Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-02-17
2001-10-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S489000, C424S490000, C424S493000, C424S494000
Reexamination Certificate
active
06299903
ABSTRACT:
This invention relates to pharmaceutical formulations for oral administration, comprising an antibiotic and a &bgr;-lactamase inhibitor.
Oral formulations of this type are known, but generally need to be administered three times daily. It is desirable to produce such a formulation in a delayed or sustained release form which may be suitable for less frequent administration. A particularly effective &bgr;-lactamase inhibitor is the known compound clavulanic acid and its derivatives (hereinafter collectively termed “clavulanate” unless otherwise specifically identified), especially the potassium salt of clavulanic acid.
The invention therefore provides a pharmaceutical tablet formulation, comprising:
a matrix which comprises a &bgr;-lactam antibiotic optionally in combination with a &bgr;-lactamase inhibitor,
and dispersed within said matrix, granules in a delayed release form (“delayed release granules”) which comprise a &bgr;-lactam antibiotic optionally in combination with a &bgr;-lactamase inhibitor,
the overall tablet formulation including a &bgr;-lactam antibiotic and a &bgr;-lactamase inhibitor.
The matrix preferably includes a &bgr;-lactamase inhibitor.
The granules may optionally also include a &bgr;-lactamase inhibitor in combination with the &bgr;-lactam antibiotic.
The matrix may also include dispersed within it granules (“rapid release granules”), in a form which release their content more rapidly than the delayed-release granules, which comprise a &bgr;-lactam antibiotic, optionally in combination with a &bgr;-lactamase inhibitor.
Preferred &bgr;-lactam antibiotics are penicillins and cephalosporins, in particular amoxycillin, for example in the form of amoxycillin trihydrate. A preferred &bgr;-lactamase inhibitor is clavulanate, particularly potassium clavulanate. In the matrix and those granules which contain a &bgr;-lactamase inhibitor the ratio antibiotic: &bgr;-lactamase inhibitor may vary independently between wide limits, in the case of amoxycillin: clavulanate for example varying between 1:1 to 30:1, for example amoxycillin: clavulanate between 1:1 to 12:1, e.g. 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1 inclusive expressed as the equivalent weight ratios of the parent free acids. In the overall tablet formulation the ratio antibiotic: &bgr;-lactamase inhibitor may also vary between similarly broad limits, for example between 1:1 to 30:1, for example between 1:1 to 12:1, e.g 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1 inclusive.
The matrix may suitably comprise a mixture of amoxycillin and potassium clavulanate in a ratio amoxycillin: clavulanate between 2:1 to 8:1, for example between 2:1 and 4:1 inclusive.
In one form of the tablet formulation of the invention, the tablet has a matrix which comprises amoxycillin and clavulanate, dispersed within which are delayed release granules which comprise amoxycillin and clavulanate. These granules may suitably comprise amoxycillin and potassium clavulanate in a ratio amoxycillin: clavulanate between 2:1 to 8:1 inclusive, for example around 4:1±10%.
In this first form of the tablet the overall distribution of the antibiotic and &bgr;-lactamase inhibitor between the matrix: granules may independently suitably vary between 2.5:1 to 1:2.5. Suitably the distribution of matrix amoxycillin: granule amoxycillin is around 1:1.5±10%, and the distribution of matrix clavulanate: granule clavulanate is around 1.5:1±10%.
In a second form of the tablet formulation of the invention, the tablet has a matrix which comprises amoxycillin and clavulanate, dispersed within which are delayed release granules which comprise amoxycillin, and rapid release granules which comprise amoxycillin.
In this second form of the tablet the overall distribution of the amoxycillin between the matrix plus rapid release granules: delayed release granules may vary between 2.5:1 and 1:2.5. Suitably the distribution may be around 1:1.5±10%. Suitably the distribution of amoxycillin between rapid release granules: matrix: delayed release granules may be around 1:1-2:2-6.
The matrix may comprise a compact of compressed ingredients including the antibiotic and optionally present &bgr;-lactamase inhibitor. In addition to antibiotic and optionally present &bgr;-lactamase inhibitor the matrix may contain conventional additives. Appropriate additives in such a tablet may comprise diluents such as calcium carbonate, magnesium carbonate, dicalcium phosphate or mixtures thereof, binders such as hydroxypropyl-methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, pre-gelatinised starch or gum acacia or mixtures thereof, disintegrants such as 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 granules 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 slugging then milling, or by 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 10-40 mesh size, for example 16-30 mesh size.
To form delayed released granules, the granules are preferably coated with a coating layer of a dissolution-retarding coating. In their uncoated form such granules are rapid release granules, which release their content more rapidly than coated granules. The dissolution-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 known for enteric coating of antibiotic granules, for example enteric polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, etc. These may be used either alone or in combination, or together with other polymers than those mentioned above. The enteric coating may also include insoluble substances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane, etc. The enteric coating may also include starch and/or dextrin.
Preferred enteric coating materials are the commercially available “Eudragit” (Trade Mark) enteric polymers, such as “Eudragit L” (Trade Mark), “Eudragit S” (Trade Mark) and “Eudragit NE” (Trade Mark) used either alone or with a plasticiser. Such coatings are normally applied using a liquid medium, and the nature of the plasticiser, depends upon whether the medium is aqueous or non-aqueous. Aqueous plasticisers include propylene glycol or “Citroflex” or “Citroflex A2” (Trade Marks) (mainly triethyl citrate or acetyl triethyl citrate). Non-aqueous plasticers include these, and also diethyl and dibutyl phthlate and dibutyl sebacate.
The quantity of plasticiser included will be apparent to those skilled in the art. The enteric coating may also include an anti-tack agent such as talc, silica or glyceryl monostearate. The quantity of plasticiser and anti-tack agent may be generally conventional to the art. Typically the c
Grimmett Francis Walter
Hartnell Michael William
Rivett Ernest Lionel Gilbert
Dinner Dara L.
Kinzig Charles M.
Page Thurman K.
Seidleck Brian K.
SmithKline Beecham p.l.c.
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