Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: Formulation of dorzolamide eye drop microparticle suspension

• DOI: 10.1016/j.ejpb.2010.07.005
• Publication Date: 2010-07-16T05:15:45Z
• Authors: Phatsawee Jansook; Einar Stefánsson; Margrét Thorstein...; Baldur B. Sigurdsson; Sigrún S. Kristjá...; Jon Fernández Bas; Hakon H. Sigurdsson; Thorsteinn Loftsson
• Keywords: Sulfonamides; Time Factors; Polymers; Administration, Topical; Thiazines; Methazolamide; Thiophenes; 04 agricultural and veterinary sciences; Hydrogen-Ion Concentration; Methylcellulose; 3. Good health; Excipients; Hypromellose Derivatives; 0404 agricultural biotechnology; Drug Stability; Solubility; Suspensions; Delayed-Action Preparations; Animals; Tissue Distribution; Rabbits; Carbonic Anhydrase Inhibitors; gamma-Cyclodextrins

Topically applied carbonic anhydrase inhibitors (CAIs) are commonly used to treat glaucoma. However, their short duration of action requiring multiple daily dosing can hamper patient compliance. The aim of this study was to develop novel aqueous CAI eye drop formulation containing self-assembled drug/cyclodextrin (D/CD) microparticles that enhance and prolong drug delivery to the eye. Phase-solubility of each drug tested (i.e. methazolamide, brinzolamide and dorzolamide HCl) was determined in either pure water or an aqueous eye drop medium. The pH was adjusted to maximize the fraction of unionized drug. Dorzolamide had the highest affinity for γ-cyclodextrin (γCD) and, thus, was selected for further investigation. Hydroxypropyl methylcellulose (HPMC) was the most effective polymer tested for stabilization of the dorzolamide/γCD complexes and gave the highest mucoadhesion at 0.5% w/v concentration. Thus, the dorzolamide eye drop vehicle containing γCD (18% w/v) and HPMC (0.5% w/v) was developed. The physicochemical properties of this formulation complied with the specifications of the eye drop suspension monograph of the European Pharmacopoeia. The in vivo testing of the formulation showed that the drug was delivered to the aqueous humor in rabbits for at least 24h with the maximum drug concentration at 4h. Furthermore, this formulation delivered the drug to the posterior segment of the eye after topical administration. These results indicate that this CAI eye drop formulation has the potential of being developed into a once-a-day product.