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.