New compositions containing taxane derivatives

Details New compositions containing taxane derivatives New compositions containing taxane derivatives

1993-08-23

1995-04-04

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514471, 514408, 424502, A61K 31335, A61K 3134, A61K 950

Patent

active

054038588

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to compositions and especially pharmaceutical dosage forms containing therapeutic agents having antitumour and antileukaemic activity. It relates more especially to compositions suitable for injection containing taxane derivatives, such as, in particular, taxol or one of its analogues or derivatives of the formula: ##STR1## in which R represents a hydrogen atom or an acetyl radical and R.sub.1 represents a tert-butoxycarbonylamino or benzoyloxyamino radical. Of these derivatives, that in which R represents an acetyl group and R.sub.1 represents a benzoyloxyamino group or that in which R represents a hydrogen atom and R.sub.1 represents a tert-butoxycarbonylamino radical are preferred. The first of these two compounds is better known by the name of taxol, and the second is known by the name of Taxotere.
These products exhibit in vivo substantial activity against malignant rumours, which has enabled them to be studied in the treatment of diseases resistant to other anticancer therapies.
Unfortunately, these products possess such low solubility in water that it has been necessary to prepare formulations for injection containing surfactant and ethanol. Ethanol is the best solvent for dissolving compounds of formula (I).
For example, according to the publication by Rowinsky, Lorraine, Cazenave and Donehower which appeared in the Journal of the National Cancer Institute, vol. 82, No. 15, pages 1247-1259 on 1st Aug. 1990, a first solution, termed "stock solution", containing approximately 6 mg/ml of taxol in a solvent mixture composed of: containing sodium chloride or dextrose (glucose). To obtain a mixture which is stable from both a physical standpoint and a chemical standpoint, the authors of this paper state that it is necessary to limit the concentration of active principle in the perfusion solution to concentrations of approximately 0.03 to 0.6 mg/ml (see above publication, page 1251, column 1, third paragraph).
Now, it is desirable to be able to inject sufficient doses of active principle; to this end, clinicians would like to inject concentrations of active principle of between approximately 0.3 and 1 mg/ml in the perfusion fluid; above these doses, anaphylactic shock phenomena which are difficult to control, due in the main to the Cremophor, are seen (see the publication by Rowinsky, page 1250, second column, last paragraph).
Still according to this publication, to obtain such concentrations (between 0.3 and 1 mg/ml), it is necessary to inject solutions containing, at the same time as the active principle, concentrations of each of the following compounds, ethanol and most especially Cremophor, of approximately 8 g per 100 ml of solution. Since the treatment often requires the administration of high doses of active principle, and since the concentration of the active principle in the solution is relatively low, the injection of a large volume has the effect of causing, in addition to anaphylactic manifestations, manifestations of alcohol poisoning during the treatment.
The present invention provides compositions that make it possible either to reduce the ethanol concentrations greatly, or to eliminate Cremophor and ethanol completely from the perfusions.
For this purpose, according to a first implementation of the present invention, a composition suitable for use as a stock solution is prepared, containing a compound of formula I as defined above dissolved in a surfactant which may be a polysorbate, e.g. as marketed under the name "Tween", a polyoxyethylene glycol ester as marketed, e.g., under the name "Emulphor", or an ester of polyethylene glycol and castor oil as marketed, e.g., under the name Cremophor, and virtually free from ethanol.
The stock solution may be prepared by dissolving the active principle in ethanol, which is the best biocompatible solvent for the taxane derivatives, and then gradually adding the surfactant. Solutions containing 10 to 100 mg/ml of active principle in a mixture containing approximately 50% of surfactant can be prepared in this manner. The

REFERENCES:
patent: 4206221 (1980-06-01), Miller et al.
patent: 4960790 (1990-10-01), Stella et al.
Chemical Abstracts: vol. 106(22) 182581c-Tarr, et al (1987).
Merck Index, 11th Edition, #7559--(1989).

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