In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics.

Mydriasis is required prior to many eye examinations and ophthalmic surgeries. Nowadays, phenylephrine hydrochloride (PHE) and tropicamide (TPC) are extensively used to induce mydriasis. Several pharmaceutic dosage forms of these two active ingredients have been described. However, no optimal therapeutic strategy has reached the market. The present work focuses on the formulation and evaluation of a mucoadhesive ion-activated in situ gelling delivery system based on gellan gum and hydroxyethylcellulose (HEC) for the delivery of phenylephrine and tropicamide. First, in vitro drug release was studied to assess appropriate sustained drug delivery on the ocular surface region. Drug release mechanisms were explored and explained using mathematical modeling. Then, in situ gelling delivery systems were visualized using scanning electron microscopy illustrating the drug release phenomena involved. Afterward, cytotoxicity of the developed formulations was studied and compared with those of commercially available eye drops. Human epithelial corneal cells were used. Finally, mydriasis intensity and kinetic was investigated in vivo. Mydriasis pharmacodynamics was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. In situ gelling delivery systems mydriasis profiles exhibited a significant increase of intensity and duration compared with those of conventional eye drops. Efficient mydriasis was achieved following the administration of a single drop of in situ gel reducing the required amount of administered active ingredients by four- to eight-fold compared with classic eye drop regimen.

Novel in situ gelling ophthalmic drug delivery system based on gellan gum and hydroxyethylcellulose: Innovative rheological characterization, in vitro and in vivo evidence of a sustained precorneal retention time.

Achieving drug delivery at the ocular level encounters many challenges and obstacles. In situ gelling delivery systems are now widely used for topical ocular administration and recognized as a promising strategy to improve the treatment of a wide range of ocular diseases. The present work describes the formulation and evaluation of a mucoadhesive and ion-activated in situ gelling delivery system based on gellan gum and hydroxyethylcellulose for the delivery of phenylephrine and tropicamide. First, physico-chemical characteristics were assessed to ensure suitable properties regarding ocular administration. Then, rheological properties such as viscosity and gelation capacity were determined. Gelation capacity of the formulations and the effect of hydroxyethylcellulose on viscosity were demonstrated. A new rheological method was developed to assess the gel resistance under simulated eye blinking. Afterward, mucoadhesion was evaluated using tensile strength test and rheological synergism method in both rotational and oscillatory mode allowing mucoadhesive properties of hydroxyethylcellulose to be point out. Finally, residence time on the ocular surface was investigated in vivo, using cyanine 5.5 dye as a fluorescent marker entrapped in the in situ gelling delivery systems. Residence performance was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. Fluorescence intensity profiles pointed out a prolonged residence time on the ocular surface region for the developed formulations compared to conventional eye drops, suggesting in vitro / in vivo correlations between rheological properties and in vivo residence performances.