Phospholipid composition and microbubbles and emulsions formed using same
Inventors
Unger, Evan C. • Evans, Daniel C.
Assignees
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Publication Number
US-10493173-B2
Publication Date
2019-12-03
Expiration Date
Abstract
A composition, and method thereof, for stabilizing a fluorocarbon emulsion includes phosphatidylcholine, phosphatidylethanolamine-PEG, and a cone-shaped lipid.
Core Innovation
The disclosure relates to phospholipid compositions for ultrasound contrast agents that comprise fluorocarbon emulsion and/or microbubbles. The compositions include octafluoropropane and lipid components based on phosphatidylcholine and phosphatidylethanolamine-polyethylene glycol (PEG), while the composition comprises no dipalmitoylphosphatidic acid (DPPA).
A primary formulation concept is the use of substantially charge-neutral lipid components at neutral pH, including dipalmitoylphosphatidylethanolamine (DPPE) as a cone-shaped third lipid. The composition is described as having a pH between about 6.2 and 6.8 and DPPE present at a concentration between about 5 and about 20 mole percent, with examples often around 10 mole percent and additional optional PEGylated/bifunctional PEG lipids for targeting.
The disclosure further characterizes DPPA ionization behavior and argues that DPPA catalyzes hydrolysis, which is presented as a contributor to instability of prior compositions. Compared with formulations including DPPA, stability data are described as showing that DPPA falls below specification earlier, while compositions without DPPA show improved potency and improved microbubble stability and size retention over time.
The document also describes fluorocarbon-loaded lipid-coated microspheres, including octafluoropropane-loaded microspheres having specified particle size targets. Imaging and animal study findings are described as indicating reduced renal retention and delayed enhancement compared with DEFINITY/MVT-100, supporting the performance of the DPPA-free, charge-neutral phospholipid approach.
Claims Coverage
The document’s relevant independent claim covers a method for ultrasound imaging that relies on administering an octafluoropropane emulsion/microbubble composition with a DPPA-free, substantially charge-neutral lipid formulation at neutral pH, and then performing ultrasound imaging. The independent claim includes four inventive features, and several dependent claims further refine composition identity, quantitative ranges, and microsphere particle-size distribution metrics.
DPPA-free octafluoropropane emulsion composition
Administering to a subject a composition of an octafluoropropane emulsion comprising octafluoropropane, phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and DPPE, wherein the composition comprises no dipalmitoylphosphatidic acid (DPPA).
Neutral pH DPPA-free formulation
Administering the DPPA-free composition having a pH between 6.2 to 6.8.
DPPE mole-percent concentration range as cone-shaped third lipid
Administering the DPPA-free composition in which the dipalmitoylphosphatidylethanolamine (DPPE) is at a concentration between about 5 and about 20 mole percent of the composition.
Ultrasound imaging performed after administration
Performing ultrasound imaging on the subject after administering the DPPA-free, neutral-pH octafluoropropane emulsion composition containing phosphatidylcholine, phosphatidylethanolamine-PEG, and DPPE at about 5 to about 20 mole percent.
Overall, the claim coverage is centered on ultrasound imaging using a DPPA-free octafluoropropane emulsion containing phosphatidylcholine, phosphatidylethanolamine-PEG, and DPPE, with a neutral pH (6.2–6.8) and DPPE at about 5–20 mole percent, followed by performing ultrasound imaging.
Stated Advantages
Improved storage stability (DPPA-free compositions are described as showing improved potency and stability compared with DPPA-containing formulations).
Reduced side effects including back pain (as stated in the provided content summary).
Reduced renal retention and delayed enhancement compared with DEFINITY/MVT-100 (as stated in the provided content summary).
Documented Applications
Ultrasound imaging in a subject using an octafluoropropane emulsion containing phosphatidylcholine, phosphatidylethanolamine-PEG, and DPPE with no DPPA, at pH 6.2–6.8, followed by performing ultrasound imaging.
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