Considerations in the use of cyclodextrins in the reformation of ophthalmic suspensions as solutions

xix, 250 leaves :ill. ; 30 cm. Includes bibliographical references. "October 2000"Purpose: Pharmacological agents administered topically to the eye often have poor bioavailability due to the efficient physiological processes that exist to protect the eye. Poor partitioning of the agent into the cornea, often the target site of action and the route of absorption of the agent into the eye, is also a major limitation. In the case of poorly water-soluble agents administered as suspensions, this is compounded by formulation difficulties. In order to exploit the advantages of solution formulations and retain the partitioning characteristics of the lipophilic parent compound, water-soluble cyclodextrins have received attention as solubilising agents for topical ophthalmic delivery. However, the effect of cyclodextrins on the bioavailability of ophthalmic drugs reported thus far is equivocal, and in addition to other formulation variables, may be influenced by both the physicochemical properties of the drug and the complex it forms with cyc1odextrins. The aim of this thesis was to elucidate the mechanism by which a water-soluble, biocompatible cyclodextrin (hydroxypropyl-β-cyclodextrin (HP-β-CD)) can modulate the ocular delivery of poorly water-soluble compounds. Methods: The interaction of hydrocortisone (HC), dexamethasone (DX) and progesterone (PG) with HP-β-CD was investigated by phase-solubility analysis to enable preparation of formulations of the compounds with HP-β-CD having a known composition of free, complexed and solid-state drug. The in vivo ocular bioavailability of HC in the NZW rabbit was determined following topical administration of solutions containing HC (1%) with HP-β-CD (69.7 mM) alone, or containing the mucoadhesive, viscosity enhancing polymer sodium hyaluronate (0.2 or 0.5% w/v). A 1% HC suspension was used as control. The mechanism of effect of HP-β-CD on ocular bioavailability was then investigated in a series of in vitro permeability studies using a series of steroids. In vitro permeability studies, using side-by-side diffusion cells, were carried out to determine the importance of cyclodextrin concentration, total drug and free drug concentrations, dissolution and diffusion rates in stirred and poorly stirred environments mimicking the rabbit precorneal area, and endogenous tear film compounds on the driving force of the flux of drug through the cornea when formulated as HP-β-CD solutions. The effect of polymers (polyvinylpyrrolidone and hydroxypropylmethylcellulose) and temperature on PG/HP-β-CD complexation and the in vitro permeability of the PG/HP-β-CD complexes formed under the conditions studied were also investigated. Results: The apparent solubility of HC, DX and PG increased linearly upon addition of HP-β-CD. The association constant of the interactions was 0.64, 0.61 and 12.16 mM⁻¹ respectively. Formulation of HC as a solution with HP-β-CD in the absence of sodium hyaluronate increased the bioavailability of HC in the aqueous humour by approximately 55% and cornea by 75% when compared to suspension. Inclusion of the polymer did not result in any further increase in ocular bioavailability over that noted for the polymer-free solution. The HP-β-CD solutions containing polymer were retained longer in the precorneal area compared to the polymer-free solution but no correlation between retention of HC in the conjunctival cul-de-sac and ocular bioavailability was observed. In vitro studies for HP-β-CD formulations showed a good correlation between transmembrane flux and the concentration of free drug in solution in both stirred and non-stirred conditions, irrespective of the total drug concentration. For suspensions, however, the flux was lower when the suspensions in the donor chamber were not stirred compared to well-stirred systems. Addition of a small amount of HP-β-CD to the suspension was able to overcome this limitation. Dissolution studies showed that under the conditions studied, membrane flux was unlikely to be dissolution rate limited in either stirred or non-stirred conditions. Diffusion studies revealed that HP-β-CD may diminish aqueous diffusion layer resistance to flux through the cornea of drug formulated as a suspension by the additional diffusion of complexed drug. This effect was found to be greater for more poorly water-soluble compounds. Phase-solubility and in vitro permeability studies showed that HP-β-CD was capable of stabilising supersaturation of PG up to 84% above its solubility following transient temperature increases up to 90°C. The polymers investigated did not significantly effect the complexation of PG or slightly decreased it compared to polymer-free systems. In formulations previously heated to 90°C, however, these polymers further stabilized the supersaturation (more than HP-β-CD alone). The in vitro transmembrane flux of PG was increased when formulated as supersaturated HP-β-CD solutions. Conclusions: Biocompatible, water-soluble cyclodextrins are a useful approach to the reformulation of ophthalmic suspensions as solutions. When incorporated into an ophthalmic formulation of HC at the minimum quantity to solubilise all solid-state drug, an increase in ocular bioavailability was observed. The mechanism of the increase may be due to enhanced transport of drug through diffusive transport regions such as the mucin layer adjacent to the corneal surface. The efficacy of such formulations may be further enhanced by HP-β-CD stabilised supersaturation. These findings challenge the current literature understanding of the effect of cyclodextrins on the ophthalmic drug delivery of poorly water-soluble compounds