Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Ion exchange resin
Reexamination Certificate
1999-01-13
2001-03-06
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Ion exchange resin
Reexamination Certificate
active
06197290
ABSTRACT:
TECHNICAL FIELD
The present invention relates to tablets and coated tablets which contain an anion exchange resin, especially a non-crosslinked anion exchange resin of a general formula (I) mentioned below, and which are useful as a cholesterol depressant. More precisely, it relates to those coated tablets with high stability, in which the content of the active ingredient is increased in order that they can be administered with ease and that the number of the tablets to be administered can be decreased.
In addition, the invention also relates to a method for producing the tablets and coated tablets.
BACKGROUND ART
Colestyramine of a crosslinked type, which is a conventional cholesterol depressant, is problematic in that its amount to be administered is large (8 to 16 g/day) and that it must be administered in the form of its suspension. Therefore, many studies have heretofore been made to produce tablets and coated tablets of anion exchange resins. For example, a method has been reported of coating tablets of a solid colestyramine resin having a water content of from 8 to 14% with a melt of polyethylene glycol and stearic acid in the presence of no solvent to give coated tablets, which do not swell in the mouth (see Japanese Patent Application Laid-Open No. 3-236326).
Regarding tablets of an imidazole-type anion exchange resin (see Japanese Patent Application Laid-Open No. 60-209523), known are a method of producing those tablets in the presence of a predetermined amount of water (see Japanese Patent Application Laid-open No. 2-286621); a method of producing coated tablets by coating those tablets as prepared in the presence of a predetermined amount of water, with hydroxypropyl cellulose or the like (see Japanese Patent Application No. 4-320155 (published before examination as Laid-Open No. 6-157325)); and a method of producing those tablets in the presence of a predetermined amount of water and silicon dioxide (see Japanese Patent Application Laid-Open No. 7-97330).
In addition, also known are methods of producing coated, anion exchange resin tablets with good moisture-resistant stability, which comprise tabletting an anion exchange resin in the presence of water to give non-coated tablets followed by coating them with a cellulosic substance or the like, and in which the hygroscopicity of the anion exchange resin in the non-coated tablets is lowered to thereby reduce the variation in the diameter of each non-coated tablet relative to the ambient humidity (see Japanese Patent Application Laid-Open Nos. 7-97330 and 6-157325). Those known methods are to coat the cores of non-coated tablets which contain a predetermined amount of water to thereby reduce the variation in the diameter in each non-coated tablet relative to the ambient humidity.
However, the conventional methods require the addition of a predetermined amount of water to the hygroscopic anion exchange resins being tabletted.
On the other hand, we, the present inventors have already reported that a non-crosslinked anion exchange resin of the formula (II):
wherein R
1
represents an aralkyl group having from 7 to 10 carbon atoms, or an alkyl group having from 1 to 20 carbon atoms; R
2
and R
3
are the same or different and each independently represents a lower alkyl group having from 1 to 4 carbon atoms; R
4
represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms; X represents a physiologically-acceptable counter ion; n represents an integer of from 1 to 3; and p represents an average degree of polymerization of from 10 to 10,000, is extremely useful as a cholesterol depressant (see WO93/13781). As being a non-crosslinked linear polymer, this anion exchange resin does not swell to increase its volume, unlike crosslinked polymers such as colestyramine, and therefore has no unfavorable side effects such as abdominal distention and constipation. In addition, the effective absorption of bile acid by the anion exchange resin per its unit weight is large. Accordingly, the anion exchange resin is very useful.
However, this resin is soluble in water and is highly bitter, and in addition, it is highly hygroscopic and deliquescent. Therefore, the novel, non-crosslinked cholesterol depressant comprising the compound of formula (II) is problematic in that, if tabletted in any of the conventional methods that require water in the mixing step, it is formed into tablets with poor strength and stability since its flowability and tablettability is very poor. Even if the cholesterol depressant comprising the compound of formula (II) is tabletted in the absence of water, the resulting tablets are still problematic in that they are very bitter because of the strong bitterness intrinsic to the compound of formula (II) itself. The dose of the compound of formula (II), though varying depending on the case to which it is administered, is relatively large or is generally from 0.1 to 9 g/day, preferably from 0.1 to 5 g/day. Tablets comprising the compound of formula (II) and containing a large amount of vehicles in order to reduce the bitterness of the compound are problematic in that the number of the tablets to be administered at a time shall be large.
In order to produce practical medicine products comprising the compound of formula (II) with such extremely high usefulness, it is desired to formulate the compound into highly-stable preparations without strong bitterness while adding thereto the smallest possible amount of vehicles as possible.
Having regard to the above problems, the present inventors already found that a mixture comprising the cholesterol depressant, non-crosslinked cation exchange resin of formula (II), along with at least silicon dioxide and crystalline cellulose could be formed into tablets in the absence of water on an industrial scale, that the cores of the thus-formed, non-coated tablets could be coated with a coating material comprising a cellulosic substance to give coated tablets, and that those coated tablets could overcome the problems in the art (see Japanese Patent Application No. 8-235718).
The non-crosslinked anion exchange resins of formula (II) have an average degree of polymerization of not larger than 10,000. As a result of additional studies, the inventors further found that non-crosslinked anion exchange resins of a general formula (I) mentioned below, having an average degree of polymerization of larger than 10,000, take excellent pharmaceutical effects as a cholesterol depressant.
The inventors still further found that the formulation of those resins of formula (I) involves the same problems as those in the formulation of the resins of formula (II) having an average degree of polymerization of from 10 to 10,000. In particular, the non-crosslinked anion exchange resins of formula (I) having an average degree of polymerization of larger than 10,000 are highly hygroscopic, therefore, the known tabletting methods requiring a predetermined amount of water were not directly applicable.
DISCLOSURE OF THE INVENTION
Having regard to the above-mentioned problems, the inventors have assiduously studied and, as a result, have found that a mixture comprising a non-crosslinked anion exchange resin of the following formula (I):
wherein X represents a physiologically-acceptable counter ion; and p represents an average degree of polymerization and is larger than 10,000,
and at least silicon dioxide and crystalline cellulose can be formed into tablets on an industrial scale, without adding water thereto, and that the cores of the non-coated tablets as obtained above can be coated with a coating agent comprising cellulose in order to coat the tablets, and also that those non-coated and coated tablets are free from the above-mentioned problems. In addition, the inventors have further found that, by that the non-coated tablets which are highly hygroscopic are coated with such a coating agent comprising cellulose, the coated tablets do not only control the bitter of the compound of formula (I) but also prevent hygroscopic of the non-coated tablets without adding water content. Therefore these
Goto Takeshi
Meno Tatsuya
Conlin David G.
Corless Peter F.
Edwards & Angell LLP
Hisamitsu Pharmaceutical Co. Inc.
Kulkosky Peter F.
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