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

Abstract

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 μg/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. Nanomicellar formulations iv (referred to as DEXM) containing >1mg/mL DEX were developed for all three polymers using design of experiment. The optimized nanomicelle formulation exhibited mean size in range of 10nm, 30nm and 60nm with unimodal size distribution and low polydispersity for DB1, DB2 and DB3 polymers, respectively. The formulation was also subjected to ex vivo transport across excised rabbit sclera to determine influence of micelle size on DEX transport across the static barrier. DEX permeability across the excised rabbit sclera for DEXM and DEX suspension (control) were found to be 2.7x10⁻⁶, 3.0x10⁻⁶, 1.5x10⁻⁶ and 1.2x10⁻⁶ cm/sec, respectively. There were 2.2, 2.5 and 1.3-fold increase in DEX permeability with nanomicelles of mean sizes 10 nm, 25 nm and 60 nm, respectively. The permeability studies across the sclera, static barrier, indicates that the nanomicelles with average sizes 10nm and 30nm may have potential to deliver therapeutic agents to the back of the eye following topical administration. Therefore, nanomicellar formulation may provide therapeutic levels in the back of the eye following topical administration.