Solvent-free gadolinium contrast agents

a gadolinium contrast agent, solvent-free technology, applied in the direction of medical preparations, emulsion delivery, dispersed delivery, etc., can solve the problems of insufficient resolution of toxicity problems, inability to use gadolinium metal in vivo, inability to completely solve toxicity problems, etc., to reduce the amount of intentional excess pentetic acid, reduce the variability of parameters, and cause skin irritation

US20190269805A1Inactive Publication Date: 2019-09-05INVENTURE LLC
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Patent Information

Authority / Receiving Office
US · United States
Patent Type
Applications(United States)
Current Assignee / Owner
Publication Date
2019-09-05
Estimated Expiration
Not applicable · inactive patent

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Abstract

Disclosed herein are complexes of gadolinium metal, ligand and meglumine that are substantially free of non-aqueous solvents. In particular, solvent-free complexes of 1) gadopentetate dimeglumine and 2) gadoterate meglumine are disclosed and methods of their preparation are disclosed. In addition, methods are disclosed for purifying reactants, monitoring and controlling pH, quantifying the free gadolinium content, quantifying the concentration of gadolinium-ligand complex in aqueous solution, and procedures for producing a drug product in one step. The one step process eliminates the need to dry the gadolinium-ligand complex, which is typically highly hygroscopic. The one step process includes purification steps that do not require the use of non-aqueous solvents.
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Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. application Ser. No. 15 / 855,570, filed Dec. 27, 2017, which claims benefit of U.S. Provisional Application No. 62 / 439,893, filed Dec. 29, 2016, both of which are hereby incorporated by reference in their entireties.TECHNICAL FIELD

[0002] The present disclosure relates generally to metal chelates, particularly those of lanthanide metals, and in one specific embodiment, those of Gd(III), which are useful as contrast agents in magnetic resonance imaging for therapeutic and diagnostic applications, as well as clinical and biomedical research applications.BACKGROUND OF THE INVENTION

[0003] Magnetic resonance imaging (MRI) is a powerful diagnostic method that yields three-dimensional images of body tissues in vivo. The tissue features obtained are the result of variations in the distribution of water in these tissues. MRI contrast agents administered prior to imaging alter the relaxation times of p...

Examples

example 1

ree Gadopentetate Dimeglumine

Raw Materials

[0176]

Raw MaterialMole Ratio1DTPA12Gd2O30.4963Water2.2V1 (DTPA)4Meglumine0.992

Preparation of DTPA Solution

[0177]1. Heat reactor to 25-30° C.[0178]2. Charge water[0179]3. Begin stirring (stir unless otherwise indicated, nominal rate 300 rpm)[0180]4. Charge 10% of the DTPA[0181]5. Stir until uniformly distributed in the water[0182]6. If all the DTPA is charged, then go to step 8[0183]7. Go to step 4[0184]8. Stir 10 min

Preparation of Gadolinium: DTPA Complex

[0185]9. Charge 25% by weight of the Gadolinium oxide[0186]10. Stir until uniformly distributed[0187]11. If all the Gadolinium oxide is charged then go to step 13[0188]12. Go to step 9[0189]13. Stir 10 min[0190]14. Raise temperature to 95+ / −2° C.[0191]15. Stir 3 hrs.[0192]16. Check clarity[0193]17. If not clear continue for 1 hr, go to step 16[0194]18. If clear, continue 1 hr and then cool to 40-45° C.[0195]19. If precipitate forms, heat to 95+ / −2° C. and stir for 1 hr, go to step 16

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example 2

ree Gadoterate Meglumine

[0238]Preparation of DOTA Solution[0239]1. Heat reactor to 25-30° C.[0240]2. Charge water[0241]3. Begin stirring (stir unless otherwise indicated, nominal rate 300 rpm)[0242]4. Charge 10% of the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)[0243]5. Stir until uniformly distributed in the water[0244]6. If all the DOTA is charged, then go to step 8[0245]7. Go to step 4[0246]8. Stir 10 min

[0247]Preparation of Gadolinium: DOTA Complex[0248]9. Charge 25% by weight of the Gadolinium oxide[0249]10. Stir until uniformly distributed[0250]11. If all the Gadolinium oxide is charged then go to step 13[0251]12. Go to step 9[0252]13. Stir 10 min[0253]14. Raise temperature to 95+ / −2° C.[0254]15. Stir 3 hrs.[0255]16. Check clarity[0256]17. If not clear continue for 1 hr, go to step 16 (this step took about 12 hours, slower than Magnevist synthesis)[0257]18. If clear, continue 1 hr and then cool to 40-45° C.[0258]19. If precipitate forms, heat to 95+ / −2° C. ...