Method of pharmaceutic production

The object of the invention is a method for preparing a compound of formula I ##STR1## wherein Me.sup.m+ is a lanthanide and n is a number from 1-3, is used for diagnosis of neoplasms. The compound is prepared by adding an aqueous solution of hydrazide hydrochloride to potassium hexachloroplatinate, the suspension is mixed about two hours at 50.degree. to 60.degree. C. then about 30 minutes at 80.degree. to 90.degree. C., and upon cooling the reaction mixture, the unreacted potassium hexachloroplatinate is separated, the solution is decanted and filtered, and the pH of the filtrate is brought to 3 to 5. Methionine is then added in a molar ratio of methionine to tetrachloroplatinate of 2:1-4:1 and upon careful mixing for about 30 minutes a metal salt is added and preferably ytterbium chloride, and tagged with Yb.sup.-169. The components are then mixed and the pH of the solution is brought to 4-6.5 and filtered through a sterile filter.

BACKGROUND OF THE INVENTION 
The object of the invention is a method for production of a compound 
designed for diagnosis of neoplasms. 
The first metallic compound known for utilization in chemotherapy for 
diagnosis of neoplasms was a platinum inorganic compound, called 
"cis-platinum", or diaminodichloroplatinum, and was discovered in 1968 by 
Rosenberger. 
Also known is an inorganic, radioactive platinum compound, .sup.195 
Pt-cis-platinum and the method of producing it. 
The disadvantages of these radioactive platinum compounds, for use as 
radiopharmaceutics, particularly for diagnosising neoplasms, results from 
the fact that they have a very short life of the isotope, amounting to 
only 4 days. The process for manufacturing them is complicated and in 
spite of the minimal doses utilized have a high toxicity. 
As shown in animal studies the higher doses equal to 2.5 mg/kg caused 
pathological effects. 
Also known is the method for producing dimethionineplatinum wherein to an 
aqueous solution of potassium tetrachloroplatinate, methionine is added in 
a molar ratio of 2 to 1 of methionine to tetrachloroplatinate, the mixture 
heated for 5 minutes, resulting in a chelated compound of 
dimethionineplatinum in which a platinum atom is coordinated by sulphur 
and nitrogen atoms. 
The compound of dimethioneplatinum has not been previously used for 
producing pharmaceutics. The disadvantage of the application of this known 
method for pharmaceutic production, results from the fact, that the 
compound contains cyclic ligands. 
SUMMARY OF THE INVENTION 
The essence of the invention is based on the fact that a change in the 
process of preparing dichlorodimethionine-platinum, as in formula I 
##STR2## 
wherein Me.sub.m.sup.+ is a salt of a lanthanide, that is, one of La, Ce, 
Pr, Nd, Pm, Sm, Er, Gd, Tb, Dy, Ho, Eu, Tm, Yb and Lu, and n is a number 
from 1 to 3, preferably 2 
produces a compound which contains non-cyclic ligands. It was shown, 
unexpectedly, that it's toxicity and mutagenicity is very low and upon 
tagging by metal salts, particularly by ytterbium.sup.-169 chloride it 
shows an affinity for neoplastic tissues and provides very good results in 
scintigraphic examinations.

DETAILED DESCRIPTION OF THE INVENTION 
The method for production of the compound according to the invention, 
involves adding an aqueous solution of hydrazide hydrochloride in the 
quantity of 96% of the calculated stoichiometric value to potassium 
hexachoroplatinate. The reaction suspension is mixed with an 
electromagnetic mixer, for about two hours at 50.degree. to 80.degree., 
and then for about 30 minutes at 80.degree. to 90.degree. C. Upon cooling 
of the reaction mixture, the unreacted potassium hexachloroplatinate is 
separated by centrifugation, the solution is decanted and filtered through 
glass wool or Milipore and the pH of the filtrate is brought to 3 to 5 by 
a solution of 0.3N NaOH. Next, to the obtained tetrachloroplatinate, 
methionine is added with continuous mixing in a molar ratio of methionine 
to tetrachloroplatinate 2:1, or more, particularly 2:1 to 4:1. Upon 
careful mixing for about 30 minutes, the dichlorodimethionineplatinum 
complex is purified on a chromatographic column. A metal salt is added, to 
the purified dichlorodimethionineplatinum complex, preferably the chloride 
of radioactive ytterbium.sup.-169. The components are mixed for 5 to 10 
minutes and the pH of the solution is brought to 4-6.5. The solution is 
filtered through a sterile filter and the product is ready for 
administration. 
The advantage of manufacturing the pharmaceutic according to the process of 
the invention is the very low toxicity and mutagenicity of the compound 
prepared in this way. The LD.sub.50 for a mouse for 
dichlorodi-D-methionineplatinum is 571 mg/kg. Some metal radionuclides, 
and particularly Yb.sup.-169 have good radioactive characteristics and 
proper biological and physical properties. I.E. the radiation energy of 
gamma Yb.sup.-169, is 60 to 300 kev, and the time for a half life--32 
days. These characteristics provide good parameters of the radionuclide 
for scintigraphic examinations. 
The metals make a stable complex with dichlorodimethionineplatinum, which 
are purged from the system of the animal with its urine. The retention of 
the Yb.sup.-169 complex in the organism of the animals under examination 
is from 3 to 6% after 24 hours, and up to 3% after 72 hours. The 
relatively long half life of .sup.169 Yb provides the possibility of 
carrying out examinations for longer time intervals and yet also decreases 
the radiation load on the organism. 
EXAMPLE I 
96 ul of an aqueous one percent solution of hydrazide hydrochloride was 
added to 10 milligrams of potassium hexachloroplatinate. The reaction 
mixture was heated in the water bath at 50.degree. to 60.degree. C. for 
two hours while being continuously mixed with a magnetic mixer. The 
temperature is then increased to 85.degree. C. for a period of 30 minutes. 
Upon cooling, the unreacted potassium hexachloroplatinate was separated by 
centrifugation. The solution was decanted and filtered through glass wool. 
The pH of the solution was brought to about 4, with a solution of 0.3N 
NaoH 5.4 milligrams of D-methionine were then added, with careful mixing, 
for about 30 minutes, the complex of dichlorodi-D-methionineplatinum was 
purified and an 100 ul solution of NaCl, physiological salt, was added, as 
well as 100 ul of ytterbium chloride tagged with Yb.sup.-169 with an 
activity of 1 mCi, i.e. 37 MBq. The reaction mixture was brought to a pH 
of about 6,5 with 0.3N NaOH. It has been ascertained that the solution is 
stable if stored at a temperature of +4.degree. C. 
For biological examination of mice, 40 ul of the above mentioned solution 
per mouse were intravenously injected. The biodistribution among the 
control animals and the mice inoculated with particular tumors is 
presented in tables 1 and 2. 
EXAMPLE II 
96 ul of an aqueous one percent solution of hydrazide hydrochloride was 
added to 10 milligrams of potassium hexachloroplatinate. The reaction 
mixture was heated in the water bath at 50.degree. to 60.degree. C. for 
two hours while being continuously mixed with a magnetic mixer. The 
temperature is then increased to 85.degree. C. for a period of 30 minutes. 
Upon cooling, the unreacted potassium hexachloroplatinate was separated by 
centrifugation. The solution was decanted and filtered through glass wool. 
The pH of the solution was brought to about 4, with a solution of 0.3N 
NaOH. 8 milligrams of D-methionine were then added, with careful mixing, 
for about 30 minutes. The complex of dichlorodi D-methionineplatinum was 
purified and an 100 ul solution of NaCl, physiological salt, was added, as 
well as 100 ul of thulium chloride tagged with Tm-167 with an activity of 
1 mCi, i.e. 37 MBq. This reaction mixture was brought to a pH of about 5 
with 0.3N NaOH. It has been ascertained that the solution is stable if 
stored at a temperature of +4.degree. C. For biological examination of 
mice, 40 ul of the above mentioned solution per mouse were intravenously 
injected. 
EXAMPLE III 
96 ul of an aqueous one percent solution of hydrazide hydrochloride was 
added to 10 milligrams of potassim hexachloroplatinate. The reaction 
mixture was heated in the water bath at 50.degree. to 60.degree. C. for 
two hours while being continuously mixed with a magnetic mixer. The 
temperature is then increased to 85.degree. C. for a period of 30 minutes. 
Upon cooling, the unreacted potassium hexachloroplatinate was separated by 
centrifugation. The solution was decanted and filtered through glass wool. 
The pH of the solution was brought to about 4, with a solution of 0.3N 
NaOH. 9 milligrams of D-methionine were then added, with careful mixing, 
for about 30 minutes, the complex of dichlorodi-D-methionineplatinum was 
purified and an 100 ul solution of NaCl, physiological salt, was added, as 
well as 100 ul of terbium chloride tagged with Tb-153 with an activity of 
1 mCi, i.e. 37 MBq. The reaction mixture was brought to a pH of about 6.5 
with 0.3N NaOH. It has been ascertained that the solution is stable if 
stored at a temperature of +4.degree. C. For biological examination of 
mice, 40 ul of the above mentioned solution per mouse were intravenously 
injected. 
It has been ascertained that the solution is stable if stored at a 
temperature of 4.degree. C. For biological examination of mice 40 ul of 
the above mentioned solution per mouse were intravenously injected. 
TABLE 1 
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Biodistribution among BALB control mice and mice 
inoculated with Ehrlich neoplasms 
Upon 24 hours 
upon 72 hours 
Organ control neoplasm control 
neoplasm 
______________________________________ 
liver 0,08 0,08 0,07 0,06 
spleen 0,03 0,03 0,07 0,03 
kidneys 0,45 0,43 0,27 0,30 
lungs 0,02 0,02 0,03 0,02 
bone 0,18 0,15 0,22 0,23 
blood 0,004 0,005 0,002 
0,002 
muscle 0,03 0,03 0,01 0,01 
neoplasm -- 0,07 -- 0,07 
neoplasm/blood 
-- 14 -- 35 
neoplasm/muscle 
-- 2,3 -- 7 
retention 6,3% 3,0% 5,6% 3,9% 
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TABLE 2 
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Biodistribution among B-10 control mice and inoculated 
with leukemic neoplasms. 
upon 24 hours 
Organ control with neoplasm 
______________________________________ 
liver 0,06 0,07 
spleen 0,02 0,02 
kidneys 0,37 0,39 
lungs 0,02 0,01 
bone 0,16 0,09 
blood 0,002 0,003 
muscle 0,006 0,002 
neoplasm -- 0,06 
neoplasm/blood -- 20 
neoplasm/muscle -- 30 
retention 6% 5,5% 
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