Topical Clear Aqueous Nanomicellar Formulation for Anterior and Posterior Ocular Drug Delivery
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The objective of this study was to develop a clear, aqueous drug loaded nanomicellar formulation (NMF) for the back-of-the-eye delivery. Hydrophobic drugs such as cyclosporine, resolvin analog (RX-10045), dexamethasone, rapamycin were entrapped in the core of polymeric micelles and solubilized. Polymeric amphiphilic molecules (e.g., hydrogenated castor oil – 40 (HCO-40) and Vit. E TPGS) are known to generate nanomicellar constructs with hydrophobic core and hydrophilic corona. However, constructs prepared from a single polymer are unstable and easily fall apart at high temperature. Inclusion of a second polymer such as Oc-40 improves stability and prevents nanomicellar destabilization. Such stable nanomicellar constructs can encapsulate hydrophobic drugs in their lipophilic core while the hydrophilic corona helps solubility in aqueous solution. We screened resolvin for efflux pumps and prepared resolvin analog nanomicelles. Studies showed that NMFs were tolerable and delivered high drug concentrations to back-of-the-eye tissues with topical eye drop application to rabbits. Negligible drug levels were quantified in systemic circulation. These nanomicellar constructs efficiently utilize their hydrophilic corona and evade the wash-out into the systemic circulation from both the conjunctival and choroidal blood vessels and lymphatics, thus overcoming the dynamic barrier. Moreover, this pathway might overcome the major drawback associated with steroid therapy (glaucoma and cataract), since a trans-scleral route of absorption is accessed. In summary, for the first time we identified that resolvin analog was substrate/inhibitor for BCRP and MRP but not P-gp. Moreover, resolvin analog was identified as a strong inhibitor of influx transporter (OCT-1). Clear, aqueous NMF encapsulating hydrophobic drugs were successfully developed. Ocular bioavailability and pharmacokinetic studies demonstrated a very high drug levels in retina-choroid (place of drug action) with a negligible drug partitioning into lens and vitreous humor. These results suggest that drug and/or NMFs cannot reach back-of-the-eye tissues following corneal pathway. Alternatively, ~12 nm - 20 nm nanomicelles efficiently permeate through 20 nm to 80 nm scleral pores and reach back-of-the-eye tissues (retina-choroid) following conjunctival-scleral pathway. In the lipoidal posterior ocular tissues, these nano-constructs may release the cargo into Bruch’s membrane/retina-choroid generating high drug levels.
Table of Contents
Introduction -- Literature review -- Topical aqueous clear cyclosporine nanomicellar formulation: optimization, in vivo ocular toxicity evaluation and pharmacokinetic study -- Topical aqueous clear resolvin E1 analog (RX-10045) nanomicellar formulation -- Part A: interaction studies of resolvin E1 analog with efflux transporters -- Part B. formulation optimization and in vivo evaluation -- Topical aqueous clear dexamethasone nanomicellar formulation: optimization and in vivo tissue distribution -- Topical aqueous clear rapamycin (sirolimus) nanomicellar formulation: develop,emt and in vivo issue distribution -- Summary and recommendations -- Appendix