Download 756. Synthesis of Poly(ester amide)

Synthesis of Poly(ester amide) Microparticles for Intra-articular drug delivery
Ian Villamagna, Frank Beier, Elizabeth R. Gillies
University of Western Ontario—Department of Biomedical Engineering
Statement of Purpose: To fabricate and characterize
degradation. In addition to release profiles, particle
poly(ester amide) microparticles that can be used in intradegradation was monitored through SEM imaging and
articular injections for the localized treatment of
showed the erosion of particles that is consistent with the
Osteoarthritis (OA).
release of celocoxib measured by UV-visible
Introduction: Osteoarthritis is a debilitating and
spectroscopy. An MTT assay, performed on ATDC5 cells
degenerative multifaceted joint disorder that affects over
to mimic cell interactions in the intra-articular space
10 million American adults over the age of 45, and is the
showed no significant cell toxicity to the material,
leading cause of disability in this age group.1,2 Despite the
poly(ester amide), in particle form (n=9). ANOVA was
prevalence of the disease, there is currently no known
used to compare the treatment groups to control and
cure, or disease modifying agent available to treat OA. In
determine no significant cell death from treatment with
2015, work from the Beier lab at UWO looked at the role
the material.
of PPARd in OA, and determined that PPARd inhibitors
could be a significant new target therapeutic in the
treatment of OA.3While these inhibitors exist they are
extremely hydrophobic in nature, and cause multiple side
effects, limiting their ability to be used in a systemic
delivery fashion. To combat the difficulty in delivery of
these sorts of molecules, poly(ester amide) microparticles
have been synthesized and characterized. These particles
are used to encapsulate the PPARd inhibitor, and due to
the amide and ester bonds in the polymer backbone,
allows for a slow release of the drug through hydrolysis in
the body.
Methods: Poly(ester amide)s that had been previously
Figure 1. Scanning electron micrograph of Poly(ester amide)
studied in the Gillies lab were used in this study.4
microparticles loaded with celocoxib. Particles were found to
Microparticles were fabricated through an oil in water
have an average size of roughly 1 micron. Visual results were
emulsion using poly(vinyl alcohol) as a surfactant in the
confirmed with dynamic light scatter.
continuous phase. Particles were centrifuged to remove
excess surfactant and drug, and lyophilized to form a final
Conclusions: This study has shown that hydrophobic
product. Size analysis of the particles was performed
drugs such as celocoxib, and more novel drugs such as the
through dynamic light scatter (DLS). Scanning electron
PPARd inhibitor GSK3787 can be successfully
microscopy was used to authenticate the DLS as well as
encapsulated and released from PEA microparticles. The
to view surface characteristics and morphology.
initial studies performed to characterize the material,
Encapsulation efficiency and drug loading for the
including cell toxicity and drug release studies, give a
particles were calculated. Release studies from the
strong indication of its usefulness in a physiological
microparticles were performed with Celocoxib as a model
setting. Future work with these particles has been planned
drug, prior to the incorporation and release studies with
and will include further in vitro testing with GSK3787
GSK3787. Cell toxicity of blank poly(ester amide)
release, explant tissue studies, and in vivo studies. The
particles was performed through an MTT assay using
current study shows a new method to successfully
ATDC5 cells.
encapsulate and release novel and potentially disease
Results: Particles were synthesized and characterized as
modifying drugs to treat OA.
described above. Microparticles were found to have an
References:
average size of ~1.0 microns by DLS. SEM imaging
1.
Sharif B. Osteoarthr Cartil. 2016:1-10.
shows uniform spherical particles with little to no surface
2.
Hunter DJ. Nat Rev Rheumatol. 2014;10(7):437defects. Encapsulation efficiency of celocoxib loaded
441.
microparticles was found to be 92% with a drug loading
3.
Ratneswaran A. Arthritis Rheumatol.
of 33%. Encapsulation efficiency of GSK 3787 loaded
2015;67(2):454-464.
microparticles was found to be 93% while drug loading
4.
Moustafa A. Can J Chem Eng. 2015;93(12):2098percentage was determined to be 29%, showing that
2106.
multiple hydrophobic drugs can be encapsulated. Release
studies of a model drug from the polymer particles agrees
with data from previously completed degradation studies
on the polymer. A slow, continuous release was observed
in particles; after 7 days of release an average of 15% of
the loaded drug had been released from the particles with
bulk erosion of the particles the most likely method of