Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-01-12
2004-03-02
Barts, Samual (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S777000, C536S123100, C536S124000, C536S004100, C424S489000
Reexamination Certificate
active
06699845
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an excipient useful for preparing tablets, capsules, powders, fine granules, granules and the like which are used as medicine, food, etc., and a pharmaceutical composition containing said excipient. More particularly, the present invention relates to an excipient comprising specific trehalose and a pharmaceutical composition containing said excipient.
BACKGROUND ART
An excipient used for formulating a drug into a pharmaceutical composition is desired to have a low reactivity with the drug and impart fluidity, compactibility and disintegrating properties of powder, with good balance among them, for the preparation of tablets by direct compressing. In order to, for example, prepare a pharmaceutical composition such as a powder, fine granules or granules by mixing the components of the pharmaceutical composition and then subjecting the resulting mixture to a processing treatment such as granulation by the use of a suitable wetting material, and, if necessary, prepare wet tablets by compressing the granules, the excipient is desired to have, for example, the following characteristics at the same time: the excipient has a good miscibility at the time of mixing powders, from the viewpoint of uniformity of the content of a drug, the excipient has a proper affinity for the wetting material and has such good granulating properties that its particles can be aggregated by the binding force of the particles, and the excipient improves the compactibility of granules and can impart sufficient disintegrating properties. In addition, since the excipient generally occupies the major portion of a pharmaceuitcal composition, it is desired to be inexpensive from the viewpoint of the cost of preparation of the pharmaceutical composition.
For thus imparting desirable physical properties to a pharmaceutical composition, the excipient is required to have various functions at the same time. In such an excipient, generally lactose are used among sugars, mannitol among sugar alcohols, and starch among natural polysaccharides. Lactose, however, is disadvantageous in that when a drug having an amino group is formulated into a pharmaceutical composition, lactose reacts with the drug and hence is difficult to be used for formulating such a drug into a pharmaceutical composition. In addition, since lactose has a low solubility in a wetting material, it has a very weak ability to aggregate the particles and hence is poor in granulating properties. Moreover, when a pharmaceutical composition having practical tablet hardness is prepared by using lactose, the pharmaceutical composition is very poor in disintegrating properties, so that the addition of a disintegrating agent has been necessary. Mannitol has no reducing properties and has a low reactivity with drugs, but it has been disadvantageous in that it strongly adheres to a die and a punch during compression into tablets and that since mannitol is poor in compactibility, a high compression pressure is required for attaining a sufficient tablet hardness to withstand impact during transportation and resulting in accelerated consumption of the die and the punch. Furthermore, mannitol has been disadvantageous in that because of its insufficient solubility in a wetting material, mannitol has a weak ability to aggregate the particles and hence is poor in granulating properties. Starch imparts disintegrating properties but has been disadvantageous in its low fluidity. Moreover, although starch has a disintegrating function, starch has been disadvantageous not only in that it cannot be formulated into a pharmaceutical composition without adding a binder because starch has almost no compactibility, but also in that it cannot be formulated into a pharmaceutical composition without adding a granulation adjuvant because starch has insufficient granulating properties.
As described above, the excipients among sugars and sugar alcohols which are used for formulating a drug into a pharmaceutical composition have both advantages and drawbacks, and a means for attaining desirable characteristics of the pharmaceutical composition, such as combination of the excipients is necessary. Therefore, much time and labor are required for the formulation and hence an excipient having a good balance among low reactivity, fluidity, miscibility, compactibility, granulating properties and the like is desired.
Trehalose is a nonreducing disaccharide and there are many reports that trehalose is not reactive with drugs. Known trehalose preparations, however, are expensive for reasons such as a high material cost, a low purity and a low yield in their production, and a mode for using them as an excipient which includes, for example, using them in a large amount in the formulation of a drug into a pharmaceutical composition has been not practical. In addition, no information has been obtained about the most suitable physical properties for imparting low reactivity, fluidity, miscibility, compactibility, granulating properties and the like to trehalose with good balance among them when trehalose is used as an excipient.
As to employment of trehalose as an excipient, International Publication No. WO 98/5305 discloses tablets of clavulanic acid and amoxycillin containing trehalose and other excipients. The specification of this reference describes the trehalose as a crystalline hydrate, a glassy amorphous substance or an anhydride (an anhydrous amorphous trehalose or an anhydrous crystalline trehalose) and describes the anhydrous amorphous trehalose as preferable from the viewpoint of drug stabilization and moisture barrier effect. The specification describes the particle size of the anhydrous amorphous trehalose or the crystalline hydrate as 50 to 500 &mgr;m, preferably 100 to 250 &mgr;m, from the viewpoint of fluidity. International Publication No. WO 97/9037 discloses effervescent tablets obtained by low-pressure compression which contain an excipient selected from trehalose, maltitol, sorbitol and the like. As to characteristics of the excipient, this reference describes the average particle size of the excipient as preferably about 100 to about 125 &mgr;m. These references, however, do not describe the proportion of particles of 75 &mgr;m or more and the apparent specific volume of the excipient, and even excipients having an average particle size within the ranges described in the references are not sufficient in fluidity and miscibility in some cases. For example, even powders of excipients having an average particle size within the ranges described in the references are poor in fluidity and are, for example, consolidated to fall in a had state of preservation when the proportion of fine particles in the powder is high. In addition, when the proportion of coarse particles in the powder is high, the powder is poor in miscibility with other components of a pharmaceutical composition. When the miscibility is bad, the pharmaceutical composition lacks uniformity of the content of a drug. The above reference do not describe granulating properties, compactibility and disintegrating properties and have given no consideration to the stability of a drug as well as physical properties of trehalose having a good balance among fluidity, miscibility, granulating properties, compactibility, disintegrating properties and the like. JP-A-6-217716 discloses an additive for preparing a pharmaceutical composition which comprises trehalose. The trehalose described therein, however, has a melting point of 203° C. and is an anhydride (according to the item “trehalose” in “Rikagaku-Jiten, 4th ed.” IWANAMI-SHOTEN Ltd. (1987), the melting point of trehalose anhydride is 203° C. and the melting point of trehalose dihydrate is 97° C.). The anhydride is not desirable because it absorbs moisture with the lapse of time which changes physical properties of a pharmaceutical composition. This prior art reference describes trehalose capable of completely passing a 200-mesh screen as preferable, but such trehalose has been disadvantageous in its low fluidity. This prior art ref
Gomi Shun'ichi
Kamada Etsuo
Oobae Kazuhiro
Asahi Kasei Kabushiki Kaisha
Barts Samual
Dickstein Shapiro Morin & Oshinsky LLP.
Henry Michael C.
LandOfFree
Excipient does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Excipient, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Excipient will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3275583