Phospholipid composition and microbubbles and emulsions formed using same
Inventors
Unger, Evan C. • Evans, Daniel C.
Assignees
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Publication Number
US-11160885-B2
Publication Date
2021-11-02
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 invention relates to phospholipid compositions for stabilizing a fluorocarbon microbubble-forming emulsion or particles used as ultrasound contrast agents. The compositions comprise a fluorocarbon selected from perfluorobutane and perfluoropentane together with phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and dipalmitoylphosphatidylethanolamine (DPPE), and are defined to exclude dipalmitoylphosphatidic acid (DPPA).
The problem being solved is that DPPA hydrolysis and instability limit cold storage stability of fluorocarbon microbubble-forming emulsions or particles, thereby reducing shelf-life. The background describes DPPA as a factor that can catalyze lipid hydrolysis and lead to instability during storage, motivating a DPPA-free stabilization approach.
Accordingly, the compositions are constrained to have a pH between 6.2 and 6.8, and to include DPPE at a concentration between about 5 and about 20 mole percent of the composition. The compositions also include a PEGylated lipid and are supported by a rationale that replacing DPPA with a cone-shaped phospholipid, preferably DPPE, enables microbubble non-aggregation without DPPA.
Claims Coverage
The patent family contains one independent claim covering a DPPA-free phospholipid formulation for stabilizing a fluorocarbon emulsion. The independent claim is bounded by multiple inventive features, and dependent claims refine specific selections and quantitative ranges for the fluorocarbon, DPPE mole percent, phospholipid proportions, and optional excipients.
DpPa-free stabilizing phospholipid system with specific component set
The composition for stabilizing a fluorocarbon emulsion comprises phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and dipalmitoylphosphatidylethanolamine (DPPE), and comprises no dipalmitoylphosphatidic acid (DPPA).
Fluorocarbon selection for the emulsion core
The fluorocarbon is selected from the group consisting of perfluorobutane and perfluoropentane.
Near-neutral pH constraint
The composition has a pH between 6.2 to 6.8.
DpPE mole-percent range
The dipalmitoylphosphatidylethanolamine (DPPE) is at a concentration between about 5 and about 20 mole percent of the composition.
Aggregate phospholipid concentration range
The phosphatidylcholine, the phosphatidylethanolamine-PEG, and DPPE have an aggregate concentration in the range of about 0.75 mg/ml to about 1.5 mg/ml.
Overall, claim coverage centers on a DPPA-free composition combining phosphatidylcholine, phosphatidylethanolamine-PEG, and DPPE to stabilize a perfluorobutane or perfluoropentane fluorocarbon emulsion under a near-neutral pH, with DPPE at 5–20 mole percent and total aggregate phospholipid in 0.75–1.5 mg/ml.
Stated Advantages
Improved shelf-life compared with DEFINITY (DPPC/DPPE-PEG(5,000)/DPPA).
Reduced back pain side-effect compared with DEFINITY.
Documented Applications
Ultrasound contrast agents using fluorocarbon microbubble-forming emulsions or particles.
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