Process for the preparation of tablets of derivatives of cephalo

Details Process for the preparation of tablets of derivatives of cephalo Process for the preparation of tablets of derivatives of cephalo

1993-05-14

1996-05-07

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

424489, 424470, A61K 920

Patent

active

055143830

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a new pharmaceutical form based on cephalosporin. It relates more particularly to a new tabletted pharmaceutical form.
The invention relates very particularly to a new tabletted pharmaceutical form based on a semi-synthetic derivative of 7-acylaminocephalosporanic acid which can be administered orally. It relates preferably to the derivatives of 7-acylamino-3-vinylcephalosporanic acid. It relates above all to the forming of (6R,7R)-7- (Z)-2-(2-amino-4-thiazolyl)-2-carbomethoxyiminoacetamido!-8-oxo -3-vinyl-5-thia-1-aza-2-bicyclo 4.2.0!octene-2-carboxylic acid. This cephalosporin is better known under the international common name of Cefixime.
The compounds of the cephalosporin class exhibit a high antibiotic activity; their use is reserved, furthermore, to relatively severe cases when another antibiotic therapy has turned out to be unsatisfactory. These compounds from sic! their very high activity have led some countries to create very strict legislation relating to their production. Thus, compounds of this kind may be manufactured and formed only in specific rooms, this being in order to avoid any cross-contamination with any other medication.
Another difficulty in the forming of these active substances is due to their cost. Indeed, these products are obtained by a lengthy process requiring a large number of stages of synthesis and are therefore offered, when purchased, at an extremely high material cost.
It is therefore indispensable, for the two reasons referred to above, to have a processing technique which avoids product losses as much as possible.
Insofar as the techniques of pharmaceutical forming into tablets are concerned, two preparative routes are known:
In the first case, that is to say in the case of forming of active substances by a wet route, the following series of stages should be envisaged: the homogeneity of the mixture obtained
This series of stages requires the presence of eight different types of apparatus. Because of the toxicity of the active substance, the whole of the forming operation requires spotless cleaning in the case of each of these pieces of equipment. The changing of equipment on the one hand increases the cost of production significantly, since the losses cannot be reduced to a value of less than 2% and, on the other hand, prevents any automation of the process. Environmental protection and industrial hygiene are proportionally more difficult to control, the higher the number of stage of synthesis and of pieces of equipment. The wet route process additionally requires a drying stage with a risk of deterioration of the product which is far from being negligible. All these technical constraints, plus the legislative constraints with regard to the environment, have led industrialists to abandon forming by a wet route.
The second possible route for preparing a tabletted pharmaceutical form of an active substance consists in carrying out a direct compression of a mixture of powders, a mixture which in the case of the present invention consists of the cephalosporin and excipients.
It appeared that this technique was also to be proscribed within the scope of the present invention, in view of the high proportion of the active substance in relation to excipients. The direct compression process applies generally to tablets in which the quantity of active substance is smaller than 100 mg and in which the proportion of the active substance in the tablet does not exceed 25%. Above this percentage it is impossible to "bury" the active substance in the mass of the excipients and thus to be free from the physical and chemical constraints on the active substance.
Quite astonishingly it has been found that within the scope of the present invention all these problems have been solved by carrying out a direct compression of a mixture containing a cephalosporin and one or more excipients in a weight proportion of the active substance in the tablet ranging between 20 and 90% and preferably between 30 and 70%.
The cephalosporin employed in the present inventio

REFERENCES:
patent: 4015000 (1977-03-01), Kocsis et al.
patent: 4708956 (1987-11-01), Hirata et al.
patent: 5151417 (1992-09-01), Sasho et al.
Chemical Abstracts, vol. 112, No. 4, Abstract No. 25681s, Jun. 12, 1989, Ono Tomoi, Antiulcer agents containing cefixime (salts) English Abstract.
Chemical Abstracts, vol. 109, No. 12, Abstract No. 98626a, Jun. 28, 1988, Antibiotic drugs; cefixime trihydrate; cefixime trihydrate tablets and cefixime trihydrate powder for oral suspension English Abstract.
Derwent, Accession No. 89-327676, Sep. 27, 1989, 2-cephem cpds. having vinyl gp. at 3-position-useful as antibacterial agents effective against Gram-positive and English Abstract.

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