Part I: Effect of nanomicelle size on trans-scleral permeability of dexamethasone. And Part II: Strategies to minimize octreotide acylation during sustained release from biodegradable polymers

PART I: EFFECT OF NANOMICELLE SIZE ON TRANS-SCLERAL PERMEABILITY OF DEXAMETHASONE. Our primary aim was to determine the effect of nanomicelle size on dexamethasone (DEX) transport across the sclera. Nanomicelles of various sizes were developed and characterized. Low molecular weight diblock co-polymers, mPEG750-PCL700 (DB1), mPEG2000-PCL1500 (DB2) and mPEG5000-PCL4000 (DB3) were synthesized by ring opening polymerization. Polymers were characterized by H1 NMR (structure), gel permeation chromatography (molecular weights and polydispersity), critical micelle concentration (CMC) and in vitro cytotoxicity studies in corneal, conjunctival and retinal cell-lines. Newly synthesized polymers were purified and characterized for their structure and molecular weights by H1-NMR and GPC, respectively. The CMCs were found to be 0.13, 4.48 and 6.04 microg/mL for DB1, DB2 and DB3, respectively. In order to understand the factors and interactions influencing drug solubilization in micelle core, an exploratory 2-factors 3-level response surface methodology was generated using SAS 9.02 (exploratory model). The independent factors were polymer amount (X1) and DEX amount (X2). Solubility of DEX in micelle solution was taken as response variable (Y). Micelle preparation method was modified based on the results obtained from exploratory model. The optimal drug:polymer ratio was identified by another response surface design (optimization model) to achieve DEX solubility of 1mg/mL for all the nanomicellar formulations. The optimized formulation was characterized for solubility of DEX, micelle size and polydispersity, morphology, in vitro release and in vitro transport across conjunctival cell line.;PART II: STRATEGIES TO MINIMIZE OCTREOTIDE ACYLATION DURING SUSTAINED RELEASE FROM BIODEGRADABLE POLYMERS. Overall aim of this research was to minimize acylation of octreotide during sustained release from biodegradable polymers. Polymeric microparticle (MPs)-in-gel formulations for extended delivery of octreotide were developed. Polymer modification and reversible hydrophobic Ion-Pairing (HIP) complex strategies were investigated to achieve-mentioned goals. Polycaprolactone (PCL), polylactic acid (PLA) and polyglycolic acid (PGA) based triblock (TB = PCL10k-PEG2k-PCL10k) and pentablock (PB; PBA = PLA3k-PCL7k-PEG2k-PCL7k-PLA3k and PBB = PGA3k-PCL7k-PEG2k-PCL7k-PGA3k) polymers were synthesized and characterized for structure, molecular weight and physical state. Octreotide was encapsulated in TB, PBA and PBB MPs using methanol-oil/water emulsion solvent evaporation method. Sodium dodecyl sulfate (SDS), dextran sulfate (DS; Mw 9-20kDa (DSA) and Mw 36-50kDa (DSB)) were used as ion-pairing agents to prepared reversible HIP complex with octreotide. Mechanics of HIP complex formation and dissociation were investigated. DSA-octreotide and DSB-octreotide complex encapsulated PLGA (50/50) microparticles (MPs) were prepared using S/O/W emulsion method. MPs were characterized for size, morphology, encapsulation efficiency, drug loading and in vitro release. Release samples were subjected to LC analysis for quantitation and LC-MS analysis for identification of native and chemically modified species. Polycaprolactone based polymers may be appropriate for extended peptide delivery. Conversely, polymers having PLA and PGA blocks may not be suitable for peptide delivery due to acylation and incomplete release. Reversible HIP complex is a viable strategy to maintain chemical stability of peptide during long-term delivery from PLA and PGA based polymers. (Abstract shortened by UMI.).