)
and the reaction is generally carried out in the presence of a
base. As usable bases, there may be mentioned organic bases such as
triethylamine and tributylamine and inorganic bases such as sodium
carbonate, potassium carbonate and sodium hydrogen carbonate. The
base is used in an amount of 1 equivalent to a slight excess. As
usable solvents, there may be mentioned, for example, chloroform,
dichloro-methane, carbon tetrachloride and acetonitrile. An
appropriate reaction temperature and an appropriate reaction can be
selected within the ranges of about 0.degree. C. (ice cooling) to
around the boiling point and several minutes to several hours,
respectively.
[0053] The above-mentioned novel benzimidazole compounds have
excellent gastric antisecretory activity, gastric mucosa-protecting
activity and antiulcer activity but have low toxicity, so that they
can be used in the treatment of digestive ulcers in mammals (e.g.
mouse, rat, rabbit, dog, cat, human).
[0054] The basic inorganic salt stabilizing agents, which are to be
used in accordance with the invention, are now described.
[0055] Especially useful basic inorganic salt stabilizing agents
are basic inorganic salts of magnesium and calcium. Said basic
inorganic salt of magnesium includes, among others, heavy magnesium
carbonate, magnesium carbonate, magnesium oxide, magnesium
hydroxide, magnesium metasilicate aluminate, magnesium silicate
aluminate, magnesium silicate, magnesium aluminate, synthetic
hydrotalcite [Mg.sub.6Al.sub.2
(OH).sub.16.multidot.CO.sub.3.multidot.4H.sub.2O] and aluminum
magnesium hydroxide
[2.5MgO.multidot.Al.sub.2O.sub.3.multidot.xH.sub.2O] and said basic
inorganic salt of calcium includes, among others, precipitated
calcium carbonate and calcium hydroxide. Other basic inorganic
salts useful as stabilizing agents include sodium and potassium
basic inorganic salts such as potassium carbonate, sodium carbonate
and sodium hydrogen carbonate, as well as aluminum basic inorganic
salts such as aluminum silicate. It is only required of such basic
inorganic salts to show basicity (pH of not less than 7) when they
are in the form of a It aqueous solution or suspension.
[0056] Said basic inorganic salts may be used either singly or in
combination of two or more species in an amount which may vary
depending on the kinds thereof but generally lies within the range
of about 0.3-20 parts by weight, preferably about 0.6-7 parts by
weight, per part by weight of the benzimidazole compounds.
[0057] The composition of the invention may further contain such
additives as vehicles (e.g. lactose, corn starch, light silicic
anhydride, microcrystalline cellulose, sucrose), binders (e.g.
.alpha.-form starch, methylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, hydroxy-propylmethylcellulose,
polyvinylpyrrolidone), disintegrating agents (e.g.
carboxymethylcellulose calcium, starch, low substituted
hydroxypropylcellulose), surfactants [e.g. Tween 80 (Kao-Atlas),
Pluronic F68 (Asahi Denka; polyoxyethylene-polyoxypropylene
copolymer], antioxidants (e.g. L-cysteine, sodium sulfite, sodium
ascorbate), lubricants (e.g. magnesium stearate, talc), etc.
[0058] The composition of the invention is prepared by
homogeneously admixing the above benzimidazole compound, the basic
inorganic salt stabilizing agent, and the above additives.
[0059] The particle sizes of said benzimidazole compound and said
inorganic salt are not especially critical in a condition that they
can be homogeneously admixed. For example, preferable particle size
is about less than 100 .mu.m, more preferable one is about less
than 20 .mu.m.
[0060] The moisture amount in the composition is preferably about
6-60%, more preferably about 20-40% as equibrium relative humidity
(E.R.H).
[0061] The method of admixing is optional if the benzimidazole
compound can finally be in contact with the basic inorganic salt
stabilizing agent evenly. Thus, for example, the additives may be
admixed with a mixture of the benzimidazole compound and the basic
inorganic salt stabilizing agent as prepared by preliminary
admixing, or the basic inorganic salt stabilizing agent may be
added to a mixture of the benzimidazole compound and the additives
as prepared by preliminary admixing.
[0062] Said mixture can be made up into dosage forms suited for
oral administration, such as tablets, capsules, powders, granules
and fine granules, by per se known means.
[0063] Tablets, granules and fine granules may be coated by a per
se known method for the purpose of masking of the taste or
providing them with enteric or sustained release property. Usable
as coating agents are, for example, hydroxypropylmethylcellulose,
ethylcellulose, hydroxy-methylcellulose, hydroxypropylcellulose,
polyoxyethylene glycol, Tween 80, Pluornic F68, cellulose acetate
phthalate, hydroxypropylmethylcellulose phthalate,
hydroxymethyl-cellulose acetate succinate, Eudragit (Rohm, West
Germany; methacrylic acid-acrylic acid copolymer) and pigments such
as titanium oxide and ferric oxide.
[0064] Tablets, granules, powders, fine granules and capsules can
be produced by a conventional method (e.g. the method described in
the 10th edition of the Japanese Pharmacopeia under General Rules
for Preparations). Thus, for example, tablets are produced by
adding the basic inorganic salt stabilizing agent to a mixture of
the benzimidazole compound, vehicle and disintegrant, mixing,
adding a binder, granulating the mixture, adding a lubricant etc.
and tableting the resultant granular composition. Granules are
produced by extrusion in approximately the same manner as in the
production of tablets or by coating nonpareils, which contain
sucrose and corn starch, with a mixture of benzimidazole compound,
a basic inorganic salt stabilizing agent, and additives (e.g.
sucrose, corn starch, crystalline cellulose,
hydroxypropyl-cellulose, methylcellulose,
hydroxypropylmethyl-cellulose, polyvinylpyrrolidone) Capsules are
produced by mere mixing and filling. The dosage forms thus obtained
show excellent stability with slight changes in appearance and
little decreases in content even after storage for a long period of
time.
[0065] The pharmaceutical composition of the present invention as
obtained in the above manner exhibits excellent gastric
antisecretory, gastric mucosa-protecting and antiulcer activities
and has low toxicity and therefore can be used in the treatment of
digestive ulcers in mammals (e.g. mouse, rat, rabbit, dog, cat,
pig, human).
[0066] The pharmaceutical composition of the invention can be
orally administered for the treatment of digestive ulcers in
mammals in admixture with pharmacologically acceptable carriers,
vehicles, diluents and so forth and in the form of capsules,
tablets, granules and some other dosage forms, as mentioned
hereinabove. The dose as the benzimidazole compound lies within the
range of about 0.01 mg to 30 mg/kg/day, preferably about 0.1 mg to
3 mg/kg/day.
[0067] The following reference examples and working examples as
well as the experimental examples described later herein illustrate
the present invention in more detail but are by no means limitative
of the present invention.
REFERENCE EXAMPLE 1
[0068] A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g),
methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05
ml), anhydrous potassium carbonate (3.29 g) and
hexamethylphosphoric acid triamide (2.07 g) was heated at
70-80.degree. C. with stirring for 4.5 days. Then, the insoluble
matter was filtered off and the filtrate was concentrated. Water
was added to the residue and the mixture was extracted with ethyl
acetate. The extract layer was dried over magnesium sulfate, then
the solvent was distilled off, and the residue was applied to a
silica gel column (50 g). Elution with chloroform-methanol (10:1)
and recrystallization from ethyl acetate-hexane gave 2.4 g of
2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as
colorless needles. Melting point 148-149.degree. C.
[0069] The following compounds (VII) were produced from the
corresponding compounds (V) in the same manner as above.
1 Compounds (VII) R.sup.3 R.sup.5 R.sup.4 Melting point (.degree.
C.) CH.sub.3 H OCH.sub.2CF.sub.3 131.0-131.5 Note 1) H H
OCH.sub.2CH.sub.2CH.sub.3 Oil Note 2) CH.sub.3 H
OCH.sub.2CH.sub.2CH.sub.3 Oil Note 1): NMR spectrum (CDCl.sub.3)
.delta.: 1.01(3H, t, J=7Hz), 1.81(2H, m), 2.50(3H, s), 3.93(2H, t,
J=7Hz), 6.50-6.80(2H, m), 8.10(1H, d, J=7Hz) Note 2): NMR spectrum
(CDCl.sub.3) .delta.: 1.07(3H, t, J=7.5Hz), 1.65-2.02(2H, m),
2.21(3H, s), 2.52(3H, s), 3.99(2H, t, J=6Hz), 6.68(1H, d, J=6Hz),
8.15(1H, d, J=6Hz)
REFERENCE EXAMPLE 2
[0070] Concentrated sulfuric acid (2 drops) was added to a solution
of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-1-oxide
(2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at
110.degree. C. for 2 hours and then concentrated. The residue was
dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml)
was added, and the mixture was stirred at room temperature for 2
hours. After concentration, water was added to the residue and the
mixture was extracted with ethyl acetate. The extract was dried
over magnesium sulfate, the solvent was then distilled off, and the
residue was applied to a silica gel (50 g) column. Elution with
chloroform-methanol (10:1) and re-crystallization from isopropyl
ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-penta-
fluoropropoxy)pyridine as a brown oil.
[0071] NMR spectrum (CDCl.sub.3) .delta.: 2.07 (3H, s), 4.28 (1H,
brs), 4.49 (2H, t, J=12 Hz), 4.67 (2H, s), 6.69 (1H, d, J=5 Hz),
8.34 (1H, d, J=5 Hz)
[0072] The following compounds (IX) were produced from the
corresponding compounds (VII) in the same manner as mentioned
above.
2 Compounds (IX) R.sup.3 R.sup.5 R.sup.4 Melting point (.degree.
C.) CH.sub.3 H OCH.sub.2CF.sub.3 93.5-94.0 Note 1) H H
OCH.sub.2CH.sub.2CH.sub.3 Oil Note 2) CH.sub.3 H
OCH.sub.2CH.sub.2CH.sub.3 Oil Note 1) NMR spectrum (CDCl.sub.3)
.delta.: 1.0(3H, t, J=7.5Hz), 1.79(2H, m), 3.92(2H, t, J=6Hz),
4.51-4.90(1H, br), 4.68(2H, s), 6.68(1H, dd, J=2 and 6Hz), 6.80(1H,
d, J=2Hz), 8.28(1H, d, J=6Hz) Note 2) NMR spectrum (CDCl.sub.3)
.delta.: 1.03(3H, t, J=7.5Hz), 1.82(2H, m), 2.02(3H, s), 3.95(2H,
t, J=6Hz), 4.62(2H, s), 5.20(1H, brd, s), 6.68(1H, d, J=6Hz),
8.25(1H, d, J=6Hz)
REFERENCE EXAMPLE 3
[0073] Thionyl chloride (0.2 ml) was added to a solution of
2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine
(350 mg) in chloroform (10 ml) and the mixture was refluxed for 30
minutes and then concentrated. The residue was dissolved in
methanol (5 ml) and the solution was added to a mixture of
2-mercaptobenzimidazole (200 mg), 28% sodium methoxide solution (1
ml) and methanol (6 ml). The resultant mixture was refluxed for 30
minutes. The methanol was distilled off, water was added to the
residue, and the mixture was extracted with ethyl acetate. The
extract was washed with dilute sodium hydroxide solution and dried
over magnesium sulfate. The solvent was then distilled off, and the
residue was applied to a silica gel (20 g) column. Elution with
ethyl acetate-hexane (2:1) and recrystallization from ethyl
acetate-hexane gave 370 mg of
2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]-methyl-
thio]benzimidazole hemihydrate as colorless plates. Melting point
145-146.degree. C.
[0074] The following compounds (II) were produced by reacting the
compound (III) with the corresponding compound (IV) in the same
manner as mentioned above.
3 Compounds (II) R.sup.1 R.sup.2 R.sup.3 R.sup.5 R.sup.4 Melting
point (.degree. C.) H H CH.sub.3 H OCH.sub.2CF.sub.3 149-150 H H H
H OCH.sub.2CH.sub.2CH.sub.3 84-86 Note) H H CH.sub.3 H
OCH.sub.2CH.sub.2CH.sub.3 Oil Note) NMR spectrum (CDCl.sub.3)
.delta.: 0.98(3H, t, J=7.5Hz), 1.54-1.92(2H, m), 2.15(3H, s),
3.80(2H, t, J=6Hz), 4.43(2H, s), 6.55(1H, d, J=6Hz), 7.09(2H, m),
7.50(2H, m), 8.21 (1H, d, J=6Hz)
REFERENCE EXAMPLE 4
[0075] A solution of m-chloroperbenzoic acid (1.3 g) in chloroform
(15 ml) was added dropwise to a solution of
2-[[3-methyl-4-(2,2,3,3,3-pentafuloro-
propoxy)-2-pyridyl]-methylthio]benzimidazole(2.2 g) in chloroform
(20 ml) with ice cooling over 30 minutes and, then, the reaction
mixture was washed with saturated aqueous sodium hydrogen carbonate
solution, dried over magnesium sulfate and concentrated. The
concentrate was applied to a silica gel (50 g) column. Elution with
ethyl acetate and recrystallization from acetone-isopropyl ether
gave 1.78 g of
2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl-sulfinyl]b-
enzimidazole [hereinafter sometimes referred to as compound (A)] as
pale yellow prisms. Melting point 161-163.degree. C.
(decomposition).
[0076] The following compounds (I) [hereinafter sometimes referred
to as compound (B), compound (C) and compound (D), respectively]
were produced in the same manner from the corresponding compounds
(II).
4 Compounds (I) R.sup.1 R.sup.2 R.sup.3 R.sup.5 R.sup.4 Melting
point (.degree. C.) (B) H H CH.sub.3 H OCH.sub.2CF.sub.3 178-182
(decomp.) (C) H H H H OCH.sub.2CH.sub.2CH.sub.3 123-125 (decomp.)
(D) H H CH.sub.3 H OCH.sub.2CH.sub.2CH.sub.3 81-83
EXAMPLE 1
[0077] Of the components given below, the compound (A), magnesium
hydroxide, L-cysteine, corn starch and lactose were mixed together,
then microcrystalline cellulose, light silicic anhydride and
magnesium stearate, each in half the intended amount, were added.
After sufficient admixing, the mixture was compression-molded on a
dry granulator (roller compactor; Freund, Japan. The compressed
mass was ground in a mortar, the resultant granular mass was passed
through a round sieve (16 mesh). The remaining portions of
microcrystalline cellulose, light silicic anhydride and magnesium
stearate were added to the sieved mass and, after admixing, the
whole mixture was made up into tablets each weighing 250 mg on a
rotary tableting machine (Kikusui Seisakusho, Japan).
5 Composition per tablet: Compound (A) 50 mg Magnesium hydroxide 30
mg L-Cysteine 20 mg Corn starch 20 mg Lactose 65.2 mg
Microcrystalline cellulose 60 mg Light silicic anhydride 1.8 mg
Magnesium stearate 3.0 mg Total 250.0 mg
EXAMPLE 2
[0078] Tablets were produced in the same manner as in Example 1
except that omeprazole (Note) was used instead of the compound
(A).
[0079] Note:
5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl-
]benzimidazole
EXAMPLE 3
[0080] Of the components given below, the compound (B),
precipitated calcium carbonate, corn starch, lactose and
hydroxypropylcellulose were mixed together, water was added, and
the mixture was kneaded, then dried in vacuum at 40.degree. C. for
16 hours, ground in a mortar and passed through a 16-mesh sieve to
give granules. To this was added magnesium stearate and the
resultant mixture was made up into tablets each weighing 200 mg on
a rotary tableting machine (Kikusui Seisakusho, Japan).
6 Composition per tablet: Compound (B) 30 mg Precipitated calcium
carbonate 50 mg Corn starch 40 mg Lactose 73.4 mg
Hydroxypropylcellulose 6 mg Magnesium stearate 0.6 mg Water (0.05
ml) Total 200.0 mg
EXAMPLE 4
[0081] Tablets were produced in the same manner as in Example 3
except that timoprazole (Note) was used instead of the compound
(B).
[0082] Note: 2-[(2-Pyridyl)methylsulfinyl]benzimidazole
EXAMPLE 5
[0083] The ingredients given below were mixed well in the
porportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
7 Composition per 200 mg of granules Compound (B) 30 mg Heavy
magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline
cellulose 20 mg Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water
(0.1 ml) Total 200 mg
EXAMPLE 6
[0084] Granules were produced in the same manner as in Example 5
except that the compound (D) was used instead of the compound
(B).
EXAMPLE 7
[0085] Enteric granules were produced by coating the granules
obtained in Example 3 with an enteric coating composition specified
below using a fluidized bed granulator (Okawara, Japan) under
conditions such that the inlet air temperature was 50.degree. C.
and the granule temperature was 40.degree. C. No. 1 hard capsules
were filled with the enteric granules thus obtained in an amount of
260 mg per capsule using a capsule filling machine (Parke-Davis,
U.S.A.).
8 Enteric coating composition: Eudragit L-30D 138 mg (solids 41.4
mg) Talc 4.1 mg Polyethylene glycol 6000 12.4 mg Tween 80 2.1 mg
Water 276 .mu.l Composition of enteric granules: Granules of
Example 5 200 mg Enteric coat 60 mg Total 260 mg Composition per
capsule: Enteric granules 260 mg No. 1 hard capsule 76 mg Total 336
mg
EXAMPLE 8
[0086] Of the components given below, the compound (B), magunesium
carbonate, socrose, corn starch and crystalline cellulose were
thoroughly mixed together to obtain dusting powder.
[0087] Nonpareils were put on a centrifugal fluidized
coating-granulatar (CF-360 Freund, Japan) and then coated with the
dusting powder as described above, while spraying
hydroxypropylcellulose solution [4% (w/w)], to give spherical
granules. The spherical granules were dried in vacuum at 40.degree.
C. for 16 hours and then passed through round sieves to give 12 to
32-mesh granules.
9 Composition per 190 mg of granules: Nonpareil 75 mg Compound (B)
15 mg Magnesium carbonate 15 mg Sucrose 29 mg Corn starch 27 mg
Crystalline cellulose 27 mg Hydroxypropylcellulose 2 mg
[Hydroxypropoxy group content: 53.4-77.5%] Water (0.05 ml) Total
190 mg
EXAMPLE 9
[0088] Enteric granules were produced by coating the granules
obtained in Example 8 with an enteric coatig composition specified
below usig a fluidized bed granulator (Okawara, Japan) under
conditions such that inlet air temperature was 50.degree. C. and
the granule temperature was 40.degree. C. No. 2 hard capsules were
filled with the enteric granules thus obtained in an amount of 240
mg per capsule using a capsule filling machine (Parke-Davis,
USA).
10 Enteric coating composition: Eudragit L-30D 104.7 mg (solids
31.4 mg) Talc 9.6 mg Polyethylene glycol 6000 3.2 mg Tween 80 1.6
mg Titanium oxide 4.2 mg Water (220 .mu.l) Composition of enteric
granules: Granules of Example 8 190 mg Enteric coat 50 mg Total 240
mg Composition per capsule: Enteric granules 240 mg No. 2 hard
capsule 265 mg Total 305 mg
EXAMPLE 10
[0089]
11 Composition 1: Compound (B) 450 g Magnesium carbonate 450 g
Sucrose 450 g Corn starch 450 g Low substituted
hydroxypropylcellulose 450 g [Hydroxypropoxy group content:
10.0-13.0% (w/w), average particle size: no more than 30 .mu.m]
Composition 2: Sucrose 420 g Corn starch 360 g Low substituted
hydroxypropylcellulose 360 g [Hydroxypropoxy group content:
10.0-13.0% (w/w), average particle size: no more than 30 .mu.m]
[0090] Ingredients of the above composition 1 and composition 2
were thoroughly mixed together to obtain dusting powder 1 and
dusting powder 2, respectively.
[0091] 2250 g of nonpareils were put on a centrifugal fluidized
coating granulatar (CF-360 Freund, Japan) and then coated with the
dusting powder 1, then with the dusting powder 2, while spraying 60
g of hydroxypropylcellulose in water (2000 ml) to give spherical
granules.
[0092] The spherical granules were dried in vacuum at 40.degree. C.
for 16 hours and then passed through round sieve to give 12 to
32-mesh granules.
EXAMPLE 11
[0093] Enteric granules were produced by coating 3800 g of the
granules obtained in Example 10 with an enteric coating composition
specified below using a fluidized bed granulatar (Okawara, Japan)
under conditions such that inlet air temperature was 50.degree. C.
and the granule temperature was 40.degree. C. No. 2 hard capsules
were filled with the enteric granules thus obtained in an amount of
240 mg per capsule using a filling machine (Parke-Davis, USA).
12 Enteric coating composition: Eudragit L30D-55 628 g Talc 192 g
Polyethylene glycol 6000 64 g Titanium oxide 64 g Tween 80 32 g
Water 4400 ml Composition per capsule: Enteric granules 240 mg No.
2 hard capsule 65 mg
EXPERIMENTAL EXAMPLE 1a
[0094] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
13 Composition per 200 mg of granules Compound (B) 30 mg Heavy
magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline
cellulose 20 mg Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water
(0.1 ml) Total 200 mg
[0095] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENT EXAMPLE 1b
[0096] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
14 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
Oxide 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0097] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1c
[0098] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
15 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
Metasilicate Aluminate 20 mg Corn starch 80 mg Microcrystalline
cellulose 20 mg Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water
(0.1 ml) Total 200 mg
[0099] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1d
[0100] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm 0). The granules were immediately
converted to spherical form in a spheronizer (Fuji Powder's
Marumerizer, Japan; 1,000 rpm). The spherical granules were then
dried under vacuum at 40.degree. C. for 16 hours and passed through
round sieves to give 12- to 42-mesh granules.
16 Composition per 200 mg of granules Compound (B) 30 mg Synthetic
Hydrotalcite 20 mg Corn starch 80 mg Microcrystalline cellulose 20
mg Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10
mg Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0101] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1e
[0102] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
17 Composition per 200 mg of granules Compound (B) 30 mg Aluminum
magnesium hydroxide 20 mg Corn starch 80 mg Microcrystalline
cellulose 20 mg Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water
(0.1 ml) Total 200 mg
[0103] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1f
[0104] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
18 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
silicate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0105] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1g
[0106] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
19 Composition per 200 mg of granules Compound (B) 30 mg
Precipitated calcium carbonate 20 mg Corn starch 80 mg
Microcrystalline cellulose 20 mg Carboxymethylcellulose calcium 10
mg Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg
Water (0.1 ml) Total 200 mg
[0107] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1h
[0108] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
20 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
hydroxide 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0109] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed no change in appearance.
EXPERIMENTAL EXAMPLE 1i
[0110] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
21 Composition per 200 mg of granules Compound (B) 30 mg Sodium
carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0111] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a moderate change in appearance to yellow.
EXPERIMENTAL EXAMPLE 1j
[0112] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
22 Composition per 200 mg of granules Compound (B) 30 mg Potassium
carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0113] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a moderate change in appearance to yellow.
EXPERIMENTAL EXAMPLE 1k
[0114] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
23 Composition per 200 mg of granules Compound (B) 30 mg Sodium
hydrogen carbonate 20 mg Corn starch 80 mg Microcrystalline
cellulose 20 mg Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water
(0.1 ml) Total 200 mg
[0115] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a moderate change in appearance to yellow.
[0116] EXPERIMENTAL EXAMPLE 1l
[0117] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
24 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
chloride 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0118] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a severe change in appearance, to violet.
EXPERIMENTAL EXAMPLE 1m
[0119] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
25 Composition per 200 mg of granules Compound (B) 30 mg Magnesium
sulfate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0120] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a severe change in appearance, to violet.
EXPERIMENTAL EXAMPLE 1n
[0121] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
26 Composition per 200 mg of granules Compound (B) 30 mg Calcium
chloride 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0122] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a severe change in appearance, to violet.
EXPERIMENTAL EXAMPLE 1o
[0123] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
27 Composition per 200 mg of granules Compound (B) 30 mg aluminum
silicate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg
[0124] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a moderate change in appearance, to violet.
EXPERIMENTAL EXAMPLE 1p
[0125] The ingredients given below were mixed well in the
proportions given below, water was added, and the mixture was
kneaded and granulated in an extruder granulator (Kikusui
Seisakusho; screen size 1.0 mm .phi.). The granules were
immediately converted to spherical form in a spheronizer (Fuji
Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules
were then dried under vacuum at 40.degree. C. for 16 hours and
passed through round sieves to give 12- to 42-mesh granules.
28 Composition per 200 mg of granules Compound (B) 30 mg Corn
starch 80 mg Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg Lactose 46 mg Water (0.1 ml) Total 200 mg
[0126] After storage at 50.degree. C. and 75% RH for 1 week, the
granules were observed for changes in appearance. The granules of
this example showed a severe change in appearance, to violet.
EXPERIMENTAL EXAMPLE 2
[0127] Granules were produced in the same manner as in Example
except that the compound (A), the compound (C), the compound (D),
omeprazole or timoprazole was used instead of the compound (B).
After storage at 50.degree. C. and 75% RH for 1 week, they were
observed for changes in appearance. As a control to each
composition, granules were also produced in the same manner except
that lactose was used instead of heavy magnesium carbonate and
stored under the same conditions.
29 Changes in appearance after 1 week Compound Additive at
50.degree. C. and 75% RH Compound (A) Invention: Heavy magnesium -
carbonate Control: Lactose ++ Omeprazole Invention: Heavy magnesium
- carbonate Control: Lactose ++ Timoprazole Invention: Heavy
magnesium - carbonate Control: Lactose ++ Compound (C) Invention:
Heavy magnesium - carbonate Control: Lactose ++ Compound (D)
Invention: Heavy magnesium - carbonate Control: Lactose ++ Notes:
-: No changes ++: Severely
[0128] As is evident from the above results, the pharmaceutical
compositions of the invention were all stable whether the active
ingredient was the compound (A), omeprazole, timoprazole, the
compound (C) or the compound (D).
EXPERIMENTAL EXAMPLE 3
[0129] Pharmaceutical compositions were produced in the same manner
as in Examples 3 and 5 except that different basic inorganic Mg or
Ca salts were used or that lactose was used as a control, and
Example 6. After strage at 50.degree. C. and 75% RH for 1 week or
at 40.degree. C. for 6 months, the compositions were observed for
changes in appearance and for active ingredient content (residual
percentage).
30TABLE 2 50.degree. C., 75% 40.degree. C., Additive Initial RH, 1
week 6 months Tablets made by the procedure of Example 3 Invention
Heavy magnesium Appearance White No change No change carbonate
Content 100% 98.0% 99.5% Precipitated calcium Appearance White No
change No change carbonate Content 100% 97.4% 96.5% Magnesium
silicate Appearance White No change No change Content 100% 94.5%
95.0% Control No addition (lactose) Appearance Pale violet Dark
violet Dark violet Content 100% 73.5% 82.1% Granudles made by the
procedure of Example 5 Invention Heavy magnesium Appearance White
No change No change carbonate Content 100% 98.2% 99.1% Precipitate
calcium Appearance White No change No change carbonate Content 100%
97.2% 98.6% Magnesium oxide Appearance White No change No change
Content 100% 99.4% 99.0% Control No addition (lactose) Appearance
Pale violet Dark violet Dark violet Content 100% 84.2% 89.4%
Capsules of Example 7 Invention Heavy magnesium Appearance White No
change No change carbonate Content 100% 98.4% 99.1%
[0130] The above results clearly indicate that the compositions of
the invention show no changes in appearance at all and are stable
in terms of the active ingredient content.
* * * * *