Dtpa prodrugs, compositions thereof, and methods of using the same

Abstract

The present invention relates to trisodium diethylenetriamine pentaacetic acid (DTPA) prodrugs, such as, for example, DTPA di-ethyl esters. The invention further relates to compositions comprising DTPA prodrugs and methods of using the same.

That which is claimed is: 
     
         1 . A method of treating a subject to remove a non-radioactive element from the subject, the method comprising:
 administering a therapeutically effective amount of a trisodium diethylenetriamine pentaacetic acid (DTPA) di-ethyl ester to the subject, thereby removing the non-radioactive element from the subject,   wherein the DTPA di-ethyl ester comprises a polymorph of 6,9-bis(carboxymethyl)-3-(2-ethoxy-2-oxoethyl)-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid that has a melting point in a range from 133° C. to 141° C. and that is characterized by a powder x-ray diffraction pattern substantially the same as that shown in  FIG. 6D  and/or a powder x-ray diffraction pattern having peaks at about 8.1, 12.0, 13.8, 15.4, 16.0, 16.6, 18.3, 19.3, 21.4, 22.1, 24.0, 26.5, and 29.2±0.2 degrees 2 theta.   
     
     
         2 . The method of  claim 1 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering a composition comprising the polymorph. 
     
     
         3 . The method of  claim 1 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises delivering to the subject about 1 mg to about 2,000 mg of the polymorph per kilogram of the subject's total body weight. 
     
     
         4 . The method of  claim 1 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering the DTPA di-ethyl ester prior to the subject's exposure to the non-radioactive element. 
     
     
         5 . The method of  claim 1 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester prevents incorporation of the non-radioactive element into the subject's tissues, organs, bones, or any combination thereof. 
     
     
         6 . The method of  claim 1 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering the DTPA di-ethyl ester after the subject's exposure to the non-radioactive element. 
     
     
         7 . The method of  claim 1 , wherein the non-radioactive element is a heavy metal. 
     
     
         8 . The method of  claim 1 , wherein the non-radioactive element is present in the subject at a concentration detrimental and/or toxic to the subject. 
     
     
         9 . The method of  claim 1 , wherein the non-radioactive element is a chemical element that is not a radioactive element and has an atomic number of 11 to 98. 
     
     
         10 . The method of  claim 1 , wherein the non-radioactive element comprises gadolinium. 
     
     
         11 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         12 . The method of  claim 1 , further comprising, prior to administering the therapeutically effective amount of the DTPA di-ethyl ester, administering a gadolinium-based contrast enhancement agent (GBCA) to the subject. 
     
     
         13 . A method of treating a subject to remove a non-radioactive element from the subject, the method comprising:
 administering a therapeutically effective amount of a trisodium diethylenetriamine pentaacetic acid (DTPA) di-ethyl ester to the subject, thereby removing the non-radioactive element from the subject,   wherein the DTPA di-ethyl ester comprises a polymorph of 6,9-bis(carboxymethyl)-3-(2-ethoxy-2-oxoethyl)-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid that has a melting point in a range from about 110° C. to about 121° C. and that is characterized by a powder x-ray diffraction pattern substantially the same as that shown in  FIG. 6A  and/or a powder x-ray diffraction pattern having peaks at about 7.6, 12.4, 13.5, 14.0, 15.3, 18.1, 18.7, 18.8, 21.0, 22.5, 23.4, 24.5, 28.7, and 35.7±0.2 degrees 2 theta.   
     
     
         14 . The method of  claim 13 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering a composition comprising the polymorph. 
     
     
         15 . The method of  claim 13 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises delivering to the subject about 1 mg to about 2,000 mg of the polymorph per kilogram of the subject's total body weight. 
     
     
         16 . The method of  claim 13 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering the DTPA di-ethyl ester prior to the subject's exposure to the non-radioactive element. 
     
     
         17 . The method of  claim 13 , wherein administering the therapeutically effective amount of the DTPA di-ethyl ester comprises administering the DTPA di-ethyl ester after the subject's exposure to the non-radioactive element. 
     
     
         18 . The method of  claim 13 , wherein the non-radioactive element is present in the subject at a concentration detrimental and/or toxic to the subject. 
     
     
         19 . The method of  claim 13 , wherein the non-radioactive element is a chemical element that is not a radioactive element and has an atomic number of 11 to 98. 
     
     
         20 . The method of  claim 13 , wherein the non-radioactive element comprises gadolinium. 
     
     
         21 . The method of  claim 13 , further comprising, prior to administering the therapeutically effective amount of the DTPA di-ethyl ester, administering a gadolinium-based contrast enhancement agent (GBCA) to the subject.