A water-soluble metallocene-complex composition which can be used as a cytostatic is described, which can be obtained by mixing a metallocene complex, a polyol, water and optionally additives, whereby glycols, sugar alcohols and carbohydrates are primarily used as the polyols.

The invention relates to a water-soluble pharmaceutical metallocene-complex 
composition which can be used as a cytostatic in cancer-therapy. 
The use of metallocene-complexes as cytostatica is known from DE-C-29 23 
334 and DE-C-35 18 447. The complexes are very poorly water-soluble due to 
the lipophilic cyclopentadienyl groups and in addition have proved 
relatively unstable in aqueous solution so that parenteral administration, 
e.g. in the form of a solution for injection, has not been possible. 
In Dokl. Akad. Nauk SSR 266, 883 (1982) water-soluble vanadocene acylates 
are described which are produced by the reaction of vanadocene with 
hydroxypropane tricarboxylic acid. This method is restricted to these 
special anions. 
DE-A-29 23 334 describes the use of dimethyl sulphoxide as solubilizer for 
the titanocenes. The dimethyl sulphoxide is disadvantageous on the grounds 
of its own pharmacodynamic effect and its embryo-toxicity. 
It is also known from a paper by K. Doppert, J. Organomet. Chem. 319, 351 
(1987) that titanocene complexes in aqueous solutions are degraded through 
hydrolysis to insoluble polymers. It therefore appeared impossible to 
convert metallocene complexes, particularly titanocene complexes, into a 
water-soluble form from which can be produced injection-solutions with 
therapeutic concentrations of the metallocene complex which have 
sufficient stability for parenteral administration. 
The basic object of the invention is to make available a physiologically 
acceptable water-soluble, pharmaceutical metal-locene-complex composition 
which is sufficiently stable in the form of an aqueous solution with 
therapeutic concentrations of the metallocene complex for administration 
by parenteral route, and a process for the production of this composition. 
Such solutions are of special interest as a cytostatic in cancer-therapy. 
This problem is surprisingly solved by the metallocene-complex composition 
of the invention according to claims 1 to 8 and the process for its 
production according to claims 9 to 11. 
The water-soluble, pharmaceutical metallocene-complex composition according 
to the invention is characterized in that it can be obtained by mixing 
together a metallocene complex, a polyol, water and optionally additives, 
and then removing the water from the mixture. 
The composition according to the invention can preferably be obtained by 
mixing 
0.01 to 2 % by weight of metallocene complex, 
0.1 to 20 % by weight of polyol, 
58 to 99.89 % by weight of water and 
optionally 0 to 20 % by weight of additives. 
The metallocene-complex composition according to the invention can be 
obtained in the most preferred way by mixing 
0.02 to 0.4 % by weight of metallocene-complex, 
0.5 to 6.0 % by weight of polyol, 
91.6 to 99.48 % by weight of water and 
0 to 3.0 % by weight of additives. 
Useful metallocene-complexes are compounds of the general formula 
(Cp).sub.2 M.sup.n X.sub.n-2, in which Cp represents the cyclopentadienyl 
anion, M a transition metal of valency n, and X a mono- or polyvalent 
anion. Preferably the complexes correspond to general formula Cp.sub.2 
MIVX.sub.2. is preferably a halide, especially a chloride, but may also be 
another anion. 
As metallocene complexes, the following are preferably used: vanadocene, 
hafnocene, zirkonocene, molybdenocene, tantalocene complexes and/or 
mixtures thereof; particularly preferred are titanocene complexes, 
particularly titanocene dichloride. The term metallocene complexes is 
understood to include both metallocene compounds which have no 
substitution on the two cyclopentadiene rings and those which are 
substituted on at least one of the cyclopentadiene rings. 
As polyols, the following are preferably used: glycols, sugar alcohols, 
carbohydrates or mixtures thereof, and particularly preferably glycerol, 
1,2-propylene glycol, 1,5-pentanediol, polyethylene glycols, 
block-copolymers of propylene glycol and ethylene glycol, pentaerythritol, 
glucose, fructose (saccharose), lactose or mixtures thereof and most 
particularly preferred sucrose, lactose, glucose, mannitol, sorbitol and 
mixtures thereof. Most useful are polyols having a glass transition 
temperature T.sub.g in the range of about -30.degree. C. to -50.degree. C. 
As additives sodium chloride can be used as an isotonicity-regulator, 
preferably in quantities of about 0.9 % by weight. 
In the preparation of the compositions according to the invention, 
metallocene complex, polyol, water and the optionally used additives are 
mixed and then the water in this mixture is removed, preferably by means 
of freeze-drying. For accelerated dissolution or dispersion of the 
metallocene complex in the aqueous solution, the mixture is preferably 
subjected to ultrasonic waves. Optionally the dissolution may also be 
carried out under heating. For a large-scale industrial production of the 
composition according to the invention, instead of ultrasound treatment, 
cosolvents such as, for example, dimethyl sulphoxide and tetrahydrofuran, 
can be used, preferably in concentrations of 0.5 to 10% by weight. They 
accelerate the dissolution or the dispersion of the metallocene complex in 
the aqueous solution. When using cosolvents it must, however, be taken 
into consideration that the eutectic temperature of the mixture and 
therefore the transition temperature and also the parameters of the 
freeze-drying process are changed. The cosolvents are removed together 
with the water by the freeze-drying, so that the metallocene-complex 
composition according to the invention is obtained as dry substance. It is 
completely re-soluble on addition of water and forms a clear solution 
sufficiently stable for a parenteral administration. The metallocene 
complex is contained therein preferably in concentrations of 0.05 to 5 
mg/ml H.sub.2 O. The increased stability of the aqueous solution of the 
composition according to the invention compared with the aqueous solution 
of metallocene complexes is indicated by the clouding due to the formation 
of di- and oligomers appearing considerably later. A water-soluble 
pharmaceutical metallocene-complex composition is therefore made available 
which is sufficiently stable in the form of its aqueous solution 
containing therapeutic concentrations of metallocene complex to be 
conveniently applied by parenteral route as a cytostatic in 
cancer-therapy. 
The invention is illustrated in more detail in the following examples.

EXAMPLE 1 
20.0 mg titanocene dichloride 
90.0 mg sodium chloride 
100.0 mg mannitol 
10.0 ml water (aqua pro injectione) 
The components indicated above were mixed, the mixture was exposed to 
ultrasonic waves for approx. 1 hour, filtered through a 0.45 .mu.m 
membrane filter and frozen at -50.degree. C. in an injection bottle. After 
the subsequent freeze-drying at -35.degree. C., the lyophilizate could be 
completely dissolved in water forming a stable, clear solution. The 
concentration of the active ingredient in this solution was 2 mg of active 
ingredient per 1 ml of solution. 
EXAMPLE 2 
10 mg titanocene dichloride 
45 mg sodium chloride 
255 mg sorbitol 
5 ml water (aqua pro injectione) 
Preparation was as described under Example 1. The solution obtained by 
dissolving the lyophilizate in water contained the active ingredient in a 
concentration of 2 mg/ml. 
EXAMPLE 3 
10 mg titanocene dichloride 
255 mg sorbitol 
5 ml water (aqua pro injectione) 
Preparation was as described under Example 1. The lyophilizate obtained by 
the freeze-drying produced a clear, isotonic solution with 5 ml of water 
with 2 mg of active ingredient per ml solution. 
EXAMPLE 4 
10 mg titanocene dichloride 
100 mg dimethyl sulphoxide 
255 mg sorbitol 
5 ml water (aqua pro injectione) 
After mixing and dissolving the above components, the solution obtained was 
filtered through a 0.45 .mu.m membrane-filter, frozen at -70.degree. C. 
and then freeze-dried. In addition to the water the cosolvent dimethyl 
sulphoxide was also removed thereby. The lyophilizate obtained was 
completely soluble in 2 ml of water and formed an isotonic, stable 
solution with an active ingredient content of 2 mg/ml. 
EXAMPLE 5 
Solutions of the following composition were prepared: 
2 mg titanocene dichloride 
51 mg polyol 
10 ml water (aqua pro injectione) 
The following were used as polyol: 
A. sucrose 
B. lactose 
C. glucose 
The following conditions were employed for the freeze drying: 
______________________________________ 
temperature 
pressure 
______________________________________ 
A -37.degree. C. 
&lt;2 .multidot. 10.sup.-1 mbar 
B -35.degree. C. 
&lt;2.5 .multidot. 10.sup.-1 mbar 
C -50.degree. C. 
&lt;3.9 .multidot. 10.sup.-2 mbar 
______________________________________ 
After removal of most of the water which was achieved after several hours 
the vacuum was gradually reduced and simultaneously the temperature raised 
by increments of 7.degree. C. up to 20.degree. C.; if necessary for the 
complete drying the temperature may be raised up to 40.degree. C. 
Essentially water-free lyophilisates were obtained which could easily be 
dissolved in water. 
EXAMPLE 6 
Example 3 was repeated using the following metallocene complex compounds 
A. 10 mg Zirconocene dichloride (white crystalline powder) 
B. 10 mg hafnocene dichloride (white crystalline powder having a certain 
caking tendency) 
C. 10 mg molybdenocene dichloride (black-brown powder of small particle 
size) 
D. 10 mg vanadocene dichloride (dark green crystalline powder) 
E. 10 mg vanadocene dichloride +10 mg ascorbic acid 
5 ml of an isotonic sorbitol solution (corresponding to 255 mg sorbitol in 
the lyophilisate) were added to samples A to E. 
Sample A was dissolved in the sorbitol solution at room temperature after 
some shaking and a colorless solution was obtained. 
Sample B dissolved more slowly, the dissolution was supported by an 
ultrasonic sound treatment. The compound yielded a clear colorless 
solution. 
Sample C dissolved rather slowly, an ultrasonic treatment increased the 
dissolution rate considerably. The dark powder yielded at first a dirty 
brown suspension which was converted into a dark green clear solution 
after a short time (3 to 4 minutes). 
Samples D and E showed a similar solubility behavior as titanocene 
dichloride. An ultrasonic treatment was used to break up the lumps of 
compound. Heating assisted considerably in dissolving the complex. The 
vanadocene dichloride dissolved in the sorbitol solution to give a clear 
dark green solution. 
After dissolution the sample vials were frozen in a deepfreezer at 
-18.degree. C. and then cooled down in the freeze dryer to -35.degree. C. 
for 24 hours whereafter the drying operation was carried on for four days. 
No complications occurred during the freeze drying of samples A and B. In 
both cases a fluffy white lyophilisate was formed. 
When drying sample C (molydenocene dichloride) the color changed from dark 
green to beige. A fluffy lyophilisate was formed. 
When freeze drying sample E (with ascorbic acid) some melting occurred at 
the surface at a temperature of -35.degree. C. The drying operation was 
nevertheless continued. The lyophilisate obtained from samples D and E 
showed a green color, the molten areas appeared somewhat darker. 
The lyophilisates of samples A and B showed excellent solubility. After 
addition of water and short shaking (maximum 30 seconds) a clear colorless 
solution was obtained. The lyophilisate of sample C had to be shaken for 
about 5 minutes with water in order to obtain a clear solution. The beige 
colored lyophilisate was slowly converted into an olive green solution. A 
freshly prepared comparative solution of molybdenocene dichloride showed 
the identical color. 
The lyophilisate of the vandocene dichloride showed a similar dissolution 
rate as titanocene dichloride, independently of the absence or presence of 
ascorbic acid. After addition of water shaking for about 2 minutes was 
necessary in order to obtain a clear dark green solution. 
The solutions formed from each of the lyophilisates proved to be stable and 
useful for parenteral administration.