Therapeutic effervescent compositions

Details Therapeutic effervescent compositions Therapeutic effervescent compositions

1998-09-03

2001-08-14

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S464000, C424S465000, C424S489000, C514S784000, C514S951000

Reexamination Certificate

active

06274172

ABSTRACT:

This invention relates to novel granulates comprising effervescent couples, pharmaceutical formulations comprising such granulates, to processes for the manufacture thereof and the use of such formulations in therapy.
Effervescent pharmaceutical formulations are well known in the art. At the simplest level, such compositions include a couple which comprises an acid such as citric acid or a mono or dihydrogen salt thereof and a carbon dioxide source such as a carbonate or hydrogen carbonate alkali metal salt, such as sodium hydrogen carbonate. These do not react together when dry but combine to release carbon dioxide and an effervescent effect in the presence of water. The pharmaceutical compositions may be in the form of a tablet for dissolving in water or a dispersible powder for sprinkling onto water, prior to administration. The components of the couple are blended together during manufacture of the composition. It is important to avoid water, to prevent premature effervescence. The latter, in the case of a citric acid or mono hydrogen salt/sodium hydrogen carbonate couple, leads to the formation of carbon dioxide and may lead to additional and undesirable degradation when the drug substance is acid sensitive.
A suitable drug for use in an effervescent formulation is cimetidine, marketed by Smith Kline & French Laboratories as Tagamet. An effervescent tablet preparation containing 200 mg cimetidine and a citric acid/sodium hvdrogen carbonate stoichiometric couple is marketed in several European countries. The couple is produced by a wet granulation process. The effervescent formulation also helps to overcome the bitter taste of cimetidine. In addition. EP 0 233 853-A (Laboratoires Smith Kline & French) describes effervescent couples particularly suitable for use with H
2
antagonists such as cimetidine which are sensitive to acid. The couple comprises a mixture of mono- and dialkali metal citrate salts in a defined ratio. This is prepared by partially neutralising citric acid by treatment thereof with an alkali metal carbonate or bicarbonate salt in water and stopping the reaction when a certain amount of carbon dioxide has been evolved. This processes involves several steps, including wet granulation and subsequent drying. A shorter, more efficient process would be commercially attractive.
We have now found that improved couples may be prepared more efficiently if a dry Granulation technique involving a roller compactor is used to blend together the components of the couple. The use of a roller compactor is becoming increasingly common in pharmaceutical technology. The technique depends upon the densification of a fine powder to obtain fragments or flakes of undefined shape. These flakes are then usually crushed to obtain granulates which are screened to the size required by the user.
The use of roller compaction to prepare granulates comprising a sodium hydrogen sulphate/sodium hydrogen carbonate couple, for subsequent incorporation into effervescent tablets for use in cleaning toilet bowls, is described in Pharmaceutical Dosage Forms: Tablets, vol 1, ed H A Lieberman and L Lachman (Marcel Dekkel, 1980).
Accordingly, the present invention provides for pharmaceutical granulates comprising an effervescent couple, characterised in that the couple comprises anhydrous powdered monosodium citrate and powdered sodium bicarbonate and the granulates are prepared using a roller compactor.
Such granulates are found to dissolve more quickly and more fully in water and there is also no chemical reaction between the components.
The most effective granulates are made using anhydrous powdered monosodium citrate of a certain particle size range. Suitable grades of anhydrous powdered monosodium citrate comprise particles which are substantially (i.e. about more than 90%) within the range 0 to 500 microns, preferably 355 microns, more preferably 0 to 250 microns. Suitable grades are available from Roche (monosodium citrate anhydrous powder, maximum of 5% w/w with grain size >0.250 mm), Boehringer Ingelheim (monosodium zilrate wasserfrei Art-Nr 661 511, minimum of 90% w/w with grain size <0.150 mm), Jungbunzlauer (maximum of 5% w/w with grain size >0.355 mm) and Haarmann & Reimer Corp. (maximum of 1% with grain size >0.500 mm).
Suitable grades of powdered sodium bicarbonate comprise particles which are substantially (i.e. about more than 90%) within the range of 0 to 500 microns, preferably 270 microns more preferably 0 to 130 microns. Suitable grades of powdered sodium bicarbonate are available from Solvay, for instance the grades 0 to 13 (particle size, by sieving method: >0.16 mm max; 15 g/kg) and extra-fine (particle size by sieving method: >0.125 mm max; 20 g/kg).
Tablets manufactured using Granulates with low particle size were found to be harder than those manufactured using granulates with large particle size but were otherwise comparable.
Granulates according to the present invention may be obtained by a process which comprises the steps of:
a) blending together the components of the couple;
b) roller compacting the blend to produce flakes;
c) crushing the flakes to obtain granulates; and
d) if desired, screening the granulates by size.
Suitably, the components of the couple are blended together at a controlled temperature, for instance about 20° C. and controlled relative humidity, for instance about 20% RH and processed in a roller compactor to form flakes. Roller compaction may be carried out over a range of linear compaction strengths, the appropriate value being influenced by the particle size of the monosodium citrate and sodium hydrogen carbonate. For smaller particle sizes (for instance, the grades of monosodium citrate from Boehringer Ingelheim and sodium hydrogen carbonate from Solvay previously mentioned), linear roller compaction strengths of about 20 KN/cm are found to give suitable granulates for further processing into final finished forms such as tablets. For larger particle sizes (for instance monosodium citrate from Jungbunzlauer), linear compaction strengths of about 30 KN/cm are preferred. The flakes thus obtained are then crushed to obtain granulates which are screened to the size required for further processing, suitably a size in the range 0 to 1250 microns is used. Suitably the granulates thus obtained are calibrated for effervescent potency using a standard assay, prior to further use.
Suitably, granulates according to the present invention are incorporated into a pharmaceutical formulation. Accordingly, in a further aspect, the present invention provides a pharmaceutical formulation comprising granulates comprising an effervescent couple and a drug substance which may optionally be incorporated into the Granulates, characterised in that the couple comprises anhydrous powdered monosodium citrate and powdered sodium bicarbonate and the granulates are processed using a roller compactor.
Suitably, granulates may comprise the components of the couple and, optionally, other pharmaceutically acceptable excipients and/or drug substance. Accordingly, in a further aspect, the present invention provides pharmaceutical formulations comprising Granulates comprising an effervescent couple and a drug substance, characterised in that the couple comprises anhydrous powdered monosodium citrate and powdered sodium bicarbonate and the granulates are prepared using a roller compactor.
Suitable drug substances include H
2
-antagonists well known in the art such as ranitidine, cimetidine, famotidine, nizatidine and roxatine or pharmaceutically acceptable salts thereof. A representative drug substance is cimetidine or the hydrochloride salt thereof. Other suitable drug substances include those obtainable directly ‘over the counter’ (OTC drugs) such as analgesics, for instance aspirin, ketoprofen, naproxen, paracetamol and ibuprofen. Other suitable products in which such effervescent couples may be incorporated include indigestion products, vitamin supplements and antibiotics.
Suitably, the drug substance is incorporated in an amount such that individual tablets

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