Methods for making ultrasound contrast agents
Provided herein are improved methods for preparing phospholipid formulations including phospholipid UCA formulations.
1. A method for preparing a phospholipid suspension useful for preparing lipid-encapsulated gas microspheres comprising
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, and
combining the phospholipid solution with an aqueous solution to form a phospholipid suspension.
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 2 , wherein DPPA has a combined calcium and magnesium concentration of less than 780 ppm, 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.
4. The method of claim 1 , wherein the non-aqueous solvent comprises propylene glycol.
5. The method of claim 1 , wherein the non-aqueous solvent has a combined calcium and magnesium concentration of less than 0.7 ppm.
6. The method of claim 1 , wherein the phospholipid solution has no detectable phospholipid precipitate.
7. 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).
8. The method of claim 1 , wherein the non-aqueous solvent comprises propylene glycol and glycerol.