Pentablock copolymers based controlled release formulations of small and macromolecules for ophthalmic applications
Abstract
Pentablock copolymers comprised of multi-polymer blocks such as polyethylene
glycol (PEG), polycaprolactone (PCL) and poly-lactide (PLA) were developed for
fabrication of nanoparticles and thermosensitive hydrogel formulations for long term delivery
of small and macromolecules. Different pentablock copolymer compositions were evaluated
to optimize drug release profile from nanoparticles and thermosensitive gel formulations. Our
composite approach i.e. pentablock copolymers based nanoparticles suspended in
thermosensitive gel provided sustained zero-order delivery of encapsulated therapeutic
agents without producing any significant burst effect. Different compositions of pentablock copolymers (polylatide- polycaprolactonepolyethylene
glycol- polycaprolactone- polylatide) (PLA-PCL-PEG-PCL-PLA) and (PEGPCL-
PLA-PCL-PEG) were synthesized and characterized to prepare nanoparticle and
thermosensitive hydrogel formulations, respectively. The effect of poly (L-lactide) (PLLA) or
poly (D, L-lactide) (PDLLA) incorporation on crystallinity of pentablock copolymers and in
vitro release profile of triamcinolone acetonide (selected as model drug) from nanoparticles was
also evaluated. Pentablock polymer with proper ratio PDLLA/PCL was amorphous in nature
whereas PLLA containing polymer has semicrystalline nature. Release of triamcinolone
acetonide from nanoparticles was significantly affected by crystallinity of the copolymers.
Burst release of triamcinolone acetonide from nanoparticles was significantly minimized
with incorporation of proper ratio of PDLLA in the existing triblock (PCL-PEG-PCL) copolymer. Moreover, pentablock copolymer based nanoparticles exhibited continuous
release of triamcinolone acetonide for longer duration. The release profile of various steroids
commonly utilized for chronic ocular diseases was also evaluated with optimized pentablock
polymer. We found that steroids with different log P values did not exhibited significant
difference in release profile. These results could be attributed with the fact that drug release
from the nanoparticles is mainly diffusion mediated process and small molecules can easily
diffuse out from the pore the polymer matrix. However, we found that pentablock copolymer
based nanoparticles can be utilized to achieve continuous near zero-order delivery of small
molecules from nanoparticles without any burst effect. Further, release profile of timolol
from composite formulations was evaluated for glaucoma therapy. We observed that
composite approach could provide sustain release of timolol for longer duration. Successful
accomplishment of this project may lead to application of this strategy for the treatment of
other chronic ocular diseases such as age related macular degeneration and diabetic macular
edema. Treatment of these diseases requires frequent intravitreal injections to maintain
therapeutic levels of antibodies at retina/choroid. Frequent administrations can cause
potential complications like endophthalmitis, retinal detachment and retinal hemorrhage. Sustained intraocular therapeutic drug concentration can be achieved by suspending the
therapeutic macromolecules in thermosensitive hydrogel. Considering this we have
characterized the release kinetics of various macromolecules from pentablock copolymer
based thermosensitive hydrogel. We observed that release kinetics of macromolecules from
thermosensitive hydrogel was depended on the size of a molecule. Our studies indicate that
pentablock copolymer based delivery systems can provide sustained drug release profile for
longer duration, and thereby eliminate the need for repeated intravitreal injections.
Table of Contents
Literature review -- Introduction -- Novel pentablock copolmer (PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery: effect of copolymer compositions on polymer crystallinity and drug release profile from nanoparticles -- A novel pentablock copolymer based composite drug delivery system for timolol maleate delivery -- Hydrolytic and enzymatic degradation of pentablock polymers -- Pentablock copolymer based thermosensitive hydrogel for macro molecule delivery -- Summary and recommendations -- Appendix
Degree
Ph.D.