Treated calcium/oxyanion-containing particles for medical diagnostic imaging

• US 5,407,659 A
• Filed: 04/13/1993
• Issued: 04/18/1995
• Est. Priority Date: 10/22/1991
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt Medical Inc. (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Medical Inc. (Mallinckrodt plc)
• Inventors: White, David H., Ralston, William H., Deutsch, Edward A., Nosco, Dennis L., Woulfe, Steven R., Wolfangel, Robert G., Deutsch, Karen F., Wilking, Janet B.
• Primary Examiner(s): Hollinden, Gary E.
• Application Number:
  US08/047,129
• Time in Patent Office: 735 Days
• Field of Search: 424/9, 424/602, 428/653.4, 428/654, 423/263, 423/301, 423/305, 556/19, 534/15, 436/173
• US Class Current: 424/9.32
• CPC Class Codes: A61B 2090/3925 ultrasonic
• CPC Class Codes: A61B 2090/3954 magnetic, e.g. NMR or MRI
• CPC Class Codes: A61B 90/39 Markers, e.g. radio-opaque or breast lesions markers
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 49/0414 Particles, beads, capsules or spheres
• CPC Class Codes: A61K 49/1818 particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 49/1842 the small organic molecule being a phosphate or a phosphonate, not being a phospholipid
• CPC Class Codes: A61K 49/1878 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating
• CPC Class Codes: A61K 49/1881 wherein the coating consists of chelates, i.e. chelating group complexing a (super)(para)magnetic ion, bound to the surface
• CPC Class Codes: A61K 49/225 Microparticles, microcapsules gas-filled to be classified in A61K49/223
• CPC Class Codes: A61K 51/1241 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
• CPC Class Codes: G01R 33/281 Means for the use of in vitro contrast agents G01R33/282 takes precedence; involving use of a contrast agent in MR imaging G01R33/5601; in vivo contrast agents A61K49/0002
• CPC Class Codes: Y10S 977/722 On a metal substrate
• CPC Class Codes: Y10S 977/881 Microscopy or spectroscopy, e.g. sem, tem
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/928 X-ray agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent
• CPC Class Codes: Y10S 977/93 MRI contrast agent
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

Treated calcium/oxyanion-containing particles are disclosed for enhancing medical diagnostic imaging such as magnetic resonance imaging ("MRI"), magnetic resonance spectroscopy ("MRS"), magnetic resonance spectroscopy imaging ("MRSI"), X-ray diagnostic imaging, and ultrasound imaging. Novel coating and manufacturing techniques are disclosed to control particle size and particle aggregation resulting in compositions for organ specific imaging of the liver, spleen, or tissue disease states is obtained. Depending on the diagnostic imaging technique, calcium/oxyanion-containing particles are treated to be paramagnetic, radiopaque, or echogenic. Also disclosed are diagnostic compositions and methods of performing medical diagnostic procedures which involve administering to a warm-blooded animal a diagnostically effective amount of the above-described particles and then performing the medical diagnostic procedure.

Claims

1. A method for enhancing magnetic resonance images of body organs and tissues which comprises:

(a) administering to a patient, a diagnostically effective amount of calcium/oxyanion-containing particles incorporating non-chelated paramagnetic species therein, in a pharmaceutically acceptable carrier, said calcium/oxyanion-containing particles having a general formula;

Ca_n M_m X_r Y_s

wherein M is a paramagnetic ion or stoichiometric mixture of paramagnetic metal ions, X is a simple anion, Y is an oxyanion, tetrahedral oxyanion, protonated or unprotonated, carbonate, or mixtures thereof, m is from 1-10, n is from 1-10, s is ≧

1, and r is adjusted as needed to provide charge neutrality; and

(b) imaging the organs and tissues using magnetic resonance techniques.

2. A method for enhancing magnetic resonance images as defined in claim 1, wherein the paramagnetic metal ion is selected from a group of elements having atomic numbers of 21-25, 27-29, 42-44, and 58-70 and a valence in the range from 2+ to 3+.

3. A method for enhancing magnetic resonance images as defined in claim 1, wherein the paramagnetic metal ion is chromium(III), manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), ytterbium (III), gadolinium (III), terbium (III), dysprosium(III), holmium(III), or erbium(III).

4. A method for enhancing magnetic resonance images as defined in claim 1, wherein the paramagnetic metal ion is manganese(II), iron(II), iron(III), or mixtures thereof.

5. A method for enhancing magnetic resonance images as defined in claim 1, wherein the calcium/oxyanion-containing particles have a size in the range from about 5 nm to about 5 μ

m and are used for imaging the liver or spleen.

6. A method for enhancing magnetic resonance images as defined in claim 3, wherein the calcium/oxyanion-containing particles have a size in the range from about 1 nm to about 50 nm and are used for imaging the blood pool.

7. A method for enhancing magnetic resonance images as defined in claim 1, wherein Y is PO₄^3-, AsO₄^3-, WO₄^2-, MoO₄^2-, VO₄^3-, SiO₄^4-, or GeO₄^4-, and protonated forms.

8. A method for enhancing magnetic resonance images as defined in claim 1, wherein the calcium/oxyanion-containing particles further comprise a coating agent to stabilize the calcium/oxyanion-containing particles.

9. A method for enhancing magnetic resonance images as defined in claim 8, wherein the coating agent is selected from the group comprising di- and polyphosphonate-containing compounds, carboxylates and polycarboxylate-containing compounds, alcohols and polyalcohol-containing compounds, phosphates and polyphosphate-containing compounds, sulfates and sulfate-containing compounds, sulfonates and sulfonate-containing compounds, and biomolecules.

10. A method for enhancing magnetic resonance images as defined in claim 8, wherein the coating agent is a di- and polyphosphonate-containing compound.

11. A method for enhancing magnetic resonance images as defined in claim 8, wherein the coating agent is hydroxyethyldiphosphonate (HEDP).

12. A method for enhancing magnetic resonance images as defined in claim 8, wherein the coating agent is a peptide, protein, antibody, or lipid biomolecule.

13. A method for enhancing magnetic resonance images as defined in claim 8, wherein the coating agent comprises a reactive functional group.

14. A method for enhancing magnetic resonance images as defined in claim 13, wherein the reactive functional group is an amine, active ester, alcohol, or carboxylate functional group.

15. A method for enhancing magnetic resonance images as defined in claim 13, wherein the coating agent having a reactive functional group comprises:

##STR5##

16. A method for enhancing magnetic resonance images as defined in claim 1, wherein the calcium/oxyanion-containing particles are administered parenterally.

20. A diagnostic composition for enhancing medical diagnostic imaging as defined in claim 11, wherein Y is PO₄^3-, AsO₄^3-, WO₄^2-, MoO₄^2-, VO₄^3-, SiO₄^4-, or GeO₄^4-, and protonated forms.

17. A diagnostic composition for enhancing magnetic resonance imaging suitable for parenteral administration to a patient which comprises:

a diagnostically effective amount of calcium/oxyanion-containing particles which are treated to be paramagnetic having a size in the range from about 5 nm to about 50 μ

m, said calcium/oxyanion-containing particles having a general formula;

Ca_n M_m X_r Y_s

wherein M is a paramagnetic metal ion or stoichiometric mixture of paramagnetic metal ions, X is a non-chelated simple anion, Y is an oxyanion, tetrahedral oxyanion, carbonate, or mixtures thereof, m is from 1 to 10, n is from 1 to 10, s is ≧

1, and r is adjusted as needed to provide charge neutrality; and

a pharmaceutically acceptable carrier.

18. A diagnostic composition as defined in claim 17, wherein the paramagnetic species is a metal ion selected from a group of elements having atomic numbers of 21-25, 27-29, 42-44, and 58-70 and a valence in the range from 2+ to 3+.

19. A diagnostic composition as defined in claim 17, wherein the paramagnetic species is manganese(II), iron(II), iron(III), or mixtures thereof.

21. A diagnostic composition as defined in claim 17, wherein the calcium/oxyanion-containing particles have a size in the range from about 5 nm to about 5 μ

m and are used for imaging the liver or spleen.

22. A diagnostic composition as defined in claim 17, wherein the calcium/oxyanion-containing particles have a size in the range from about 1 nm to about 50 nm and are used for imaging the blood pool.

23. A diagnostic composition as defined in claim 17, wherein the calcium/oxyanion-containing particles further comprise a coating agent to stabilize the calcium/oxyanion-containing particles.

24. A diagnostic composition as defined in claim 23, wherein the coating agent is selected from the group comprising di- and polyphosphonate-containing compounds, carboxylates and polycarboxylate-containing compounds, alcohols and polyalcohol-containing compounds, phosphates and polyphosphate-containing compounds, sulfates and sulfate-containing compounds, sulfonates and sulfonate-containing compounds, and biomolecules.

25. A diagnostic composition as defined in claim 23, wherein the coating agent is a di- and polyphosphonate-containing compound.

26. A diagnostic composition as defined in claim 23, wherein the coating agent is hydroxyethyldiphosphonate (HEDP).

27. A diagnostic composition as defined in claim 23, wherein the coating agent is a peptide, protein, antibody, or lipid biomolecule.

28. A diagnostic composition as defined in claim 23, wherein the coating agent comprises a reactive functional group.

29. A diagnostic composition as defined in claim 28, wherein the reactive functional group is an amine, active ester, alcohol, or carboxylate functional group.

30. A diagnostic composition as defined in claim 28, wherein the coating agent having a reactive functional group comprises:

##STR6##

31. A calcium/oxyanion-containing particle for use in magnetic resonance imaging of body organs and tissues comprising an calcium/oxyanion-containing particle, a paramagnetic non-chelated metal species adsorbed to the surface of the calcium/oxyanion-containing particle, and a di- or polyphosphonate coating agent.

32. A calcium/oxyanion-containing particle for use in magnetic resonance imaging as defined in claim 31, wherein the paramagnetic metal species is manganese(II), iron(II), iron(III), or mixtures thereof.

33. A calcium/oxyanion-containing particle for use in magnetic resonance imaging as defined in claim 31, wherein the phosphonate coating agent is HEDP.