Development of Random Triblock Copolymer Based Nanoparticulate Formulation for Sustained Release of Macromolecules/Biologics in Treatment of Posterior Segment Ocular Diseases
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Random triblock copolymers (RTB) were successfully synthesized by ring opening copolymerization method. RTB copolymers are composed of FDA approved materials such as polyethylene glycol (PEG), glycolide (GA), lactide (LA) and ɛ-caprolactone (CL). RTB copolymers were synthesized and developed for sustained delivery of macromolecules to the posterior segment of the eye. RTB copolymers of different composition and molecular weights were synthesized. The polymers were evaluated for their molecular weight, purity, crystallinity, functionality, cytotoxicity and biocompatibility. No toxicity was observed when ocular cell lines were treated with RTB polymers. Moreover, polymers did not induce inflammatory mediators when treated with macrophage cells. These data confirm lack of in vitro cytotoxicity and production of inflammatory mediators, which suggests RTB copolymers may be good candidates for ocular delivery of macromolecules. In this project, several formulation strategies have been employed to enable sustained delivery of macromolecules by employing nanoparticle approach. In the first approach, synthesized RTB copolymers were further utilized to encapsulate macromolecules with various molecular weights ranging from 237-1 kDa. These macromolecules include catalase, IgG, bovine serum albumin, IgG Fab fragment, lysozyme, insulin and octreotide. Our results observed the effect of macromolecule molecular weight on drug loading and entrapment efficiency. In order to ensure sustained and prolonged release, nanoparticles were suspended in thermosensitive gel which acted as a secondary barrier. The second approach was combining the benefit of two technologies i.e. nanoparticle and liposome to formulate hybrid nanoparticles encapsulating IgG, IgG F(ab)’₂ and IgG Fab fragments. JMP full factorial design was employed in order to understand factors and interactions influencing particle size, entrapment efficiency and drug loading of nanoparticles. Optimized formulation was obtained based on the results from the design. Nanoparticles were prepared according to the optimized formulation and characterized for particle size, PDI, entrapment efficiency and drug loading. In vitro release of macromolecules from hybrid nanoparticles suspended in thermosensitive gel revealed prolonged release of macromolecules. The final approach was the modification of octreotide by ion pairing agents to form hydrophobic ion pairing complexes. The complexes were found to be reversible at physiological pH with high amounts of counter ions. The complexes were further encapsulated inside nanoparticles using RTB copolymer. Encapsulation efficiency and drug loading was found to be higher since the complexes are hydrophobic in nature and partition well into polymer matrix. In vitro release studies indicated prolonged release for extended period. Moreover, acylation of octreotide was observed in smaller quantity, while large amounts of native octreotide were released.
Table of Contents
Literature review -- Hypothesis and rationale -- Synthesis and characterization of biodegradable and biocompatible random tribblock copolymers (RTB) -- Nanoforumlation for long term ocular delivery of macromolecules effect of molecular weight in drug release -- Development of hybrid lipid-polymer nanoformulation for sustained release of IGG, IGG(FAB)’2 fragment and IGG FAB fragment -- Improvement of octreotide acylation by octreotide modification utilizing ion pairing agents and preparing nonoformulation for sustained release -- Summary and recommendations -- Appendix. Abbreviations ; Permission request
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Ph.D.