Optimally stabilized microgranule comprising...

Details Optimally stabilized microgranule comprising... Optimally stabilized microgranule comprising...

1999-05-03

2001-08-28

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S488000, C424S494000, C424S496000, C514S338000

Reexamination Certificate

active

06280773

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a microgranule prepared by using an alkali compound as a stabilizer for a 5-pyrrolyl-2-pyridylmethylsulfmylbenzimidazole derivative having the following formula (1), which is a very effective antiulcerative but highly unstable under acidic conditions, and by using a water-soluble polymer as a binding agent.
in which
X represents S, SO or SO
2
,
R
1
and R
2
independently of one another represent hydrogen or alkyl,
R
3
represents hydrogen, C
1
-C
8
-alkyl, —SR
6
, —N(R
7
)
2
, 1-piperidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl, or a group of general formula —OR
6
or —O(CH
2
)
m
—Z,
wherein
R
6
represents C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, optionally substituted C
3
-C
10
-cycloalkyl, C
2
-C
5
-fluoroalkyl, or phenyl or benzyl each of which is optionally substituted by one or more halogen, or C
1
-C
4
-alkyl or alkoxy each of which is optionally substituted by halogen,
R
7
represents hydrogen or C
1
-C
5
-alkyl,
Z represents a group of general formula —O(CH
2
)
p
—OR
8
, —O(CH
2
)
q
—R
9
or —O(CH
2
)
r
O(CH
2
)
s
—OR
10
, wherein p and q independently of one another represent an integer of 1 to 3, r and s independently of one another represent an integer of 1 to 5, R
8
represents hydrogen, lower alkyl, aryl or aralkyl, R
9
represents hydrogen, alkoxycarbonyl, aryl or heteroaryl, and R
10
represents hydrogen or lower alkyl,
m represents an integer of 2 to 10,
R
4
and R
5
independently of one another represent hydrogen or C
1
-C
5
-alkyl, or
R
4
and R
3
or R
3
and R
5
represent —CH═CH—CH═CH—, —O(CH
2
)
n
—, —O(CH
2
)
n
O—, —CH
2
(CH
2
)
n
— or —OCH═CH— when R
4
or R
5
together with the adjacent carbon atoms on the pyridine ring form a ring, wherein n represents an integer of 1 to 4.
BACKGROUND ART
The 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative of formula (1), as defined above, is a novel compound developed by the present inventors, and applications for approval as a product patent are presently pending or granted in 17 countries including Korea, Japan, the United States, etc. It acts as a proton pump inhibitor like the widely known omeprazole, lansoprazole, etc., but is very unstable under acidic or neutral conditions, which may cause several problems in formulation processes.
The 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative (in the present specification, it is referred to as ‘the active ingredient of the present invention’) is very stable under alkali conditions of pH 7.6 or more, and yet it has a half time of 40 minutes or less under acidic conditions (about pH 4.0) and has a half time of 35 hours at neutral conditions (pH 7.0). Therefore, it has been recognized as more unstable under acidic or neutral conditions than omeprazole or lansoprazole which is also unstable under the same condition. Such unstability may cause many problems during storage or distribution. Particularly, it is desired to adjust the ambient circumstance to a low temperature of 4° C. or less, anhydrous and alkaline condition since the degradation of the active ingredient of the present invention is highly facilitated by the moisture and acidic conditions when the storage or distribution temperature becomes 40° C. or more.
The general way for stabilizing the acid-unstable substances is to make an alkaline environment as well as to intercept the influx of moisture from the ambient. But, the present inventors have found that the desired stabilizing effect can hardly be obtained by simply mixing the acid-unstable active ingredient of the present invention with an alkali compound.
Thus, the present inventors have extensively studied to establish a method through which the active ingredient of the present invention can be stablized in a form of microgranule. As a result, we found that such a microgranule can be prepared by combining an alkali compound with the active ingredient of the present invention in a specific mole ratio to adjust the acidity and simultaneously by using a water-soluble polymer as a binding agent in a specific content, and then completed the present invention. Particularly, we have noticed as a result of intensive researches that a certain alkaline salt, that is magnesium hydroxide, among the known alkali compounds, is highly appropriate for stabilizing the active ingredient of the present invention.
DISCLOSURE OF THE INVENTION
Therefore, the present invention provides a microgranule comprising a 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative which is optimally stabilized. More specifically, the present invention provides a microgranule prepared by combining a 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative of formula (1) with an alkali compound in 0.2 to 7.0 times molar amount with respect to the active ingredient, and by using a water-soluble polymer as a binding agent in 0.1 to 50% by weight with respect to the granule.
In the present specification, the term “microgranule” is used in a meaning that it is not the conventional granule having an average diameter of 1.5 mm or more. Such a microgranule form can be advantageously used when the active ingredient of the present invention is stored or distributed as a medicinal stuff.
DETAILED DESCRIPTION OF THE INVENTION
The alkali compounds which can be used for stabilizing the active ingredient of the present invention in the microgranule according to the present invention include magnesium oxide, sodium phosphate (dibasic), potassium phosphate (dibasic), magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, aluminum phosphate, calcium phosphate, sodium phosphate, potassium phosphate, aluminum citrate, calcium citrate, sodium citrate, potassium citrate, complexed aluminum/magnesium compound (Al
2
O
3
.6MgO.12H
2
O or MgO.Al
2
O
3
.2SiO
2
.nH
2
O), arginine, lysine and histidine. These stabilizers contribute to the stability of the acid-unstable active ingredient by maintaining the ambient pH of 7 to 13. However, their contribution degrees to the stability are different from each other depending on their solubility, alkaline reaction efficiency, compatability with the active ingredient, etc. Unexpectedly, it has been identified that magnesium hydroxide exhibits a superior stabilizing effect upon the active ingredient of the present invention compared with the other stabilizers (see, Examples 1 and 2). In contrast, aluminum hydroxide, lysine, etc. have a much less stabilizing effect than magnesium hydroxide although they also have a considerable effect when compared with the control. The present inventors have tested the stabilizing effect for the active ingredient of the present invention using omeprazole, which similarly has an acid-unstable property, as a comparative substance. As a result, it has been recognized that the difference in stabilizing effect depending on the kind of stabilizer is more conspicuous in the active ingredient of the present invention than in omeprazole.
The alkali compound as a stabilizer may be used in 0.2 to 7.0 times molar amount with respect to the active ingredient of the present invention. Although there are some differences according to the kind of stabilizer, this is because the stabilizing effect is trivial in an amount of less than 0.2 times molar amount, and the increased hygroscopicity of the stabilizer may act as an obstacle for the formulation in an amount of more than 7.0 times molar amount. More preferably, the stabilizer is used in an amount of 0.5 to 5.0 times molar amount for convenience' sake in formulation and for excellent stabilizing effect.
The stabilizer may be combined with the active ingredient using a binding agent to prepare the microgranule according to the present invention. The binding agent used herein should be water-soluble and represent neutral to weak acidic property in a solution. Some other coating materials or binding agents may produce acidic conditions, and use of them may cause t

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