Topical Clear Aqueous Nanomicellar Formulations For Anterior And Posterior Ocular Drug Delivery
Abstract
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,
iv
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 vitro & 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 -- Summary and recommendations -- Appendix
Degree
Ph.D.