Compositions containing taxane derivatives

The invention provides new compositions containing taxane derivatives, consisting of solutions of such derivatives in a solvent mixture composed of ethanol and polysorbate. These compositions are used to prepare perfusions.

The present invention relates to compositions containing therapeutic agents 
having antitumour and antileukaemic activity. It relates more especially 
to pharmaceutical, and in particular injectable, dosage forms containing 
taxane derivatives, such as, in particular, taxol or one of its analogues 
or derivatives of the following general formula: 
##STR1## 
Wherein R represents a hydrogen atom or an acetyl radical and R.sub.1 
represents a tert-butoxycarbonylamino or benzoylamino radical. The two 
derivatives in which R represents an acetyl group and R.sub.1 a 
benzoylamino group or in which R represents a hydrogen atom and R.sub.1 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 
tumours, 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 a formulation for an injectable preparation 
based on surfactant and ethanol. Ethanol is the best solvent for 
dissolving compounds of the formula (I). 
As an 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: 
50% by volume of ethanol 
50% by volume of Cremophor EL, 
is prepared. For injection, this solution is mixed with a perfusion fluid 
containing sodium chloride or dextrose. 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). 
This publication also discloses that, to obtain such concentrations 
(between 0.3 and 1 mg/ml), it is necessary to inject solutions containing, 
as well 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 intoxication during the 
treatment. 
It has been discovered that, by the use of the pharmaceutical dosage forms 
of the present invention, it is possible to avoid the use of Cremophor and 
greatly to reduce the ethanol concentrations used. 
For this purpose, a stock solution is prepared, containing the active 
principle of formula I in a solvent mixture composed of ethanol, which is 
the best biocompatible solvent for active principles of this class, and a 
polysorbate surfactant, e.g. as marketed, in particular, under the name 
"Tween". 
The stock solution is prepared by dissolving the active principle in 
ethanol 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 present invention then makes it possible to replace the Cremophor, 
described in the publication of the Journal of National Cancer Institute, 
by a polysorbate. In effect, when an injectable solution containing 
ethanol and a polysorbate 80 surfactant in place of Cremophor was used in 
the clinical situation, it became apparent that the anaphylactic reactions 
were greatly reduced compared with the use of the same solution prepared 
with Cremophor. In addition to this considerable advantage, it became 
apparent, most surprisingly, that, in the bottles of stock solution, the 
concentration of active principle can reach 15 mg/ml. The perfusion fluid 
after dilution of these bottles contains an amount of ethanol, and also an 
amount of surfactant, which is reduced a little over twofold. 
The perfusions prepared from the above stock solutions, and containing a 
concentration of active principle of, e.g., 1 mg/ml, which is a 
preference, or less, contain less than 50 ml/l and preferably less than 35 
ml/l of surfactant and of ethanol, which represents a reduction of 
approximately 40% relative to the perfusions of the prior art. 
The new perfusions are stable from a physical standpoint, that is to say no 
precipitation phenomenon is seen to appear within approximately 8 hours. 
The taxol or Taxotere perfusions may be injected into humans at a 
predetermined flow rate depending on the amount of active principle it is 
desired to inject. The anaphylactic shock phenomena which were observed 
with the solutions of the prior art are not observed with these solutions. 
The invention is described more completely in the Examples which follow, 
which are not to be considered as limiting the invention.

EXAMPLES ACCORDING TO THE INVENTION 
EXAMPLE 1 
Taxotere (0.450 g) is dissolved in ethanol (15 ml). The mixture is made to 
30 ml with polysorbate 80 to obtain a solution containing Taxotere (15 
mg/ml). The physicochemical stability of this solution is satisfactory. 
After mixing with a 5% glucose solution so as to obtain a final 
concentration of 1 mg/ml, this solution contains 33 ml/l of polysorbate 80 
and 33 ml/l of ethanol. 
The perfusion is stable for more than 21 hours, i.e. no precipitation 
phenomenon is seen during this period. 
EXAMPLE 2 
Example 1 is reproduced with an initial concentration of 10 mg/ml of 
Taxotere; the results are shown in Table 1. 
COMATIVE EXAMPLE ACCORDING TO THE PRIOR ART 
Taxol (0.180 g) is dissolved in ethanol (15 ml). The mixture is made to 
volume with Cremophor to obtain a solution (30 ml) which contains taxol (6 
mg/ml). 
This solution is diluted in the same perfusion solution as above to five a 
final concentration of 1 mg/ml; the perfusion solution contains 87.7 ml/l 
of Cremophor and 87.7 ml/l of ethanol. The perfusion solution is stable 
for more than 21 hours. 
EXAMPLE 3 
Taxotere (65 g) is dissolved in ethanol (2083 ml). The volume is adjusted 
to 4147 ml by adding polysorbate 80 (2083 ml). The mixture is homogenised 
by mechanical stirring. It is filtered through a filter of pore size 0.2 
.mu.m. A solution containing Taxotere (approximately 15 mg/ml) is 
obtained. 
After dilution to a Taxotere content of 1 mg/ml in a perfusion bag 
containing 5% dextrose, this solution is stable for at least 96 hours. 
TABLE 1 
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Stock Active Ethanol in 
solution 
principle in 
Surfactant in 
the 
Example 
Product 
Solvent 
concentration 
the perfusion 
the perfusion 
perfusion 
Stability 
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Comparative 
taxol 
EtOH/Crem 
6 mg/ml 
1 mg/ml 
87.7 ml/l 
87.7 ml/l 
&gt;21 H 
taxol 
EtOH/Poly 
6 mg/ml 
1 mg/ml 
83.3 ml/l 
83.3 ml/l 
&gt;21 H 
1 Taxotere 
EtOH/Poly 
15 mg/ml 
1 mg/ml 
33.3 ml/l 
33.3 ml/l 
&gt;21 H 
2 Taxotere 
EtOH/Poly 
10 mg/ml 
1 mg/ml 
50 ml/l 
50 ml/l 
&gt;21 H 
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