Timolol Maleate in Situ Ophthalmic Mucoadhesive-Thermosensitive Gel: Development and Characterization

The aim of this study was to prepare a sustained-delivery mucoadhesive-thermosensitive formulation containing poloxamer 338 (P338), poloxamer 188 (P188), and mucoadhesive agents, such as chitosan (CHT) and carboxymethylcellulose (CMC), to increase the ophthalmic bioavailability of timolol maleate (TM).

Gels were prepared by mixing different amounts of P338, P188, and a mucoadhesive agent in cold isotonic water using a magnetic stirrer. The sol-gel gelation time of the gels was determined using the test tube inversion method. Viscosity measurements and analysis of the mechanical properties of the gel formulations were performed. In vitro release using dialysis membranes and ex vivo permeation studies using fresh-warmed cow eyes were performed.

The gelation times of formulations containing 20:2.5 (P338:P188) and 0.1% CMC and formulations containing 20:2.5 (P338:P188) and 0.1% CHT were 35 s and 26.67 s, respectively. An optimally selected CHT mucoadhesive-thermosensitive in situ gelling system can successfully control the release of moderately hydrophilic drugs, such as TM. In the viscosity study, both formulations showed Newtonian fluid, and the CHT gel's viscosity was found to be higher. The CHT gel showed better mechanical properties than the CMC gel. The amount of TM penetrating the cow cornea after 24 hours was 73.38%, 71.80%, 67.25%, and 60.55% from the CHT gel, CMC gel, TM solution, and commercial preparation, respectively.

The improved mucoadhesive-thermosensitive in situ gelling system successfully controlled the release of TM. The significantly lower drainage of TM into the circulation compared with eye drops is an advantage in treating glaucoma, and the use of mucoadhesive agents increases drug penetration.