Background <p>Acetazolamide, a carbonic anhydrase inhibitor, reduces intraocular pressure and helps in the management of glaucoma. The primary barriers to ocular formulations are poor bioavailability, intolerance following oral administration, and a short biological half-life.</p> Purpose <p>To overcome these barriers, films have been developed by adding different plasticizers to mucoadhesive polymer bases for sustained drug delivery.</p> Methods <p>Films were prepared by casting a drug-HPMCK15M mixture using the solvent evaporation technique. Triethanolamine, dimethyl sulfoxide, polyethylene glycol 400, and propylene glycol has been used as a plasticizer. Physicochemical, In-vitro, Ex-vivo &amp; In-vivo characteristics were evaluated in simulated lacrimal fluid (pH7.4).</p> Results <p>The prepared films were thin and had uniform thickness. Good folding endurance indicated good flexibility and mechanical strength of the film. The compatibility research resulted in a transition of crystalline acetazolamide into amorphous state. No significant changes in any band were observed, confirming drug-excipient compatibility. The endothermic peak at 267.84&#xa0;°C indicated the melting of the pure drug. The HPMC matrix contributes to the inhibition of crystal growth. In the drug release study, controlled release was observed for 5&#xa0;h and ex vivo showed an improved release for up to 6&#xa0;h. Intraocular pressure was reduced by more than 30% from the baseline and sustained for 6&#xa0;h, where eye drop lasted for 3&#xa0;h.</p> Conclusion <p>These results suggest that the HPMC-loaded ocular films of acetazolamide offer a promising platform for sustained glaucoma therapy.</p> Graphical Abstract <p>Schematic illustration of sustained ocular delivery of acetazolamide HPMC films for glaucoma management</p> <p></p>