Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-31
2003-01-07
Shippen, Michael L. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S960000
Reexamination Certificate
active
06503918
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel D-mannitol and its preparation. More specifically, it relates to D-mannitol which can be used as an excipient with excellent compressibility in the fields of preparation of medicaments and food processing industry, and a process for preparing it.
2. Description of the Related Art
D-mannitol is excellent in safety and in its compatibility with physiologically active substances. And, since it is not hygroscopic and retains no substantial moisture, it is of high value as an excipient for formulation of, especially, a physiologically active substance of high moisture sensitivity into tablets or capsules. On the other hand, D-mannitol is poor in bindability when subjected to compression and, besides, its friction with a metal wall is strong. These shortcomings tend to cause die friction or capping upon compression, which fails to give sufficient hardness to the aimed tablets, giving wear on the wall of a die and on the side face of a punch, even making sometimes the running of a tabletting machine difficult. In view of the foregoing, use of D-mannitol as excipient has been restricted in very limited dosage forms such as chewable tablets.
D-mannitol is a crystalline powder having polymorphic forms classified into &agr; form, &bgr; form and &dgr; form by X-ray diffraction patterns [Walter-Levy, L., Acad. Sc. Paris, t. 267 Series C, 1779 (1968)]. For improving the compressibility of crystalline powder, it has been known that, in general, crystals are finely ground to increase the binding points to give a better compressibility. However, in the case of D-mannitol, mere grounding of it into fine powder enhances the friction with the metal wall when subjected to compression, and also involves problems on its handling such as dusting and lowering of fluidity.
And, in Journal of Pharmaceutical Sciences, 53 (2), 188-192 (1964), there is a report on a method of obtaining D-mannitol improved in its compressibility, which comprises fusing D-mannitol and, immediately cooling. However, the improvement in compressibility brought by this method is not the one sufficiently meeting the requirements in the formulation process. Besides, the procedure is specific, so that it is difficult to apply to a industrial production scale, leaving a problem from the viewpoint of cost.
One object of the present invention is to provide D-mannitol by a simple procedure, which is excellent in powder properties and dramatically improved in compressibility.
Another object of the present invention is to provide a process for preparing D-mannitol.
Still another object of the present invention is to provide a solid composition comprising D-mannitol as an excipient.
These objects as well as other objects and advantages of the present invention will be apparent to those skilled in the art from the following description with reference to the accompanying drawings.
Under these circumstances, the present inventors have studied intensively to establish a process for preparing D-mannitol excellent in powder properties and improved in compressibility, by a simple procedure. As a result, it has been found that, when &dgr; form crystals are brought into contact with a water-soluble solvent, they are transformed into &bgr; form at the contact interface to give fine crystalline precipitates. This phenomenon has suggested to the present inventors that D-mannitol composed of an aggregation of fine crystals could be obtained. The present invention has been completed by the present inventor's further intensive investigation based on this suggestion.
SUMMARY OF THE INVENTION
That is, according to the present invention, there is provided D-mannitol having a specific surface area of not less than about 1 m
2
/g, in particular, such D-mannitol comprising a mixture of &dgr; form crystals and &bgr; form crystals.
In another aspect, the present invention provides a process for preparing D-mannitol having a specific surface area of not less than about 1 m
2
/g which comprises treating &dgr; form D-mannitol crystals with a water-soluble solvent, followed by drying. In this aspect, it is preferred to use the water-soluble solvent in an amount of about 3 to about 70 W/W% based on the weight of the &dgr; form D-mannitol crystals.
In still another aspect, the present invention provides a solid composition comprising D-mannitol having a specific surface area of not less than about 1 m
2
/g. Preferably, the solid composition of the present invention further comprises a pharmacologically active component, for example, a highly moisture-sensitive component, in particular, sodium 3R, 5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
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Remington: “The Science and Practice of Pharmacy”, 19thEd. pp. 1615-1641, (1995).
Maegata Shinji
Poellinger Norbert
Schueckler Fritz
Yoshinari Tomohiro
Shippen Michael L.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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