Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-08-26
2002-07-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C514S960000, C514S961000
Reexamination Certificate
active
06423341
ABSTRACT:
TECHNICAL FIELD
This invention relates to &bgr;-lactam antibiotic-containing tablets and a method of producing the same. More particularly, it relates to tablets of the above variety which can be orally taken either as such or, for taking by, for example, the aged who have difficulties in swallowing, as a dispersion available upon dropping the same into water in a glass for self-disintegration, and to a method of producing the same.
BACKGROUND TECHNOLOGY
Particularly in Europe and America, where &bgr;-lactam. antibiotics such as cefixime and cefdinir are administered generally in single doses of as great as 200 mg to 400 mg potency, unit dosage forms, whether they are capsules or tablets, have to be considerably large in size. When 400 mg potency capsules are prepared, for instance, the capsule size reaches approximately No. 0, so that not only patients having difficulties in swallowing but also ordinary adult patients become reluctant to take them or get a repulsive sensation in taking them. Such capsules are indeed difficult to take. In the case of tablets, too, 400 mg potency tablets generally weigh 700 to 1,000 mg per tablet and accordingly are large-sized.
The problems encountered in taking such large dosage forms give an unnecessary sensation of oppression to patients on the occasion of taking them. Improvements in their administrability have thus been required.
Therefore, the present inventor attempted to provide a dosage form with improved administrability by reducing the tablet size as much as possible to thereby facilitate the taking of tablets by the recipient and at the same time to provide a dosage form capable of being taken in the form of a dispersion resulting from rapid self-disintegration upon its being simply dropped into water or the like in a glass, for instance, to thereby make said dosage form administrable to persons of advanced age or children having difficulties in swallowing the dosage form as such. The expression “rapid self-disintegration” as used herein means that when the preparation is dropped into a glass containing a liquid such as water, the tablet form spontaneously collapses generally within 3 minutes, preferably within 1 minute, so that said preparation can be orally taken in dispersion form without awaiting long before taking.
It is indeed easy to produce tablets capable of self-disintegrating very rapidly by incorporating an effervescent agent comprising a combination of sodium hydrogen carbonate and tartaric acid, for instance. However, when such tablets are orally taken, they give off bubbles in the oral cavity, so that patients feel a discomfort or an unnecessary sensation of anxiety. For securing a good shelf-life in a humid environment, it is necessary to use a moisture-proof packaging material, which increases the production cost. Therefore, in developing the dosage form which the present invention is intended to provide, it has been a tough problem to find out a formulation enabling very rapid self-disintegration without the aid of any effervescent component.
For producing &bgr;-lactam antibiotic-containing tablets which can be easily ingested as they are and be also ingested in the form of a dispersion resulting from self-disintegration thereof, a technology is described in European Patent EP 0281200 B (corresponding Japanese patent application: Kokai Tokkyo Koho S63-301820), which comprises adding 24 to 70% by weight, based on the weight of the &bgr;-lactam antibiotic, of microcrystalline cellulose or microfine cellulose as a first disintegrator and 2 to 20% by weight, on the same basis, of low-substituted hydroxypropylcellulose or the like as a second disintegrator.
However, said first disintegrator, which is used in a large amount, increases the tablet size. In addition, the proportion of a binder component for wet granulation is as low as 0 to 0.1% by weight based on the antibiotic, hence is substantially nil. This is because the use of a binder renders tablets extremely poor in self-disintegrating properties. In the process for producing these tablets, in which no binder is used, a special method of insuring an integrity of the artefact is employed which comprises mixing the antibiotic bulk substance with microcrystalline cellulose and kneading the mixture with the aid of water under application of a great deal of force, without using any alcohol. As a result, large lumps are formed inevitably and they are milled in the wet state and then dried, followed by further milling to provide granules for tableting. It is a problem that these steps are very inefficient.
Meanwhile, tablets containing amoxicillin, which is a &bgr;-lactam antibiotic, are commercially available under the trade name of Flemoxin Solutab 500 from Brocades Pharma (Netherlands), the patentee to whom said European patent has been granted. Said tablets each contains 500 mg potency (about 570 mg) of amoxicillin and weighs about 970 mg, hence is very large and not entirely suited for oral administration.
Most &bgr;-lactam antibiotics are bitter. Therefore, aqueous dispersions prepared from tablets containing them, when orally taken, give a bitter taste, although the tablets, when taken as such, taste not so bitter. For masking the bitter taste, it thus becomes necessary to incorporate a sweetener, preferably a synthetic sweetener which is effective at low addition levels and thus suited for tablet miniaturization. However, when a commercial synthetic sweetener is incorporated, a problem arises, namely the self-disintegrating properties of tablets become poor, since synthetic sweeteners are soluble in water and become viscous and sticky.
DISCLOSURE OF THE INVENTION
In an attempt to develop a method of improving the rate of self-disintegration of tablets and at the same time miniaturizing the same, the present inventor made investigations concerning the disintegrator species to be used, the level of addition thereof, the binder addition level, the synthetic sweetener particle size and the method of incorporating the same, among others and, as a result, the inventor invented &bgr;-lactam antibiotic-containing tablets which are small-sized, show good self-disintegrating properties and can be produced by a conventional method.
Furthermore, the inventor found that when granulation is performed using ethanol, isopropyl alcohol or an aqueous solution of ethanol or isopropyl alcohol, tablets showing better dispersibility upon self-disintegration can be obtained.
The &bgr;-lactam antibiotic-containing tablets of this invention contain, per tablet, 60 to 85% by weight of an &bgr;-lactam antibiotic, 1 to 10% by weight of low-substituted hydroxypropylcellulose and/or crosslinked polyvinylpyrrolidone as a disintegrator, and 0.5 to 2% by weight of a binder.
Preferably, the &bgr;-lactam antibiotic-containing tablets of this invention further contain, per tablet, 0.5 to 15% by weight of a synthetic sweetener and/or a granulated synthetic sweetener.
The &bgr;-lactam antibiotic-containing tablet production method of this invention is characterized in that the above-specified respective proportions of a &bgr;-lactam antibiotic, the disintegrator and a binder, optionally together with one or more excipients, are granulated using ethanol, isopropyl alcohol or an aqueous solution of ethanol or isopropyl alcohol, the granulation product is mixed with the above-specified proportion of a synthetic sweetener and/or a granulated synthetic sweetener, optionally together with one or more other additives, and the resulting mixture is compressed.
The &bgr;-lactam antibiotic to be used in the practice of this invention is one capable of producing a beneficial effect upon oral administration and includes, for example, cefixime and cefdinir respectively represented by the structural formulas shown below as well as cefaclor, cefroxadine, cefadroxil, cefaloglycin, cefalexin, cefradine, amoxicillin, ampicillin and the like.
Each tablet contains such &bgr;-lactam antibiotic in a proportion of 60 to 85% by weight, preferably 65 to 80% by weight.
As a result of investigations concerning the disintegra
Fujisawa Pharmaceutical Co. Ltd.
Page Thurman K.
Seidleck Brian K.
LandOfFree
&bgr;-lactam antibiotic-containing tablet and production... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with &bgr;-lactam antibiotic-containing tablet and production..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and &bgr;-lactam antibiotic-containing tablet and production... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2887866