Metal complex-containing pharmaceutical agents

Abstract

Improved metal complex-containing pharmaceutical agents are described which, as an additive, contain one or more complexing agents and/or one or more weak metal complex(es) or mixtures thereof.

What is claimed is:  
     
         1 . In a pharmaceutical agent comprising a metal complex, useful for NMR, X-ray, ultrasound or radio-diagnostics or radiotherapy, the improvement wherein said agent further comprises a metal complexing agent, a weak metal complex or a mixture thereof.  
     
     
         2 . An agent of  claim 1 , comprising said metal complexing agent.  
     
     
         3 . An agent of  claim 1 , comprising said weak metal complex, wherein said metal is physiologically acceptable and the binding constant of said weak metal complex is lower than that of said diagnostically or therapeutically useful metal complex.  
     
     
         4 . An agent of  claim 1 , wherein the metal of said weak metal complex is calcium, magnesium, zinc or iron.  
     
     
         5 . An agent of  claim 2 , wherein the complex portion of all of said complexes and complexing agents is, independently., e.g., ethylenediaminetetraacetic acid. (EDTA), diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA), trans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid, N 6 -carboxymethyl-N 3 ,N 9 -[2,3-dihydroxy-N-methylpropylcarbamoylmethyl]-3,6,9-triazaundecanedioic acid, N 6 -carboxymethyl-N 3 ,N 9 -bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid, N 3 ,N 6 -bis(carboxymethyl)-N 9 -3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic acid or N 3 ,N 6 -bis(carboxymethyl)-N 9 -[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]-3,6,9-triazaundecanedioic acid.  
     
     
         6 . An agent of  claim 3 , wherein the complex portion of all of said complexes and completing agents is, independently, e.g., ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA), trans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid, N 6 -carboxymethyl-N 3 ,N 9 -[2,3-dihydroxy-N-methylpropylcarbamoylmethyl]-3,6,9-triazaundecanedioic acid, N 6 -carboxymethyl-N 3 ,N 9 -bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid, N 3 ,N 6 -bis(carboxymethyl)-N 9 -3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic acid or N 3 ,N 6 -bis(carboxymethyl)-N 9 -[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]3,6,9-triazaundecanedioic acid.  
     
     
         7 . An agent of  claim 1 , wherein the total amount of said complexing agent and/or weak metal complex is 0.01.-50 mol % based on the amount of said diagnostically or therapeutically effective complex, up to a maximum of 250 mmol/l of said effective complex.  
     
     
         8 . An agent of  claim 1 , wherein the total amount of said complexing agent and/or weak metal complex is 0.1-10 mol % based on the amount of said diagnostically or therapeutically effective complex, up to a maximum of 50 mmol/l of said effective complex.  
     
     
         9 . An agent of  claim 1 , further comprising a pharmaceutically acceptable carrier.  
     
     
         10 . An agent of  claim 1 , comprising the di-N-methylglucamine salt of the gadolinium(III) complex of DTPA and the calcium trisodium salt of DTPA.  
     
     
         11 . An agent of  claim 1 , comprising the di-N-methylglucamine salt of the gadolinium(III) complex of DTPA and the penta-N-methylglucamine salt of DTPA.  
     
     
         12 . An agent of  claim 1 , comprising the sodium salt of the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA) and the calcium disodium salt of DOTA.  
     
     
         13 . An agent of  claim 1 , comprising the lysine salt of the gadolinium(III) complex of DOTA and the zinc disodium salt of DOTA.  
     
     
         14 . An agent of  claim 1 , comprising the di-N-methylglucamine salt of the gadolinium(III)-complex of N 6 -carboxymethyl-N 3 ,N 9 -bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid and N 6 -carboxymethyl-N 3 ,N 9 -bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid.  
     
     
         15 . An agent of  claim 1 , comprising the di-N-methylglucamine salt of the gadolinium(III) complex of N 6 -carboxymethyl-N 3  ,N 9 -bis (3-oxapentamethylene-carbamoylmethyl)-3,6,9-triazaundecanedioic acid and the tetrasodium salt of N 3 ,N 6 -bis-(carboxymethyl)-N 9 -3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic acid.  
     
     
         16 . An agent of  claim 1 , comprising the disodium salt of the manganese(II) complex of trans-1,2-cyclohexylenediaminetetraacetic acid and trans-1,2-cyclohexylenediaminetetraacetic acid.  
     
     
         17 . An agent of  claim 1 , comprising the N-methyl-glucamine salt of the iron(III) complex of ethylenediamine-N-N′-bis(2-hydroxyphenylacetic acid) (EHPG) and EHPG.  
     
     
         18 . An agent of  claim 1 , comprising the sodium salt of the gadolinium(III) complex of N 3 ,N 6 -bis(carboxymethyl)-N 9 -[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl carbamoylmethyl]-3,6,9-triazaundecanedioic acid and N 3 ,N 6 -bis(carboxymethyl)-N 9 -[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl carbamoylmethyl]-3,6,9-triazaundecanedioic acid.  
     
     
         19 . An agent of  claim 1 , comprising the gadolinium(III) complex of the conjugate of DTPA with a monoclonal antibody and the calcium disodium salt of DTPA.  
     
     
         20 . An agent of  claim 1 , comprising the gadolinium(III) complex of the dextran-DTPA conjugate and the calcium disodium salt of EDTA.  
     
     
         21 . In a method of performing an NMR, X-ray, ultrasound or radio-diagnosis or image, or radiotherapy of a patient, comprising administering an effective amount of a metal complex, the improvement wherein there is coadministered a metal complexing agent, a weak metal complex or a mixture thereof.