Quickly disintegrating solid preparations

Details Quickly disintegrating solid preparations Quickly disintegrating solid preparations

2001-12-17

2004-05-25

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S439000, C424S440000, C424S441000, C424S465000

Reexamination Certificate

active

06740339

ABSTRACT:

TECHNICAL FIELD
The present invention relates to solid preparations that disintegrate quickly in the presence of saliva or a small amount of water in the oral cavity, particularly those useful as intraorally disintegrating solid preparations.
BACKGROUND ART
For aged people and children who are difficult to swallow drugs, solid preparations that disintegrate or dissolve quickly in the oral cavity have long been developed. For example, an intraorally disintegrating tablet preparation is described in the International Publication No. WO93/12769, which is obtained by suspending a drug, lactose, and mannitol in aqueous agar solution, filling the resulting suspension in a molding pocket or the like, and drying the molding under reduced pressure. This molding shows quick disintegration but is more fragile than usual tablets so that it is readily cracked, chipped, etc. and a long time is required for its production; thus the process for production is poor in productivity. In Japanese Patent Laying-Open No.6-218028(1994) and Japanese Patent Laying-Open No.8-19589(1996), a process for production of a tablet preparation is described, where moist powder after kneading is filled in the tablet molding well for wet shaping followed by drying. The resulting tablet preparation, being porous and having a moderate void fraction, shows quick disintegration. However the industrial productivity of this process for production is poor because a wet material with low fluidity is filled and compressed so that the amount filled in each well varies greatly and a special dryer is necessary.
Then a few processes for production of an intraorally disintegrating tablet preparation by dry tabletting excellent in productivity have also been reported. For example, a process for production of an intraorally disintegrating tablet preparation by dry tabletting using a saccharide with a good moldability and a saccharide with a poor moldability in combination is described in the International Publication No. WO95/20380. Also a process for production of an intraorally disintegrating tablet preparation by dry tabletting using granules obtained by wet or dry granulation using an excipient and erythritol, a sugar alcohol, in combination is described in the International Publication No. WO98/02185.
In addition, a process for production of a tablet preparation that disintegrates quickly in the oral cavity, by combining a saccharide or a sugar alcohol having a mean particle diameter of not more than 30 &mgr;m, an active ingredient, and a disintegrating agent is described in the International Publication No. WO97/47287. According to this process, the molding obtained by pulverization of a saccharide or a sugar alcohol, such as D-mannitol or lactose, followed by addition of a disintegrating agent, etc. and compression molding shows quick disintegration, whereas when coarse particles of a saccharide (lactose, mean particle diameter of 80 &mgr;m) or a sugar alcohol (D-mannitol, mean particle diameter of 60 &mgr;m) before pulverization are used, molding is difficult under a low tabletting pressure and even the molding obtained under a high tabletting pressure does not show a sufficient mechanical hardness.
D-mannitol is known to produce a very high friction (binding) at the surface of the mortar wall during compression molding. In addition, pulverization is undesirable not only because it strengthens the friction at the surface of the mortar wall but also from the viewpoint of handling because it reduces fluidity during the production of the tablet preparation (Summary of lectures at the 14
th
Symposium on Particulate Preparations and Designs, p.115 (1997), Handbook of Pharmaceutical Excipients 2
nd
Ed., p.294 (1994), The Pharmaceutical Press).
DISCLOSURE OF THE INVENTION
The inventors have conducted extensive studies on intraorally disintegrating tablet preparations that can be industrially produced with common installations without requiring any special manufacturing technique. As the result of the studies, the inventors found that an intraorally disintegrating tablet preparation that has a practically not problematic hardness, disintegrates quickly, and has no problem in productivity can be obtained by dry tabletting even under a low compression pressure when an active ingredient is combined with a relatively coarse powder of a saccharide or a sugar alcohol, a disintegrating agent, and a cellulose compound. As a result of further studies, the inventors have completed the present invention. That is, the invention relates to:
(1) a quickly disintegrating solid preparation comprising a) an active ingredient, b) a saccharide or a sugar alcohol with the mean particle diameter of 30 &mgr;m to 300 &mgr;m (not less than 30 &mgr;m and not more 300 &mgr;m), c) a disintegrating agent, and d) a cellulose compound;
(2) the preparation according to the above-mentioned (1), wherein the preparation is an intraorally quickly disintegrating solid preparation;
(3) the preparation according to the above-mentioned (1), wherein the preparation is a tablet preparation;
(4) the preparation according to the above-mentioned (1), wherein 40 to 95 parts of a saccharide or a sugar alcohol is contained in 100 parts of the solid preparation by weight;
(5) the preparation according to the above-mentioned (1), wherein 0.5 to 15 parts of a disintegrating agent is contained in 100 parts of the solid preparation by weight;
(6) the preparation according to the above-mentioned (1), wherein 0.5 to 40 parts of a cellulose compound is contained in 100 parts of the solid preparation by weight;
(7) the preparation according to the above-mentioned (1), wherein the saccharide is one or more saccharides selected from the group consisting of glucose, fructose, lactose, sucrose, and trehalose;
(8) the preparation according to the above-mentioned (1), wherein the saccharide is lactose;
(9) the preparation according to the above-mentioned (1), wherein the sugar alcohol is one or more sugar alcohols selected from the group consisting of D-mannitol, erythritol, xylitol, maltitol, and sorbitol;
(10) the preparation according to the above-mentioned (1), wherein the sugar alcohol is D-mannitol;
(11) the preparation according to the above-mentioned (1), characterized in that D-mannitol with the mean particle diameter of 30 &mgr;m to 300 &mgr;m is used as the saccharide or sugar alcohol with the mean particle diameter of 30 &mgr;m to 300 &mgr;m;
(12) the preparation according to the above-mentioned (1), wherein the disintegrating agent is one or more disintegrating agents selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, and crospovidone;
(13) the preparation according to the above-mentioned (1), wherein the cellulose compound is one or more substances selected from the group consisting of crystalline cellulose, powder cellulose, low substituted hydroxypropylcellulose, and carmellose;
(14) the preparation according to the above-mentioned (1), wherein the active ingredient is manidipine hydrochloride;
(15) the preparation according to the above-mentioned (1), wherein the active ingredient is voglibose;
(16) the preparation according to the above-mentioned (1), wherein the active ingredient is candesartan cilexetil;
(17) the preparation according to the above-mentioned (1), wherein the active ingredient is pioglitazone hydrochloride;
(18) the process for production of the preparation according to the above-mentioned (1), characterized in that a mixture containing a) an active ingredient, b) a saccharide or sugar alcohol with the mean particle diameter of 30 &mgr;m to 300 &mgr;m (not less than 30 &mgr;m and not more than 300 &mgr;m), c) a disintegrating agent, and d) a cellulose compound is molded by compression;.
(19) a quickly disintegrating solid preparation containing a) an active ingredient, b-1) a saccharide or sugar alcohol with the mean particle diameter of 5 &mgr;m to below 90 &mgr;m (not less than 5 &mgr;m and below 90 &mgr;m), b-2) a saccharide or a sugar alcohol with the mean particle diameter of 90 &mgr;m to 50

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