Clevidipine nanoparticles and pharmaceutical compositions thereof
Inventors
Motheram, Rajeshwar • Hanley, David • Tureli, Akif Emre • Kanter, Monika
Assignees
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Publication Number
US-12383507-B2
Publication Date
2025-08-12
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 invention relates to pharmaceutical compositions comprising clevidipine or a pharmaceutically acceptable salt thereof in therapeutic nanoparticles formulated with at least one excipient. The excipient is selected from water soluble excipients and/or water insoluble excipients, including PEG 200, sodium deoxycholate, tocopheryl polyethylene glycol succinate (vitamin E TPGS), vitamin E, deoxycholic acid, and phosphotidylcholine. The therapeutic nanoparticle is configured as a core portion containing clevidipine or salt and an outer portion surrounding the core and comprising the excipient.
A key aspect is forming the therapeutic nanoparticle by dissolving clevidipine or a pharmaceutically acceptable salt in a first solvent to form a solution, pumping the solution into a heated microjet reactor, precipitating with a second solvent, and removing a portion of the solvents to form a core portion and an outer portion. The excipient is present in the first solvent and/or the second solvent such that it resides in the outer portion surrounding the clevidipine-containing core.
The disclosure further addresses physical and chemical stability in aqueous dispersions intended for parenteral administration, including ambient-storage stability enabled by excipient-based stabilization and microjet reactor formation. Impurity control includes maintaining the level of any single impurity at or below 1.8% weight-to-weight for at least three months at room temperature, with monitoring of impurity profiles including oxidative degradants such as H324/78 and evaluation of solvent/non-solvent exposure, autoclaving, accelerated and long-term storage, and the influence of oxygen, headspace, and antioxidants.
Claims Coverage
The independent claim defines the core pharmaceutical nanoparticle composition and a specific microjet-reactor-based formation structure, with explicit requirements for room-temperature storage and impurity limits. The listed dependent claims further add inventive refinements covering selected excipient and antioxidant choices, concentration constraints, impurity thresholds for specified substances, and an administration route.
Clevidipine therapeutic nanoparticle with specified water soluble and water insoluble excipients
A pharmaceutical composition comprising a therapeutic nanoparticle comprising clevidipine or a pharmaceutically acceptable salt thereof, and at least one excipient that is water soluble or water insoluble or combinations thereof, wherein the water soluble excipient is polyethylene glycol 200 (PEG 200), sodium deoxycholate, tocopheryl polyethylene glycol succinate (vitamin E TPGS) or combinations thereof, and wherein the water insoluble excipient is vitamin E, deoxycholic acid, phosphotidylcholine or combinations thereof.
Room-temperature storage with single-impurity limit
The therapeutic nanoparticle is storable 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.
Heated microjet reactor precipitation with solvent removal forming core and excipient outer portion
The therapeutic nanoparticle is formed by dissolving clevidipine or a pharmaceutically acceptable salt thereof in a first solvent to form a solution, pumping the solution into a heated microjet reactor, precipitating the solution with a second solvent, and removing a portion of the solvents forming a core portion and an outer portion of said nanoparticle, wherein the core portion comprises clevidipine or pharmaceutically acceptable salt thereof, and the outer portion surrounds the core and comprises the at least one excipient.
Excipient present in first and/or second solvent during nanoparticle formation
The at least one excipient is present in the first solvent and/or the second solvent.
Clevidipine concentration range in the composition
The composition specifies clevidipine or a pharmaceutically acceptable salt thereof at 0.5 to 10.0 mg/mL.
Antioxidant included in the composition
The pharmaceutical composition further comprises an antioxidant.
Antioxidant selected from specified antioxidant compounds
The antioxidant is selected from a specified list of antioxidant compounds, or combinations thereof.
Impurity thresholds for specified substances under defined storage
Impurities are limited to no more than 0.2% w/w for Substance 23, Substance 24, and Substance 25 and no more than 1.5% w/w for H168/79 after storage for at least three months at room temperature.
Intravenous administration of the therapeutic nanoparticle
The therapeutic nanoparticle is administered intravenously.
Overall, the claim set centers on clevidipine-containing therapeutic nanoparticles formed using a heated microjet reactor precipitation process that places specified excipients in an outer portion around a clevidipine core, while requiring room-temperature storage for at least three months with defined impurity limits. Dependent claims refine the formulation by adding concentration and antioxidant selections, tightening impurity thresholds for specified substances, and limiting administration to intravenous delivery.
Stated Advantages
Provides a therapeutic nanoparticle storable for at least three months at room temperature.
Maintains the level of any single impurity at no more than 1.8% weight-to-weight after at least three months at room temperature.
Maintains impurity thresholds for specified impurities (Substance 23, Substance 24, Substance 25, and H168/79) after storage for at least three months at room temperature.
Documented Applications
Parenteral administration of the clevidipine-loaded nanoparticle aqueous dispersion.
Intravenous administration.
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