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 an ultrasound contrast agent comprising
selecting an MPEG5000-DPPE having a calcium concentration of less than 115 parts per million (ppm),
combining the MPEG5000-DPPE with DPPA, DPPC and propylene glycol, to form a phospholipid solution having a calcium 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 DPPA, DPPC and MPEG-5000-DPPE are present in the phospholipid solution in a mole % ratio of 10 to 82 to 8 (10:82:8).
3. The method of claim 1 , wherein DPPA has a calcium concentration of less than 780 ppm, DPPC has a calcium concentration of less than 90 ppm, and propylene glycol has a calcium concentration of less than 0.7 ppm.
4. The method of claim 1 , further comprising placing the phospholipid suspension in a container.
5. The method of claim 4 , wherein the container comprises perfluorocarbon gas.
6. The method of claim 5 , wherein the perfluorocarbon gas is perfluoropropane gas.
7. The method of claim 4 , further comprising introducing a perfluorocarbon gas into the container.
8. The method of claim 7 , wherein the perfluorocarbon gas is perfluoropropane gas.
9. A method for preparing a phospholipid suspension useful for preparing an ultrasound contrast agent comprising
selecting an MPEG5000-DPPE having a combined calcium and magnesium concentration of less than 115 parts per million (ppm),
combining the MPEG5000-DPPE with DPPA, DPPC and propylene glycol, to form a phospholipid solution having a combined calcium and magnesium concentration of less than 0.7 ppm, and
combining the phospholipid solution with an aqueous solution to form a phospholipid suspension.
10. The method of claim 9 , wherein DPPA, DPPC and MPEG-5000-DPPE are present in the phospholipid solution in a mole % ratio of 10 to 82 to 8 (10:82:8).
11. The method of claim 9 , 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 propylene glycol has a combined calcium and magnesium concentration of less than 0.7 ppm.
12. The method of claim 9 , further comprising placing the phospholipid suspension in a container.
13. The method of claim 12 , wherein the container comprises perfluorocarbon gas.
14. The method of claim 13 , wherein the perfluorocarbon gas is perfluoropropane gas.
15. The method of claim 12 , further comprising introducing a perfluorocarbon gas into the container.
16. The method of claim 15 , wherein the perfluorocarbon gas is perfluoropropane gas.