A Novel,
Concentrated, High loading Nanoparticle-based Formulation of Progesterone for
Emergency Traumatic Brain Injury
Princeton Docket #
12-2766-1
Unmet
Need
Progesterone is a water-insoluble steroidal hormone that is a
promising therapeutic for treating traumatic brain injury (TBI). However, it is
difficult to formulate the steroid for emergency administration due to its
hydrophobicity, crystallinity, and poor bioavailability. In the literature, many
different nanoparticulate formulations for progesterone have been described, but
the highest concentration and drug loading reported remain low at 12 wt% of the
particle solids, reaching 2.6 mg/mL progesterone in the aqueous dispersions
(Yuan et al. Colloids Surf. B.
Biointerfaces 60(2), 174-179 (2007)). A high concentration of progesterone
is needed in the formulation, such that a relatively large dose can be
administered in a small volume. Furthermore, quick delivery of the steroid to
the bloodstream is desired, since administration of progesterone within 24 hours
of the TBI produces the most benefit (Roof et al. Exp. Neurol. 138, 246-251 (1996)). It is
known that progesterone rapidly crosses the blood-brain barrier and reaches
equilibrium with plasma (Xiao et al. Crit. Care
12(2), R61 (2008)), thus quick
release of the steroid to the bloodstream from a vehicle is
favorable.
Proposed Solution
and Potential Commercial Markets
Researchers in the Department of Chemical and Biological
Engineering, Princeton University
have successfully used Flash Nanoprecipitation (FNP) to produce
polymeric nanoparticles (NPs) at a base concentration of 10 mg/mL of the
steroid. The progesterone-loaded nanoparticles were made using only components
that are classified by the FDA as GRAS (generally recognized as safe). The
resulting nanoparticles are 300 nm in diameter with 24 wt% progesterone loading
and active concentrations close to 10 mg/mL, of which approximately 80% is
dissolved in the α-tocopherol. For prolonged stability, the nanoparticles are
lyophilized with Pluronic F68. The nanoparticle suspensions can be reproducibly
reconstituted to the original size and at higher concentrations (3X
concentration) by hand agitation for 1 minute. The reconstituted progesterone
dispersion can be readily expressed through a 25 gauge syringe needle. This
formulation can allow for administration of large amounts of progesterone in
small volumes.
This approach to formulating progesterone is also applicable to
other water-insoluble steroids, of which are common therapeutics to disease
areas such as inflammation, cancer, and neurological disease. Potential markets
include patients in need of pharmaceutical treatment of such
diseases.
Stage of Development
A pharmacokinetics study was conducted in Harlan Sprague Dawley
male rats to determine pharmacokinetic parameters of the nanoparticle
formulation. The data which is available under
an appropriate confidentiality agreement, demonstrates that the
nanoparticle formulation provides a vehicle for progesterone that yields high
bioavailability.
Intellectual Property Status
Various aspects of the FNP process have been successfully patented
(US 8137699) and continuation applications are pending. A PCT patent application has been filed
for the work described here.
Inventors
Robert K Prud¿homme, Professor of Chemical and Biological
Engineering
A major focus on our research is on using self-assembly to
construct nanoparticles for drug delivery and imaging. Our work is highly
interdisciplinary as many of the projects involve joint advisors and
collaborations with researchers at NIH, Argonne National Labs, CNRS in France,
in addition to corporate sponsored research.
Carlos E Figueroa, Graduate student, Department of Chemical and
Biological Engineering
Contacts:
Laurie
Tzodikov
Princeton
University Office of Technology Licensing ¿ (609) 258-7256¿
tzodikov@princeton.edu