Formulation of Water Insoluble Drugs for Ocular Delivery

Abstract

Cyclodextrins are unique cyclic molecules with a hydrophobic interior and hydrophilic exterior that can be used to solubilize, stabilize and enhance targetability of the encapsulated molecules. Chapter 1 will discuss uses of CDs as it applies to nanoparticle-based drug carriers. Ocular drug delivery is a challenging field due to the large number of ocular barriers. Therefore, producing a new ophthalmic formulation requires consideration when it comes to the administration route, dosage form and site of action. Chapter 2 will cover the basics of ophthalmic formulation development. Nepafenac is a common NSAID commercially available as a suspension, Nevanac®, due to the poor water solubility. Hydroxypropyl-beta-cyclodextrin (HPBCD) was complexed with nepafenac to increase the water solubility and transcorneal permeation of the drug. The complex in the liquid and solid state was confirmed. Perfusion studies using whole porcine eyes proved the solution had a significantly higher drug distribution and corneal retention compared to Nevanac®. The HPBCD-nepafenac complex was formulated into an ion-activated in-situ gel to improve residence time in the eye, using sodium alginate. A sodium alginate concentration of 0.3% revealed the largest increase in viscosity following the addition of simulated tear fluid, allowing for the formulation of a nepafenac in-situ gel system for comparison with Nevanac®. Perfusion studies revealed an increased retention of nepafenac on the sclera when using the in-situ gel system, due to the gel formation in the presence of calcium ions.

Difluprednate is a corticosteroid used to treat anterior ocular inflammation. Due to the poor solubility of difluprednate, it is only available as an emulsion, Durezol®. Difluprednate was complexed with HPBCD to produce a positive-relationship complexation, meaning more than one cyclodextrin is needed to solubilize difluprednate. The solution exhibited higher ocular distribution, corneal permeation and retention compared to Durezol®. Difluprednate loaded in poly(lactic-co-glycolic acid) (PLGA) based microneedles for delivery to the posterior segment of the eye. The patches contained a PAA backing that rapidly dissolved upon instillation in the eye; leaving the microneedles embedded in the sclera for sustained drug release. Microneedles containing PLGA of varying molecular weights and lactide content were compared in release, failure force, and permeation studies.