Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1996-03-26
1998-06-02
Spear, James M.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424489, 514770, 514784, A61K 916, A61K 946
Patent
active
057595755
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/03018 filed Sep. 9, 1994.
The invention relates to effervescent granules for the preparation of a pharmaceutical formulation containing citric acid and calcium carbonate, and a process for the preparation of said granules. The preparation of such products is described, for example, in FR-A-2 552 308 and U.S. Pat. No. 4,867,942. However, high-dose effervescent calcium tablets which contain 2.5 g of calcium carbonate (equivalent to 1000 mg of calcium) and 4-4.5 g of citric acid show that effervescent solutions containing a relatively high concentration of calcium ions dissolved in 150 or 200 ml of water tend to form precipitates of insoluble tricalcium citrate on prolonged standing of the ready-to-drink solution. The time up to precipitation of the tricalcium citrate and the amount of the precipitate are dependent on the concentration of the calcium ions and citric acid in the ready-to-drink solution. However, since the consumer prefers to dissolve a tablet in 150 to not more than 200 ml of water, and very often the solution is not drunk immediately, this phenomenon is always a point of criticism, and all the more so since even effervescent tablets which contain only 500 mg of calcium ions in 150 ml of water exhibit such a precipitation, even if with a substantial delay, i.e. of up to about 1 hour.
WO 94/00107 has already proposed delaying this undesired effect by replacing a significant part (25 to 73%) of the citric acid with malic acid, and optionally by various salts. They interfere with the formation of pure tricalcium citrate--evidently by partial binding of the calcium carbonate and by formation of mixed salts--so that it takes substantially longer for the law of mass action to apply.
However, such large amounts of malic acid make the product considerably more expensive and restrict the use essentially to powder mixtures which can be compressed to give tablets only by special measures. The granulation properties of the material are in fact seriously impaired by these large additions: the material becomes very pasty. In addition, such tablets dissolve too slowly and residue formation may occur under certain circumstances during dissolution, since the conversion to, for example, calcium malate takes place too slowly during the dissolution process; this then results in residues of unreacted calcium carbonate.
The addition of the delta-lactone of gluconic acid, proposed in FR-A-2 552 308 (Example 4), also exhibits the effect according to the invention much too weakly, since said lactone liberates gluconic acid only in the presence of relatively large amounts of water, so that the advantages expected for the preparation of the effervescent granules (see below) are not achieved.
These problems are now solved in a surprising manner for the first time by replacing 5 to 20, preferably 10 to 15, percent by weight of the citric acid with at least one foreign acid which, apart from malic acid, may also be gluconic acid or lactic acid. Other acids are therefore less advantageous because tartaric acid forms an insoluble calcium tartrate; adipic acid and ascorbic acid exhibit the desired effect only weakly, if at all, and adipic acid itself is moreover only slightly soluble. On the other hand, the stated lower limit is also important: the claimed acids too exhibit the desired effect only too weakly, if at all, when they are used in amounts of only less than 5 percent by weight.
During many attempts to solve the problem, it was found that replacing as little as 100 mg of citric acid with malic acid in an effervescent tablet with 1000 mg of calcium delays the precipitation time in 125 ml of water: a batch with a very strong tendency towards precipitation was improved from an original value of 7 min by 30% to 9.5 min and, with the addition of 200 mg, by 50% to 11 min. The turbidity was tested photometrically as absorbance at 480 nm at an identical value in order to obtain objective parameters.
BRIEF DESCRIPTION OF THE DRAWING
Replacing only 5-15% by weight of the citric acid wit
REFERENCES:
patent: 4783331 (1988-11-01), Alexander et al.
patent: 4867942 (1989-09-01), Gergely et al.
patent: 5401524 (1995-03-01), Burkes et al.
Gergely Gerhard
Gergely Irmgard
Gergely Stephen
Gergely Thomas
Gergely Gerhard
Spear James M.
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