In situ-forming gels for ophthalmic drug delivery.

Abstract

Poor bioavailability of ophthalmic solutions caused by dilution and drainage from the eye can be overcome by using in situ-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible phase transitions. Joshi et al. (1), have demonstrated that aqueous compositions that reversibly gel in response to simultaneous variations in at least two physical parameters, such as temperature, pH, and ionic strength, can be formed by appropriate combinations of macromolecular polymers which exhibit reversible gelation properties. In the present study, the rheological characterization of such a system, prepared by a combination of Carbopol (C) and methyl cellulose (MC), was carried out at two different pH (4.0 and 7.4) and temperatures (25 and 37 degrees C) by rotational cone and plate viscometry. The shear stress (tau) vs. shear rate (D) flow curves of the aqueous polymer solutions indicated a pseudoplastic behavior, with a yield point. An increase in pH from 4.0 to 7.4, or temperature from 25 to 37 degrees C, resulted in an increase in viscosity (eta), tau, and yield point, the magnitude of changes being highest when both the parameters were altered simultaneously. An increase in concentration of either C or MC, or an increase in MC molecular weight results in an increase in eta, tau, and yield point. Among the compositions studied, a solution containing 1.5% MC 0.3% C was found to have low eta, and formed a strong gel under simulated physiological conditions. Such a system can be formulated as drug containing liquid suitable for administration by instillation into the eye, which upon exposure to physiological conditions will shift to the gel (semi-solid) phase, thus increasing the precorneal residence time of the delivery system and enhancing ocular bioavailability.