Development of a Nanoparticle Cross-linked Collagen Formulation for the Management of Posterior Uveitis
Year: 2022
Type: dissertation
Abstract: Background: Uveitis is an inflammatory disorder affecting the middle layer of the eye (uvea). Current steroid treatment involves oral dosing, with only low drug concentrations reaching the back of the eye, or intravitreal injections which can be associated with ocular complications. This study aims to overcome these limitations by applying the steroid, dexamethasone (Dex), via the periocular route (tissue surrounding the eye) and using a sustained delivery formulation to prolong the duration of therapeutic action, thereby reducing the application frequency. Aim: To develop a novel periocular depot formulation, using nanoparticle cross-linked collagen, to deliver Dex for the management of posterior uveitis. Methods: An isocratic high performance liquid chromatography (HPLC) method was optimized and validated for the simultaneous quantification of Dex and dexamethasone sodium phosphate (DexP) in the sclera and retina/choroid. Scleral Dex and DexP penetration was compared using the Ussing chamber and an ex vivo porcine whole-eye model. Collagen was cross-linked with different concentrations of polyvinylpyrrolidone coated zinc oxide nanoparticles (ZPVP) and then characterized for its physical and mechanical properties via texture analysis and rheological studies. The hydrogel with the best properties was selected as the formulation vehicle. In vitro release studies were then conducted to determine the drug and ZPVP release profile from the formulation. Finally, LPS-induced inflammation cell models were developed to test the efficacy of the formulation in vitro. Results: Ex vivo penetration studies revealed no significant difference in the amount of Dex and DexP in the retina/choroid tissue after periocular application. Texture analysis showed that cross-linking collagen with ZPVP significantly enhanced its mechanical properties in terms of hardness and adhesiveness while rheological characterization confirmed an increase in viscosity upon cross-linking. Moreover, in vitro drug release from the cross-linked collagen was significantly more sustained than from unmodified collagen. Finally, in vitro cell studies showed poor biocompatibility of the formulation, likely due to released ZPVP. However, when the formulation was pre-washed, there was no significant difference in cell viability between the formulation and standard DexP treatment. Conclusion: The results obtained in this study suggest that the cross-linked collagen depot formulation may offer sustained drug release for the management of uveitis. However, due to the low biocompatibility of ZPVP, alternative cross-linking methods should be explored.
Author: Agban, Yosra
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7046518838