Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-08-17
2002-03-19
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S471000, C424S472000, C424S480000, C424S482000
Reexamination Certificate
active
06358528
ABSTRACT:
This invention relates to tablet formulations for oral administration, particularly to formulations, which comprise a &bgr;-lactam antibiotic, optionally together with a &bgr;-lactamase inhibitor.
Many known tablet formulations which include a &bgr;-lactam antibiotic are required to be taken orally three times a day. There is a need for oral formulations which need only be taken twice or less often per day. Methods of forming delayed or sustained release tablet formulations are known, for example coating the tablet with a release-retarding coating, or coating individual granules with such a coating, and compressing these coated granules into a tablet. “Release-retarding” as used herein, unless otherwise defined, refers both to release which is retarded so as to be sustained, i.e. active material is released gradually from the tablet, and to release which is retarded so as to be delayed, i.e. release begins or the rate of release increases after an initial delay.
Particular problems occur in the preparation of delayed or sustained release forms of the known antibacterial combination of the &bgr;-lactam antibiotic amoxycillin, in the form of its trihydrate, and the &bgr;-lactamase inhibitor clavulanic acid, in the form of an alkali metal salt, such as potassium clavulanate. This is because amoxycillin trihydrate is relatively insoluble in aqueous media, whereas potassium clavulanate is extremely soluble, hygroscopic and moisture-sensitive, and it is difficult to achieve sustained or delayed release of two such components at a compatible rate from a single formulation containing both.
According to this invention, a tablet formulation comprises a core which includes a first pharmaceutically active material, the core being coated with a release retarding coating, the coated core being itself surrounded by a casing layer which includes a second pharmaceutically active material.
The tablet formulation of the invention is suitable for oral administration, and provides a sustained and/or delayed release as a result of initial quick release of the second active material from the casing layer, and a sustained or delayed release of first active material from the coated core. Also the casing layer may serve to protect the core from the ingress of air and atmospheric moisture. Also coating of a single relatively large core in the tablet of the invention with a release-retarding coating requires less coating material than is required to coat a large number of smaller granules, and can therefore lead to a relatively low tablet weight.
The first and second pharmaceutically active materials in the tablet formulation may each individually, and/or together, comprise a &bgr;-lactam antibiotic optionally together with a &bgr;-lactamase inhibitor. Suitably the &bgr;-lactam antibiotic may be amoxycillin, e.g. in the form of its trihydrate, optionally together in combination with the &bgr;-lactamase inhibitor clavulanate, (the term “clavulanate” used herein, unless otherwise identified, refers both to clavulanic acid and its salts) e.g. in particular potassium clavulanate. The first and second active materials may both comprise the same active material, for example both comprising a &bgr;-lactam antibiotic optionally in combination with a &bgr;-lactamase inhibitor. When both the first and second active materials comprise amoxycillin and clavulanate, the relative ratios of amoxycillin:clavulanate may be different in the core and the casing layer, making up the overall ratio in the tablet.
The amoxycillin:clavulanate ratios in the core and casing layer and the overall ratio may each vary between broad limits, e.g. between 30:1 to 1:1, typically 12:1 to 2:1. A preferred ratio is around 8:1 to 4:1±25%.
The quantity of active material(s) in the tablet may vary up to the maximum allowed daily dose, and may typically be around a nominal single unit dose. For example in the case of amoxycillin and clavulanate, a single tablet may contain around 125, 250, 500, 750 or 875 mg of amoxycillin, and 62.5, 125 or 250 mg of clavulanate, both sets of weights being expressed in terms of the respective free acids. Typically the overall tablet may contain nominally 500 mg amoxycillin and 125 mg clavulanate, or 875 mg amoxycillin and 125 mg of clavulanate. Alternatively these weights may be divided between two or more tablets.
Typically for example the core may contain 25-75% of the total weight of the first and second components, and the casing layer may contain 75-25% thereof.
In the case of amoxycillin and clavulanate, in one embodiment both the core and the casing layer may contain clavulanate and amoxycillin. For example the core may contain 25-75% of the clavulanate and 25-75% of the amoxycillin, the balance being contained in the casing layer. For example the core may contain 100-400 mg of amoxycillin and 30-95 mg of clavulanate, expressed as the respective free acids. In an alternative embodiment, all of the clavulanate may be contained in the casing layer, e.g. in a rapid release form, with none of the clavulanate contained in the core. Such an embodiment may assist in maximising the clavulanate plasma level peak. In another alternative embodiment, all of the clavulanate may be contained in the core, with none of the clavulanate contained in the casing layer.
The core may be any convenient shape and need not necessarily be directly related to the shape of the overall tablet, typically the core may be spherical, ellipsoidal, or oblate spheroidal, within any suitable or convenient, e.g. a conventional, tablet shape.
The core and the casing layer may both comprise a compact of compressed ingredients including the respective active materials such as amoxycillin trihydrate optionally combined with potassium clavulanate. The active material(s) in the core may be present in a micronised or solubilised form. In addition to active materials the core and casing layer may contain additives conventional to the art of compressed tablets. Appropriate additives in such a tablet may comprise diluents such as calcium carbonate, magnesium carbonate, dicalcium phosphate or mixtures thereof, binders such as microcrystalline cellulose hydroxypropylmethylcellulose, hydroxypropyl- cellulose, polyvinylpyrrolidone, pre-gelatinised starch or gum acacia or mixtures thereof, disintegrants such as microcrystalline cellulose (fulfilling both binder and disintegrant functions) cross-linked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium or mixtures thereof, lubricants, such as magnesium stearate or stearic acid, glidants or flow aids, such as colloidal silica, talc or starch, and stabilisers such as desiccating amorphous silica, colouring agents, flavours etc. The core and casing layer may contain the same or different additives, in the same or different proportions.
The core may be made from a compacted mixture of its components, suitably in the form of granules, which may be made by a conventional granulating process as known in the art. Preferably the granules are made by a procedure of dry granulation of the granule components, for example milling, blending, slugging then milling, or by milling, blending or roller compaction then milling. The granules may include conventional additives introduced as a result of the granulation process, e.g. lubricants such as magnesium stearate, in conventional quantities, e.g. ca. 0.5-1 wt % of magnesium stearate. Suitably the granules are of 10-80 mesh size, suitably 10-40 mesh size, for example 16-30 mesh size.
The release-retarding coating may be a polymeric material, for example an enteric polymer (the term “enteric polymer” is a term of the art referring to a polymer which is preferentially soluble in the less acid environment of the intestine relative to the more acid environment of the stomach).
An enteric coating may be an essentially conventional coating material, for example enteric polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate
Davidson Nigel Philip McCreath
Grimmett Francis Walter
Dinner Dara L.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Venetianer Stephen
Webman Edward J.
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