Claims for Patent: 11,529,431

Summary for Patent: 11,529,431

Title:	Methods for making ultrasound contrast agents
Abstract:	Provided herein are improved methods for preparing phospholipid formulations including phospholipid UCA formulations.
Inventor(s):	Simon P. Robinson, Robert W. Siegler, Nhung Tuyet Nguyen, David C. Onthank, Tarakeshwar Vishwanath Anklekar, Charles Chester Van Kirk
Assignee:	Lantheus Medical Imaging Inc
Application Number:	US17/688,532
Patent Claims:	1. A method of ultrasound contrast imaging a subject comprising (a) combining one or more phospholipids and a non-aqueous solvent, in a methanol and toluene free and methyl t-butyl ether free condition, to form a phospholipid solution having calcium and/or magnesium divalent metal cation present at a total divalent metal cation concentration of less than 0.7 ppm, (b) combining the phospholipid solution with an aqueous solution to form a phospholipid suspension, (c) activating the phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, (d) administering the lipid-encapsulated gas microspheres to a subject, and (e) obtaining an ultrasound image of the subject. 2. The method of claim 1, wherein the one or more phospholipids comprise (a) DPPC and MPEG-5000-DPPE or (b) DPPA, DPPC and MPEG-5000-DPPE. 3. The method of claim 1, wherein the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE. 4. The method of claim 2, wherein DPPC has a combined calcium and magnesium concentration of less than 90 ppm, and MPEG5000-DPPE has a combined calcium and magnesium concentration of less than 115 ppm. 5. The method of claim 1, wherein the non-aqueous solvent comprises propylene glycol. 6. The method of claim 1, wherein the non-aqueous solvent has a combined calcium and magnesium concentration of less than 0.7 ppm. 7. The method of claim 1, wherein the non-aqueous solvent comprises propylene glycol and glycerol. 8. The method of claim 1, wherein the phospholipid solution has no detectable phospholipid precipitate. 9. The method of claim 1, wherein the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE in molar percentages of 5-15%, 77-90% and 5-15%, respectively. 10. The method of claim 1, wherein the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE in a mole % ratio of 10 to 82 to 8 (10:82:8). 11. The method of claim 1, wherein the perfluorocarbon gas is perfluoropropane gas. 12. The method of claim 1, wherein the one or more phospholipids comprise DPPC and MPEG-5000-DPPE, the phospholipid solution comprises DPPC, MPEG5000-DPPE and propylene glycol, the aqueous solution comprises water, propylene glycol and glycerol, and the phospholipid suspension comprises DPPC, MPEG5000-DPPE, propylene glycol, water and glycerol. 13. The method of claim 1, wherein the aqueous solution further comprises one or more salts. 14. The method of claim 1, wherein the aqueous solution further comprises one or more buffers. 15. A method of ultrasound contrast imaging a subject comprising (a) selecting an MPEG5000-DPPE having calcium and/or magnesium divalent metal cation present at a total divalent metal cation concentration of less than 115 parts per million (ppm), (b) combining the MPEG-5000-DPPE with one or more phospholipids and a non-aqueous solvent, in a methanol and toluene free and methyl t-butyl ether free condition, to form a phospholipid solution having calcium and/or magnesium divalent metal cation present at a total divalent metal cation concentration of less than 0.7 ppm, (c) combining the phospholipid solution with an aqueous solution to form a phospholipid suspension, (d) activating the phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, (e) administering the lipid-encapsulated gas microspheres to a subject, and (f) obtaining an ultrasound image of the subject. 16. The method of claim 15, wherein the MPEG-5000-DPPE with the one or more phospholipids comprise (a) DPPC and MPEG-5000-DPPE or (b) DPPA, DPPC and MPEG-5000-DPPE. 17. The method of claim 15, wherein the MPEG-5000-DPPE with the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE. 18. The method of claim 16, wherein DPPC has a combined calcium and magnesium concentration of less than 90 ppm, and MPEG5000-DPPE has a combined calcium and magnesium concentration of less than 115 ppm. 19. The method of claim 15, wherein the non-aqueous solvent comprises propylene glycol. 20. The method of claim 15, wherein the non-aqueous solvent has a combined calcium and magnesium concentration of less than 0.7 ppm. 21. The method of claim 15, wherein the non-aqueous solvent comprises propylene glycol and glycerol. 22. The method of claim 15, wherein the phospholipid solution has no detectable phospholipid precipitate. 23. The method of claim 15, wherein the MPEG-5000-DPPE with the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE in molar percentages of 5-15%, 77-90% and 5-15%, respectively. 24. The method of claim 15, wherein the MPEG-5000-DPPE with the one or more phospholipids comprise DPPA, DPPC and MPEG-5000-DPPE in a mole % ratio of 10 to 82 to 8 (10:82:8). 25. The method of claim 15, wherein the perfluorocarbon gas is perfluoropropane gas. 26. The method of claim 15, wherein the MPEG-5000-DPPE with the one or more phospholipids comprise DPPC and MPEG-5000-DPPE, the phospholipid solution comprises DPPC, MPEG5000-DPPE and propylene glycol, the aqueous solution comprises water, propylene glycol and glycerol, and the phospholipid suspension comprises DPPC, MPEG5000-DPPE, propylene glycol, water and glycerol. 27. The method of claim 15, wherein the aqueous solution further comprises one or more salts. 28. The method of claim 15, wherein the aqueous solution further comprises one or more buffers.