United States Patent:  6,071,536

Assignee:  Shionogi & Co., Ltd. (Osaka, JP)

Filed:  December 18, 1997

A gelatin capsule having adjusted water activity and preserved in a closed system, which contains, packed herein, an additive(s) selected from the group consisting of carboxymethyl cellulose calcium, crosscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone in the proportion of 50 to 150 wt. % of the total quantity of the gelatin of the said capsule.

PREFERRED EMBODIMENT TO CARRY OUT THE INVENTION

The coating of the gelatin capsules of the present invention preferably contains as a principal component gelatin and optionally a small amount of an additive(s) for capsule coating generally used in the field of pharmaceutical industries, for example, polyethylene glycol and the like.

For purposes of the present invention, an selected additive serves as a water activity regulating agent (or a regulator) as mentioned above is packed in a capsule in the proportion of about 50 to 150 wt. %, preferably about 50 to 120 wt. %, more preferably about 50 to 100 wt. %, further more preferably about 70 to 100 wt. %, especially preferably about 75 to 90 wt. % of the total quantity of the gelatin coating.

If the amount of an additive(s) is too little, the internal water activity cannot be controlled effectively when a capsule is preserved under high temperature and high humidity, or for a long time, which possibly leads to the unstabilization or discoloration of the capsule or its content. If the amount of an additive(s) is too large, the internal water activity could be greatly decreased under a mild condition of at room temperature and a crack may happen on a gelatin capsule.

Throughout the specification, the term "water activity (A_W)" means a ratio of water vapor pressure (P) in a certain measurement system and that (Po) of pure water under the same temperature and pressure as those of the said measurement system, and is defined by the formula:

A_W =(P/Po) x 100(%).

The water activity of each of gelatin, additive(s) and the whole capsule can be measured with any one of commercially available measuring device (e.g., Water activity (A_W) measurement system of DT type, manufactured by Rotronic, Inc. (Gunze Industrial Co., Ltd.)).

The total water activity of a capsule (A_WT) is in principle the same as the mean water activity (A_W) which can be calculated from the water activity of each of the gelatin as a component of capsule coating and the additive(s) packed in the capsule in accordance with the following formula. However, they differ from each other in such a case where a shift of moisture between coating and additives occurs due to the packing of an additive(s) into a capsule.

A_W =[A_W .multidot.M(gelatin)+A_W .multidot.M(additive)]/[M(gelatin)+M(additive)]

A_W : mean water activity

A_W : individual water activity

M: individual water content

Throughout the specification, when "a change in water activity" is discussed in relation to the moisture stability of capsules, the difference between the mean water activity (A_W) calculated according-to the formula on the basis of the individual water activity before packing an additive(s) and the A_WT value of a capsule calculated after packing the additive(s) is more important than the change in the absolute water activity measured for each of the gelatin and the additive(s). That is, the greater the reduction of A_WT from A_W of a capsule, the more the water transferred from the capsule coating to an additive(s), which means that the elevation of water activity inside of the said capsule is under suppression. The capsules of the present invention may contain any of pharmacologically active and pharmaceutically acceptable drugs, as long as it does not interact with additives adversely. However, a substance which is liable to change in pharmacological activity and physicochemical characteristics such as color, particle size and the like due to the change in water activity, especially elevation thereof, is suited. Examples of such substances include antibiotics, e.g., 7.beta.-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide]-(1,2,3-triaz ol-4-ylthimetylthio)-1-carba-3-cephem-4-carboxylic acid, and aspirin. Incidently, in some cases, such physicochemical change of a drug is attributable not only to the active substance but also the contaminants accompanying to the active substance.

The gelatin capsules obtained according to the present method are unexpectedly stable when preserved in a closed system, where the gelatin capsules are usually instable. Especially, a content drug(s) which otherwise is adversely affected by high water activity can be kept stably in a gelatin capsule even in a closed system at elevated temperature. At the same time, the gelatin capsule coating itself has also been stabilized. Accordingly, the present invention can contribute to the maintenance of the quality of capsules which have been considered to be subject to quality deterioration during the transportation or preservation.

Throughout the specification, the term "closed system" means a system where the distribution of outside air is blocked as completely as possible and is preferably constructed by packaging with a press-through package (PTP), alumi-pillow or the like.

The capsules of the present invention can be prepared in a conventional manner using conventional carriers, excipients and the like, except that an appropriate amount of additive(s) which serves as a water activity regulator is included. However, since an experiment revealed that additives such as cornstarch, crystalline cellulose, lactose, mannitol, sucrose and the like, which are commonly formulated into standard capsules, affect adversely on the water activity reduction, it is preferable to adjust the content of these additives adequately when they are used in the preparation of capsules of the present invention. For example, a relatively slight amount of such a substance, e.g., lactose, is usable as an excipient when preparing the capsules of the present invention on condition that it does not affect adversely the reduction of water activity.

Claim 1 of 10 Claims

1. A gelatin capsule having adjusted water activity and preserved in a closed system, which contains, packed therein, an additive(s) selected from the group consisting of carboxymethyl cellulose calcium, crosscarmellose sodium, and polyvinyl polypyrrolidone in the proportion of 50 to 150 wt. % of the total quantity of the gelatin of said capsule, wherein said gelatin capsule is a pharmaceutically acceptable gelatin capsule.

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