Phosphate-binding polymer preparations

Details Phosphate-binding polymer preparations Phosphate-binding polymer preparations

1999-09-21

2002-05-07

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S474000, C514S781000, C514S783000

Reexamination Certificate

active

06383518

ABSTRACT:

TECHNICAL FIELD
This invention relates to a tablet containing a phosphate-binding polymer. More particularly, it relates to the tablet containing a phosphate-binding polymer, which has an average particle size of 400 &mgr;m or less, contains particles of 500 &mgr;m or less in particle size at a ratio of 90% or more and has a moisture content of 1 to 14%, together with crystalline cellulose and/or low substituted hydroxypropylcellulose, and showing a rapid disintegration, dispersibility and an ability to bind to phosphate, and a process f or producing the same.
BACKGROUND ART
Phosphate-binding polymers, which are non-absorptive polymers capable of adsorbing phosphate, are useful as remedies for hyperphosphatemia induced by renal hypofunction such as renal insufficiency. As described in, for example, U.S. Pat. No. 5,496,545, phosphate-binding polymers are publicly known as cationic polymer compounds comprising primary and secondary amines which are prepared by crosslinking polyallyamine with the use of a crosslinking agent such as epichlorohydrin.
With respect to phosphate-binding polymer preparations as remedies for hyperphosphatemia, for example, U.S. Pat. No. 5,496,545 points out that tablets can be produced by using various additives including crystalline cellulose. However, the patent cited above presents no particular example of such preparations. Although the present inventors attempted in practice to produce tablets by blending various additives with the phosphate-binding polymer obtained by the method as described in the above patent, no tablet could be successfully produced thereby.
Moreover, known adsorbents for oral administration, for example, a calcium polystyrene sulfonate preparation (Kalimate™ manufactured by Nikken Chemicals Co., Ltd.), a sodium polystyrene sulfonate preparation (Kayexalate™ manufactured by Torii & Co., Ltd.), an adsorptive carbon preparation (Kremezin™ manufactured by Kureha Chemical Industry Co., Ltd.), a cholestyramine preparation (Questran™, manufactured by Bristol-Myers Squibb Co.) and a precipitated calcium carbonate preparation (manufactured by Emisu Yakuhin K. K.), are all in dosage forms of bulk powders, powder preparations or capsules containing powders. Namely, there has been reported no example of preparations of this type in the form of tablets so far.
When orally administered, phosphate-binding polymers adsorb phosphorus in foods followed by excretion into the feces to thereby inhibit the absorption of phosphorus via the digestive tracts, thus regulating the phosphorus concentration in the blood. These phosphate-binding polymers are taken in a relatively large single dose, i.e., from 1 to 2 g. Because of reacting with water and thus swelling rapidly, the phosphate-binding polymers can be hardly taken as such.
Patients with dialysis to whom the phosphate-binding polymers are to be administered as remedies for hyperphosphatemia are frequently under restriction in water intake. It is therefore required to develop phosphate-binding polymer preparations which can be taken with a small amount of water. One of the promising dosage forms is tablets which can be small-sized by compression, in particular, coated tablets which would not disintegrate in the mouth and can be smoothly ingested. When processed into tablets by compressing, however, a phosphate-binding polymer alone gives only a poor tablet hardness and thus cannot be processed as such into a tablet preparation. Due to the high hygroscopicity and swelling properties of the phosphate-binding polymer, it is also impossible to produce a phosphate-binding polymer preparation by the wet granulation method with the use of water or a binder solution containing alcohols, etc. followed by drying.
To overcome these problems, it has been required to develop a production process which comprises blending a powdery phosphate-binding polymer with powdery additives having excellent molding characteristics and compressing the obtained mixture. Such a preparation should be designed by taking into consideration changes in the disintegration properties and dispersibility accompanying the compression. Since a phosphate-binding polymer is to be taken in a relatively large single dose, special regard should be paid to give a preparation with a high content of the active component.
Although the present inventors attempted to produce phosphate-binding polymer preparations in the form of tablets by using various additives described in U.S. Pat. No. 5,496,545, they could not produce any favorable tablets which contain phosphate-binding polymer having a sufficient hardness, a rapid disintegrative dispersibility and an ability to bind to phosphate.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, they have successfully found that a phosphate-binding polymer tablet which contains a large amount of the phosphate-binding polymer, has a sufficient hardness and shows rapid disintegrative dispersibility and an ability to bind to phosphate can be obtained by adding specific additives to a phosphate-binding polymer which has certain characteristics, thus completing the present invention. More particularly speaking, they have found that a tablet, which contains a phosphate-binding polymer having an average particle size of 400 &mgr;m or less, preferably 250 &mgr;m or less, containing particles of 500 &mgr;m or less, preferably 300 &mgr;m or less, in size at a ratio of 90% or more and having a moisture content of 1 to 14%, together with crystalline cellulose and/or low substituted hydroxypropylcellulose, has excellent characteristics.


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