Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1994-11-21
1996-10-15
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
424464, 424465, 424490, 424492, 424494, 424497, C07C 53134
Patent
active
055656137
DESCRIPTION:
BRIEF SUMMARY
This application is filed under 35USC 371 of PCT/EP93/01243 filed May 19, 1993.
The invention concerns new preparations of 2-arylpropionic acids with improved tablettability and improved strength which, in particular, contain ibuprofen racemate, S-ibuprofen or mixtures of R- and B-ibuprofen, as well as usual adjuvant and/or carrier materials, as well as processes for their production.
2-Arylpropionic acid derivatives, such as ibuprofen, flurbiprofen, ketoprofen, tiaprofen or pirprofen, as well as their enantiomers, are used in therapy as non-steroidal antiphlogistics, anti-rheumatics, analgesics or antipyretics.
From technological point of view, these medicaments possess disadvantages. They are only poorly soluble in water and possess relatively low melting ranges. Thus, e.g. ibuprofen melts at about 75.degree.-77.degree. C., the flurbiprofen racemete at about 110.degree.-111.degree. C. and the ketoprofen racemate at about 94.degree. C. The enantiomers of ibuprofen even already melt at about 50.degree. C.
As is known, materials with low melting range lead, in the case of the tabletting as a result of sintering occurrences and due to adhesion to the stamps and matrices of the tabletting presses, to more or less strongly disturbing production problems (H. Sucker, P. Fuchs and P. Speiser: Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart 1978, p. 381).
The adhesion of these low melting medicaments can be removed by admixture of large amounts of anti-adhesives (mould separation agents). However, the mixtures thereby become hydrophobic. From this in turn results a delayed liberation of the medicament, involved with a delayed resorption or even poor bioavailability. As a result of overdosing of the anti-adhesive, the tablets can also become too soft.
Up to a certain extent, the complications in the case of the tablet production can be overcome by the addition of certain tabletting adjuvant materials, such as anti-adhesives or lubricants, in comparatively high doses, as well as by a drastic reduction of the rate of pressing. Furthermore, according to experience, in the case of tablets which contain low melting ingredients, after certain storage times, there is to be reckoned with post-hardenings as a result of sinterings (K. H. Bauer, K. H. Fr omming and C. F uhrer: Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart, New York, 1986). These post-hardenings bring with them impairments of the breakdown time and not sufficient medicament liberations or not sufficient bio-availabilities.
Hitherto, a tabletting of 2-arylpropionic acids was attempted with varying successs to remove these disadvantages by addition of mould separating or lubricating agents, drying agents (e.g. highly dispersed silicic acid), suitable filling agents and of strong breakdown accelerators (e.g. Kollidon CL.RTM., cross-linked PVP), above all, however, by more than average increases of the added amounts of these adjuvant materials.
In the European Patent Application EP-A-O 267 321 is described an ibuprofen-containing medicament which contains ibuprofen only in the S(+)-form. However, this known medicament possesses the above-mentioned disadvantages, i.e. it can only be poorly tabletted.
The sintering or melting together can also be prevented by addition of comparatively large amounts of filling agent, for example cellulose powder or lactose, or by means of disintegration agents, for example starch. However, too high additions of disintegration agent most result in soft tablets with increased friability since starch or other similarly elastic materials alone or in high dosaging can only be poorly compressed or the tablets become so large that they can only be swallowed with difficulty.
In the German Patent Application P 39 22 441.4 is described a process to improve the tablettability of ibuprofen and S(+)-ibuprofen. It was found that when ibuprofen or S(+)-ibuprofen are converted wholly of partly into their calcium salts and these are used for the tablet production, the tablettability can be clearly improved. Already 25% of ca
REFERENCES:
patent: 4873231 (1989-10-01), Smith
Bauer Kurt
Brune Kay
Geisslinger Gerd
Huber Anton S.
Killos Paul J.
Pharmatrans Sanaq AG
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