Impact of Different Mucoadhesive Polymeric Nanoparticles Loaded in Thermosensitive Hydrogels on Transcorneal Administration of 5-Fluorouracil

Abstract

In a previous paper a thermosensitive hydrogel formulation based on chitosan or its derivatives (TSOH), containing medicated chitosan nanoparticles (Ch NP) for transcorneal administration of 5-fluorouracil (5-FU) was described. The Ch NP-containing TSOH allowed a time-constant 5-FU concentration in the aqueous for 7 h from instillation. The aim of the present work was to study the impact of the surface characteristics of new NP contained in TSOH on ocular 5-FU bioavailability. The Ch derivatives used to prepare NP were quaternary ammonium-Ch conjugate (QA-Ch), S-protected derivative thereof (QA-Ch-S-pro), and a sulphobutyl chitosan derivative (SB-Ch). All NP types had 300–400 nm size, 16–18% encapsulation efficiency, and retained the entrapped drug for at least 15 h. Drug release from TSOH containing NP based on QA-Ch or QA-Ch-S-pro was virtually equal, whereas with TSOH containing NP based on SB-Ch was significantly slower. Instillation, in rabbit eyes, of NP-containing TSOH based on QA-Ch or SB-Ch led to a plateau in the aqueous concentration vs. time plot in the 1–10 h range with significantly enhanced area under curve (AUC). Negative charges on the NP surface slowed down 5-FU release from TSOH while positive charges increased NP contact with the negatively charged ocular surface. Either results in enhanced ocular bioavailability.

Chitosan and its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments

“…Thanks to the strong interactions between the active substance and the polymer matrix, the prepared derivative appeared promising for future processing into 3D solid forms, such as controlled drug delivery systems, films, or medical devices. In line with this work, Fabiano et al explored three different CS derivatives for the formation of NPs and the ocular delivery of 5-fluorouracil: quaternized CS derivative (positively charged), 12 in Scheme 1, a derivative bearing a protected thiol group, 14 in Scheme 1, and one bearing a sulfobutyl group (negatively charged), 15 in Scheme 1 [203]. NPs were prepared by self-assembly upon the addition of HA.…”

“…Moreover, the gel did not cause any visual disturbances. Fabiano et al incorporated 5-fluorouracil-loaded CS-based NPs in a CS/quaternary ammonium CS hydrogel [203]. Three different derivatives were studied, 12, 14, and 15 in Scheme 1, producing NPs with different ζ-potential.…”

Quaternary Ammonium Chitosans: The Importance of the Positive Fixed Charge of the Drug Delivery Systems

“…The introduction of 5-fluorouracil-medicated NPs based on Ch in TSOH increased the transcorneal penetration of the drug when administered in rabbit eyes, leading to a time-constant 5-fluorouracil concentration in the aqueous for 7h from instillation. Subsequently, TSOH containing Ch-nanoparticles was compared with TSOH containing QA-Ch nanoparticles in order to study the impact of the surface characteristics of nanoparticles on 5-fluorouracil bioavailability [67]. The instillation, in rabbit eyes, of TSOH containing NPs based on QA-Ch or sulfobutyl chitosan (SB-Ch) led in both cases to a plateau of the concentration in the aqueous humour for 10 h. Negative charges on the surface of SB-Ch-based NPs slowed down the release of 5-FU from TSOH, while the positive charges of the QA-Ch-based NPs increased NP contact with the negatively charged ocular surface.…”

“…The instillation, in rabbit eyes, of TSOH containing NPs based on QA-Ch or sulfobutyl chitosan (SB-Ch) led in both cases to a plateau of the concentration in the aqueous humour for 10 h. Negative charges on the surface of SB-Ch-based NPs slowed down the release of 5-FU from TSOH, while the positive charges of the QA-Ch-based NPs increased NP contact with the negatively charged ocular surface. Both resulted in a higher ocular bioavailability [67].…”

Special Issue on Designing Hydrogels for Controlled Drug Delivery: Guest Editors’ Introduction

“…The aim of the work of Fabiano et al was to study the impact of the surface characteristics of new nanoparticles contained in a thermosensitive hydrogel formulation based on chitosan or its derivatives, on ocular 5-fluorouracil bioavailability [6]. The chitosan derivatives used to prepare nanoparticles were quaternary ammonium-chitosan conjugate (QA-Ch), S-protected derivative thereof (QA-Ch-S-pro), and a sulphobutyl chitosan derivative (SB-Ch).…”