Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs

Abstract

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) were used to enhance DXMa concentration in aqueous solution. The β and γ HPCD derivatives allowed the increase of the DXMa amount in solution at 25 °C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC^®, GEL-LARMES^®, and VISMED^®) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HPβCD) and 2% (HPγCD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX^® and DEXAFREE^®, in the case of mixed gel containing HPβCD, more than 90% of the drug was released within 2 h, while in mixed gel containing HPγCD, the release of DXMa was partial, reaching ≈60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.

Keywords: cyclodextrins; dexamethasone acetate; dissolution assay; experimental design; eye drops; hydrogels; phase solubility.

Figure 1

Chemical structure of dexamethasone-21-acetate with perhydro-cyclopentano-phenanthrene ring system, A = A-ring, B= B-ring, C= C-ring, and D = D-ring.

Figure 2

Steps implemented for the experimental design with 29 experiments.

Figure 3

Phase-solubility diagrams of DXMa in water under various concentrations of HPβCD () or HPγCD (). Each data point represents a mean (n = 3), with SD smaller than the symbol size.

Figure 4

Plots of 1/k vs. [HPβCD] () or [HPγCD] () (assuming 1:1 stoichiometry) for dexamethasone acetate at a column temperature equal to 40 °C. Stationary phase: phenyl silica gel; mobile phase: mixture methanol: water (70:30 v/v).

Figure 5

Van’t Hoff plots (lnK vs. 1/T) for DXMa/HPβCD () or DXMa/HPγCD () associations.

Figure 6

Rheological profiles of the two optimized mixed gels based on HPβCD () or HPγCD ().

Figure 7

In vitro drug release from MAXIDEX^®, DEXAFREE^® and optimized mixed gels A and B in PBS, at 35 °C.