Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Patent
1997-01-24
1998-02-10
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
A61K 3128
Patent
active
057169888
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/1B95/00614 filed Aug. 7, 1995.
The present invention is concerned with a pharmaceutically stable preparation of oxaliplatinum for administration by the parenteral route.
Oxaliplatinum (International Nonproprietary Name) is an optical isomer prepared in 1978 by Y. Kidani from a mixture of diaminocyclohexane derivatives (dach-platinum), namely the cis-oxalato complex of platinum II, from the trans-1-1,2-diaminocyclohexane or according to "Who Drug Information" vol. 1, N.degree. 4, 1987, the (oxalato(2-)0,0') platinum from the (1R,2R)-1,2-cyclohexane-diamine-N,N'. This complex compound of platinum is known to exhibit a therapeutic activity comparable or superior to that of other known complex compounds of platinum, such as cis-platinum for example.
As the latter, oxaliplatinum is a cytostatic antineoplastic agent which can be used in the therapeutic treatment of various types of cancers and, more particularly, those of the colon, of the ovaries, of the upper respiratory tract and also epidermoid cancers and cancers of germinal cells (testicles, mediastina, pineal gland, etc.). In addition to the above-mentioned examples of the use of oxaliplatinum, one can furthermore mention colon cancers which are resistant to pyrimidines, non-small cell lung cancers, non-Hodgkin's lymphoma, breast cancers, cancers of the upper respiratory/digestive tract, malignant melanoma, hepatocarcinoma, urothelial cancers, prostate cancers, etc, and more broadly, other types of solid tumors.
At the present time, oxaliplatinum is available for pre-clinical and clinical trials in vials as a lyophilisate, for reconstitution, just before the administration, with injectable water or an isotonic 5% glucose solution, and dilution with a 5% glucose solution, the administration being carried out by infusion, intravenously.
However, such a dosage form implies the use of a manufacturing process (lyophilization) which is relatively complicated and expensive as well as a reconstitution step at the time of use which requires both skill and care. Furthermore, in practice, such a method has proved to carry the risk of an error being made when reconstituting extemporaneously the solution; in actual fact, it is quite common for the reconstitution from lyophilisates of injectable pharmaceutical preparations or for diluting liquid preparations, to use a 0.9% NaCl solution; the mistaken use of such a solution in the case of the lyophilized form of oxaliplatinum would be quite harmful to the active principle, which would form a precipitate (dichloro-dach-platinum derivative) with NaCl and would bring about the rapid breakdown of said product.
Thus, in order to avoid all risk of misuse of the product and to make available to the medical practitioner or the nurse an oxaliplatinum preparation which may be used without requiring the above-mentioned operations, investigations were made to obtain an injectable solution of oxaliplatinum which would be ready to use and which, furthermore, would remain pharmaceutically stable before use for an acceptable duration of time according to recognized standards, and be easier and less expensive to manufacture than lyophilisates, while exhibiting a chemical purity (absence of isomerization) and a therapeutic activity equivalent to that of the reconstituted lyophilisate. This is the objective of the present invention.
The present inventors were able to show that this objective can be attained, in a totally surprising and unexpected manner, by using as the dose form for the administration by the parenteral route, an aqueous solution of oxaliplatinum, wherein the concentration of the active principle and the pH are within well determined respective ranges and wherein the active principle is free of any acidic or alkaline agent, buffer or other additive. It has been found, in particular, that aqueous solutions of oxaliplatinum having a concentration lesser than approximately 1 mg/ml are not sufficiently stable.
Accordingly, the object of the present invention is a stable pharmaceutical preparation of oxali
REFERENCES:
patent: 4169846 (1979-10-01), Kidani et al.
Ibrahim Houssam
Mauvernay Rolland-Yves
Debiopharm S.A.
Henley III Raymond
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