Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-21
2004-02-24
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S419000, C548S452000, C548S492000
Reexamination Certificate
active
06696481
ABSTRACT:
The present invention relates to a new salt of perindopril and to pharmaceutical compositions containing it. Perindopril, or (2S)-2-[(1S)-carbethoxybutylamino]-1-oxo-propyl-(2S,3aS,7aS)perhydroindole-carboxylic acid, an angiotensin I converting enzyme inhibitor (CEI), is a compound known especially for the treatment of arterial hypertension and heart failure.
Perindopril has previously been described in the Patent Specification EP 0 049 658. In that European patent it is mentioned, as is usual, that the compounds of the invention may be presented in the form of addition salts with a pharmaceutically acceptable, mineral or organic, base or acid. The compounds described in that patent are in a non-salt form and primarily, when addition salts with a pharmaceutically acceptable base or acid are mentioned by way of example, the sodium salt or the maleate are given.
In the development of that product, however, it has proved very difficult to find a pharmaceutically acceptable salt having not only good bioavailability but also adequate stability to be suitable for the preparation and storage of pharmaceutical compositions.
In the studies originally carried out on the product, the tert-butylamine salt of perindopril proved to have adequate qualities for development of the product and it is this tert-butylamine salt of perindopril that is currently marketed.
The non-salt form has been studied, as well as the maleate and the sodium salt. In the course of temperature and humidity stability studies it was found that the sodium salt was not suitable for handling because it is immediately converted into an oil on contact with the atmosphere; as for the non-salt form and the maleate, they degrade rapidly under such conditions (approximately 25 to 30% of product degraded in 8 days at 50° C.).
The tert-butylamine salt was thus alone in exhibiting the best stability compared to the other forms studied. However, in view of the intrinsic fragility of perindopril, the tert-butylamine salt has not been capable of providing a complete solution to the problems of the product's stability to heat and humidity. Indeed, for marketing, tablets of perindopril tert-butylamine salt must, in certain countries, be protected with additional packaging measures. Moreover, even for temperate-climate countries, that instability has made it impossible to obtain a shelf-life of more than 2 years for the tablets. Finally, for marketing of the tablets, they have to be marked “to be stored at a temperature less than or equal to 30 degrees”.
These constraints are, of course, onerous, especially in terms of organisation and cost, and it has appeared especially useful to try to develop a new perindopril salt in order to reduce the constraints due to the tert-butylamine salt.
Numerous salts were studied and, as indicated hereinbefore, the salts customarily used in the pharmaceutical sector proved to be unusable.
On the other hand, and in surprising manner, it has been found that the arginine salt of perindopril, besides being new, has entirely unexpected advantages over all the other salts studied and, more especially, over the tert-butylamine salt of perindopril.
REFERENCES:
patent: 0049658 (1982-04-01), None
Damien Gerard
Lefoulon François
{acute over (M)}archand Bernard
Les Laboratoires Servier
McKane Joseph K.
The Firm of Hueschen and Sage
Wright Sonya
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