Phospholipid composition and microbubbles and emulsions formed using same
Inventors
Unger, Evan C. • Evans, Daniel C.
Assignees
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Publication Number
US-9801959-B2
Publication Date
2017-10-31
Expiration Date
Abstract
A composition for stabilizing a fluorocarbon emulsion. That composition includes phosphatidylcholine, phosphatidylethanolamine-PEG, and a cone-shaped lipid.
Core Innovation
The invention relates to an ultrasound contrast agent phospholipid system for stabilizing an octafluoropropane emulsion. The composition comprises octafluoropropane, phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and dipalmitoylphosphatidylethanolamine (DPPE), and excludes dipalmitoylphosphatidic acid (DPPA). The formulation maintains a pH between 6.2 and 6.8 and uses DPPE at a concentration between about 5 and about 20 mole percent of the composition.
The specification describes DPPE combined with phosphatidylcholine and PEGylated phosphatidylethanolamine as the stabilizing lipid components, maintaining the near-neutral pH range to support formulation stability. The background comparison emphasizes that DEFINITY includes DPPC/DPPE-PEG5000/DPPA, and that DPPA limits cold-storage stability and accelerates hydrolysis.
The document further describes formulation and performance outcomes for stabilized octafluoropropane microbubble/emulsion systems using DPPE-inclusive, DPPA-free compositions. Reported results include improved stability/potency at extended storage, comparable microbubble size distribution to DEFINITY, improved microbubble counts when cone-shaped lipid inclusion is used at specified mol% ranges, and in vivo imaging outcomes including mouse renal cortex ultrasound results suggesting reduced renal retention.
Claims Coverage
The document contains three independent claims. Across these claims, there are four main inventive feature areas: an octafluoropropane-containing lipid/PEG/DPPE composition excluding DPPA, a constrained near-neutral pH range, a constrained DPPE mole-percent range, and an encapsulated microsphere particle-size/aggregate-concentration definition.
Octafluoropropane emulsion stabilizing lipid/PEG/DPPE without DPPA
A composition for stabilizing an octafluoropropane emulsion comprising octafluoropropane, phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and dipalmitoylphosphatidylethanolamine (DPPE), wherein the composition comprises no dipalmitoylphosphatidic acid (DPPA).
Near-neutral pH constraint for the DPPA-free composition
The composition has a pH between 6.2 and 6.8.
DPPE mole-percent range within the stabilizing composition
The dipalmitoylphosphatidylethanolamine (DPPE) is at a concentration between about 5 and about 20 mole percent of the composition.
Lyophilized DPPA-free octafluoropropane composition
A lyophilized composition comprising octafluoropropane, phosphatidylcholine, phosphatidylethanolamine-polyethylene glycol (PEG), and DPPE, wherein the composition comprises no dipalmitoylphosphatidic acid (DPPA), the composition has a pH between 6.2 and 6.8, and the dipalmitoylphosphatidylethanolamine (DPPE) is at a concentration between about 5 and about 20 mole percent of the composition.
Encapsulated octafluoropropane in phospholipid coated microspheres with defined size distribution
The octafluoropropane is encapsulated in phospholipid coated microspheres with a mean particle size of 1.1 μm to 3.3 μm, with 98% less than 10 μm, and a maximum diameter of 20 μm.
Defined aggregate concentration of phosphatidylcholine/PEGylated lipid/DPPE components
The phosphatidylcholine, phosphatidylethanolamine-PEG, and dipalmitoylphosphatidylethanolamine (DPPE) together have an aggregate concentration from about 0.75 mg/ml to about 1.5 mg/ml.
Across the independent claims, the coverage centers on DPPA-free compositions containing octafluoropropane stabilized by phosphatidylcholine, phosphatidylethanolamine-PEG, and DPPE, with a pH between 6.2 and 6.8 and DPPE present at about 5–20 mole percent. Additional coverage includes encapsulation in phospholipid coated microspheres with defined particle-size distribution and a defined aggregate concentration range for the lipid/PEG/DPPE components.
Stated Advantages
Improved stability/potency at extended storage versus DEFINITY, including at 40°C and up to 38–48 months.
Comparable microbubble size distribution to DEFINITY.
Improved microbubble counts with cone-shaped lipid inclusion.
Reduced renal retention suggested by mouse renal cortex ultrasound results versus DEFINITY.
Reduced back/flank pain incidence in a study/proposed statement versus DEFINITY.
Documented Applications
Ultrasound imaging applications using an octafluoropropane-based ultrasound contrast agent microbubble/emulsion formulation, including mouse renal cortex ultrasound imaging outcomes.
Assessment of adverse effects, including back/flank pain incidence, in a study/proposed statement comparing the formulation (MVT-100) with DEFINITY.
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