Novel Thermo-setting Gel Eliminates Cold Storage Requirement For Improved Ocular Surface Drug Bioavailability

Abstract

Purpose: : The thermo-setting gel containing methyl cellulose (MC) is effective for enhancing drug bioavailability. However, this delivery system must be cold stored to permit its application as a solution. To overcome this drawback, we developed a novel thermo-setting gel, which can be stored at ambient temperature, and is readily transformed back into a solution once gelation has occurred. The dependence was determined between composition changes and rheological properties as well as pharmacokinetics.

Methods: : Effects were determined of changes in composition of each thermo-setting gel on their rheological properties. Gels were modified by using various additives such as MC, sodium citrate, hydroxyethyl cellulose, mannitol and polyvinyl pyrrolidone k25. The effects were evaluated of changes in temperature and shear stress on their viscosity using a rheometer. Time dependent ocular penetrance was evaluated of either 0.5% timolol or 1% dorzolamide in rabbits using each gel using LC or tandem LC-MS-MS.

Results: : A novel gel composition was identified whose viscosity dependence on temperature was the same as that of the conventional gel formulation. With both formulations, their viscosities were higher at 35°C than those at 20°C. At 35°C, increases in shear stress caused continuous increases in conventional gel viscosity. Similarly, the viscosity of the novel gel composition initially increased, but declined at higher stress levels. Furthermore, the pharmacokinetic profiles were comparable of 0.5% timolol and 1% dorzolamide in the novel gel and its conventional counterpart.

Conclusions: : A novel thermo-setting gel composition was developed for drug delivery of an ophthalmic solution. It has rheological properties that are different from those of the conventional thermo-setting gel. Unlike the conventional gel, after gelation only the novel gel can be transformed into a solution by gentle agitation such as shaking. The conventional gel must instead be cold stored to prevent gelation prior to its administration onto the ocular surface. Therefore, the novel thermo-setting gel is expected to improve patient drug compliance.

Keywords: intraocular pressure • quality of life