Oral DTPA for radionuclide chelation

Abstract

A composition for oral radionuclide chelation therapy comprises a DTPA chelate selected from Zn-DTPA and Ca-DTPA and a permeation enhancer that preferentially increases jejunal uptake of the DTPA chelate. The composition has a DTPA chelate bioavailability of at least 10% of the chelate when orally administered to a mammal.

1. A composition for oral radionuclide chelation therapy, said composition consisting of:
 a DTPA (diethylenetriaminepentaacetate) chelate selected from the group consisting of calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA); 
 a permeation enhancer that preferentially increases jejunal uptake of the DTPA chelate; and 
 one or more excipients or binders to facilitate formulation; 
 wherein the permeation enhancer is caprylocaproyl macrogol-8-glycerides, and the composition has a DTPA chelate bioavailability of at least 10% when orally administered to a mammal, as measured in a Beagle dog model and using the calculation: BA=AUCPO×Doseiv /AUCiv×DosePO; where BA=bioavailability, and AUC=area under plasma concentration-time curve, and said composition is (a) in an enteric-coated unit dosage form, or (b) in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
 
     
     
       2. The composition of  claim 1  in an enteric-coated unit dosage form. 
     
     
       3. The composition of  claim 1  in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
     
     
       4. The composition of  claim 1  in a thixotropic form contained within a capsule. 
     
     
       5. The composition of  claim 1  in a unit dosage form comprising 250, 275, 300, 325, 350, 375, 400, 450, or 500 mg of the DTPA chelate. 
     
     
       6. The composition of  claim 1  wherein the excipients or binders consist of HEPES buffer. 
     
     
       7. A composition for oral radionuclide chelation therapy, said composition consisting of:
 a DTPA (diethylenetriaminepentaacetate) chelate selected from the group consisting of calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA); 
 a permeation enhancer that preferentially increases jejunal uptake of the DTPA chelate; 
 a P glycprotein (Pgp) inhibitor; and 
 one or more excipients or binders to facilitate formulation; 
 wherein the permeation enhancer is caprylocaproyl macrogol-8-glycerides, the Pgp inhibitor is d-α-tocopheryl polyethylene glycol 1000 succinate, and the composition has a DTPA chelate bioavailability of at least 10% when orally administered to a mammal, as measured in a Beagle dog model and using the calculation: BA =AUCPO×Doseiv/AUCiv×DosePO; where BA =bioavailability, and AUC =area under plasma concentration-time curve, and said composition is (a) in an enteric-coated unit dosage form, or (b) in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
 
     
     
       8. The composition of  claim 7  in an enteric-coated unit dosage form. 
     
     
       9. The composition of  claim 7  in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
     
     
       10. The composition of  claim 7  in a thixotropic form contained within a capsule. 
     
     
       11. The composition of  claim 7  in a unit dosage form comprising 250, 275, 300, 325, 350, 375, 400, 450, or 500 mg of the DTPA chelate. 
     
     
       12. The composition of  claim 1  wherein the excipients or binders consist of HEPES buffer. 
     
     
       13. A method for chelating radionuclides in a mammal, the method comprising:
 administering to the mammal the composition of  claim 1 . 
 
     
     
       14. The method of  claim 13  wherein prior to the administering step, the mammal is administered a Pgp inhibitor. 
     
     
       15. A method for chelating radionuclides in a mammal, the method comprising:
 administering to the mammal the composition of  claim 7 . 
 
     
     
       16. A kit comprising the composition of  claim 1 , where a unit dosage form of the composition is contained in a blister. 
     
     
       17. A kit comprising the composition of  claim 7 , where a unit dosage form of the composition is contained in a blister. 
     
     
       18. A composition for oral radionuclide chelation therapy, said composition consisting of:
 a DTPA (diethylenetriaminepentaacetate) chelate selected from the group consisting of calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA); 
 a permeation enhancer that preferentially increases jejunal uptake of the DTPA chelate; and 
 one or more excipients or binders to facilitate formulation; 
 wherein the permeation enhancer is caprylocaproyl macrogol-8-glycerides, and said composition is (a) in an enteric-coated unit dosage form, or (b) in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
 
     
     
       19. A composition for oral radionuclide chelation therapy, said composition consisting of:
 a DTPA (diethylenetriaminepentaacetate) chelate selected from the group consisting of calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA); 
 a permeation enhancer that preferentially increases jejunal uptake of the DTPA chelate; 
 a P glycprotein (Pgp) inhibitor; and 
 one or more excipients or binders to facilitate formulation; 
 wherein the permeation enhancer is caprylocaproyl macrogol-8-glycerides, the Pgp inhibitor is d-α-tocopheryl polyethylene glycol 1000 succinate, and said composition is (a) in an enteric-coated unit dosage form, or (b) in the form of extruded beads contained within a capsule, wherein the beads have an average diameter between 0.1-1 mm. 
 
     
     
       20. A method for chelating radionuclides in a mammal, the method comprising:
 administering to the mammal the composition of  claim 18 . 
 
     
     
       21. A method for chelating radionuclides in a mammal, the method comprising:
 administering to the mammal the composition of  claim 19 . 
 
     
     
       22. The composition of claim 1 in tablet form. 
     
     
       23. The composition of claim 2 in tablet form. 
     
     
       24. The composition of claim 5 in tablet form. 
     
     
       25. The composition of claim 6 in tablet form. 
     
     
       26. The composition of claim 7 in tablet form. 
     
     
       27. The composition of claim 8 in tablet form. 
     
     
       28. The composition of claim 11 in tablet form. 
     
     
       29. The composition of claim 12 in tablet form.