methylcellulose and gamma-cyclodextrin

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.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Delayed-Action Preparations; Drug Stability; Excipients; gamma-Cyclodextrins; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methazolamide; Methylcellulose; Polymers; Rabbits; Solubility; Sulfonamides; Suspensions; Thiazines; Thiophenes; Time Factors; Tissue Distribution

In recent years cyclodextrins (CDs) have been acknowledged by the pharmaceutical industry as very useful enabling excipients for solubilization and stabilization of drugs in aqueous formulations. Their effect is however strongly influenced by other commonly used excipients. The purpose of this investigation was to examine the effects of excipients and drug combinations on the effects of CD solubilization of drugs and drug availability. The model drug was dexamethasone, the competing drugs tested were hydrocortisone, indomethacin and amphotericin B, and the sample CDs were gamma-cyclodextrin (gammaCD) and 2-hydroxypropyl-gamma-cyclodextrin (HPgammaCD). Benzalkonium chloride and hydroxypropyl methylcellulose enhance the solubilizing effect of the CDs whereas in general EDTA decreased the effect. The effect of second drug present in the aqueous formulation did depend on the affinity of that drug for the CD. Drugs which readily formed complexes with the CDs (e.g. hydrocortisone) decreased their ability to solubilize dexamethasone. Drugs that have little affinity for CDs (e.g. amphotericin B) did in some cases improve the CD solubilization of dexamethasone. Flux diagrams obtained through semi-permeable cellophane membrane indicated that drug/CD complexes self-assemble to form aggregates, especially at CD concentrations above 5% (w/v). This aggregate formation was affected by the excipients and did influence drug availability from the formulations.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Amphotericin B; Benzalkonium Compounds; beta-Cyclodextrins; Chemistry, Pharmaceutical; Dexamethasone; Edetic Acid; Excipients; gamma-Cyclodextrins; Hydrocortisone; Hypromellose Derivatives; Indomethacin; Methylcellulose; Solubility