Clevidipine nanoparticles and pharmaceutical compositions thereof
Inventors
Motheram, Rajeshwar • Hanley, Sr., David C. • Tureli, Akif Emre • Kanter, Monika
Assignees
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Publication Number
US-11737989-B2
Publication Date
2023-08-29
Expiration Date
Abstract
Provided is a pharmaceutical composition comprising clevidipine in a sterile, ready to use, physically stable, aqueous dispersion of nanoparticles that stabilizes clevidipine against formation of impurities and is suitable for parenteral administration.
Core Innovation
The patent describes therapeutic nanoparticle aqueous dispersions and compositions comprising clevidipine or a pharmaceutically acceptable salt thereof. The nanoparticles include a clevidipine core portion and an excipients outer portion that surrounds the core, and the formulations are intended to be sterile, ready-to-use parenteral administration with ambient storage stability and impurity and oxidative degradation control.
The document addresses controlled impurities and improved oxidative stability during storage at room temperature by producing clevidipine therapeutic nanoparticles in a method that dissolves clevidipine in a first solvent, optionally with at least one excipient, and pumps the solution through heated capillaries into a heated microjet reactor.
In the microjet reactor, the solution is precipitated with a second solvent and a portion of the solvents is removed to form nanoparticles having the clevidipine core portion and the excipients outer portion. The at least one excipient is selected from water soluble excipients, water insoluble excipients, and combinations thereof, including PEG 200, sodium deoxycholate, vitamin E TPGS, vitamin E, deoxycholic acid, and phosphotidylcholine, with excipient presence in the first solvent and/or the second solvent.
Claims Coverage
The partial content provides three independent claims. Across the independent claims, the coverage centers on a microjet reactor-based method to make clevidipine therapeutic nanoparticles with a clevidipine core and an excipient outer portion, followed by storage at room temperature under defined impurity constraints, and in one independent claim a stabilization requirement tied to the excipient selection.
Microjet reactor precipitation forming a clevidipine core and excipient outer portion
Dissolving clevidipine, or a pharmaceutically acceptable salt thereof, in a first solvent to form a solution; pumping the solution through heated capillaries into a heated microjet reactor; precipitating the solution with a second solvent using the microjet reactor; removing a portion of the solvents to form a core portion and an outer portion of the nanoparticle; wherein the core portion comprises clevidipine or a pharmaceutically acceptable salt thereof, and the outer portion surrounds the core and comprises the at least one excipient.
Excipient selection and solvent presence for outer portion formation
The at least one excipient is selected from water insoluble excipients, water soluble excipients, and combinations thereof; the at least one excipient is present in the first solvent and/or the second solvent; the water soluble excipient is polyethylene glycol 200 (PEG 200), sodium deoxycholate, vitamin E tocopheryl polyethylene glycol succinate (vitamin E TPGS), or combinations thereof; and the water insoluble excipient is vitamin E, deoxycholic acid, phosphotidylcholine, or combinations thereof.
Room temperature storage with single impurity constraint
Storing the nanoparticle for at least three months at room temperature and the level of any single impurity is no more than 1.8% on a weight-to-weight basis.
Substance-specific impurity minimization during room temperature storage
Storing the nanoparticle for at least three months at room temperature and the level of impurities is minimized to no more than 0.2% on a weight-to-weight basis for any of Substance 23, Substance 24, and Substance 25, and no more than 1.5% for H168/79 on a weight-to-weight basis.
Clevidipine stabilization by specified excipient types with room temperature impurity limit
Clevidipine is stabilized in the nanoparticle with the at least one excipient selected from water insoluble excipients, water soluble excipients, and combinations thereof; the water soluble excipient is polyethylene glycol 200 (PEG 200), sodium deoxycholate, vitamin E tocopheryl polyethylene glycol succinate (vitamin E TPGS), or combinations thereof; the water insoluble excipient is vitamin E, deoxycholic acid, phosphotidylcholine, or combinations thereof; clevidipine is a core portion of the nanoparticle, and the at least one excipient comprises an outer portion surrounding the core; the at least one excipient is present in the first solvent and/or the second solvent; and the nanoparticle is stored for at least three months at room temperature and the level of any single impurity is no more than 1.8% on a weight-to-weight basis.
Across the independent claims, the core inventive subject matter is a method that uses heated capillaries and a heated microjet reactor to precipitate clevidipine, with selected water soluble and/or water insoluble excipients, to form nanoparticles with a clevidipine core and an excipient outer portion, followed by room temperature storage with defined impurity constraints. One independent claim additionally specifies clevidipine stabilization by the selected excipient types within the nanoparticle.
Stated Advantages
Ambient storage stability with controlled impurities during room temperature storage.
Oxidative degradation control.
Impurity limitation for any single impurity to no more than 1.8% after at least three months at room temperature.
Impurity minimization to no more than 0.2% (w/w) for Substance 23, Substance 24, and Substance 25, and no more than 1.5% for H168/79 after at least three months at room temperature.
Documented Applications
Sterile, ready-to-use parenteral administration of clevidipine therapeutic nanoparticle aqueous dispersions and compositions.
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