Patent Publication Number: US-4921944-A

Title: Method of pharmaceutic production

Description:
This is a continuation-in-part of Ser. No. 07/055,550 filed on May 27, 1987, now abandoned. 
    
    
     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 &#34;cis-platinum&#34;, or diaminodichloroplatinum, and was discovered in 1968 by Rosenberger. 
     Also known is an inorganic, radioactive platinum compound,  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 m   +   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&#39;s toxicity and mutagenicity is very low and upon tagging by metal salts, particularly by ytterbium -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° to 80°, and then for about 30 minutes at 80° to 90° 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 -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 50  for a mouse for dichlorodi-D-methionineplatinum is 571 mg/kg. Some metal radionuclides, and particularly Yb -169  have good radioactive characteristics and proper biological and physical properties. I.E. the radiation energy of gamma Yb -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 -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  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° to 60° C. for two hours while being continuously mixed with a magnetic mixer. The temperature is then increased to 85° 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 -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° 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° to 60° C. for two hours while being continuously mixed with a magnetic mixer. The temperature is then increased to 85° 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° 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° to 60° C. for two hours while being continuously mixed with a magnetic mixer. The temperature is then increased to 85° 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° 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° 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                             
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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                                     
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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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