Carboxyvinyl Polymer and Guar-Borate Gelling System Containing Natamycin Loaded PEGylated Nanolipid Carriers Exhibit Improved Ocular Pharmacokinetic Parameters

Abstract

Purpose: Natamycin (NTM) ophthalmic suspension is the only FDA-approved formulation commercially available for treating ocular fungal infections. However, precorneal residence times and losses/drainage remain the foremost challenges associated with current ocular antifungal pharmacotherapy. In our previous investigations, NTM loaded polyethylene glycol nanolipid carriers (NTM-PNLCs) showed enhanced corneal permeation, both in vitro and in vivo. To further improve the corneal retention of NTM-PNLCs, this study aimed to develop a gelling system composed of carboxyvinyl polymer, guar gum, and boric acid in which the NTM-PNLCs were loaded. Methods: A 2³ factorial design was employed in formulating and optimizing the gelling system for NTM-PNLCs, where the independent factors were the gelling excipients (guar gum, boric acid, and Carbopol^® 940) and dependent variables were gelling time, gel depot collapse time, rheology, firmness, and work of adhesion. Optimized gel was evaluated for transcorneal permeation using rabbit cornea, in vitro; and tear pharmacokinetics and ocular biodistribution in male New Zealand White rabbits, in vivo. Results: Optimized NTM-PNLC-GEL was found to exhibit shear thinning rheology, adequate firmness, and spreadability, and formed a depot that did not collapse immediately. In addition, the in vitro transcorneal evaluation studies indicated that the NTM-PNLC-GEL exhibited a lower/slower flux and rate in comparison to Natacyn^® suspension. NTM-PNLC-GEL (0.3%), at a 16-fold lower dose, exhibited mean residence time and elimination half-life comparable to Natacyn (5%), and provided similar in vivo concentrations in the innermost tissues of the eye. Conclusion: The data indicate that the NTM-PNLC-GEL formulation could serve as an alternative during ophthalmic antifungal therapy.

Keywords: antifungal pharmacotherapy; fungal infections; gelling systems; in vivo evaluations; pharmacokinetic evaluations.

FIG. 1.

Plot of viscosity versus shear rate for selected NTM-PNLC-GEL formulations (B2, B4, B6, and B8) exhibiting shear-thinning rheology. NTM-PNLC-GEL, gelling system containing Natamycin loaded polyethylene glycol nanolipid carriers.

FIG. 2.

Plot of rate (μg/min), flux (μg/min/cm²), and permeability ( × 10⁻⁵ cm/s) for NTM permeation across the isolated cornea from NTM-PNLC-GEL-B2, NTM-PNLC-GEL-B6, NTM-PNLC, and Natacyn^® (dose normalized: diluted to 0.3% w/v) over 3 h, (n = 3); data represented as mean ± standard error of mean. *Denotes statistically significant difference at P < 0.05.

FIG. 3.

(A) Comparison of NTM release from NTM-PNLC-GEL (formulation B2) and NTM solution; (B) fit to Higuchi model for drug release kinetics for NTM-PNLC-GEL (formulation B2).

FIG. 4.

Plot of dose-normalized NTM concentrations (μg/μL) versus time (hours) profile for NTM-PNLC-GEL, NTM-PNLC, and Natacyn. *,**Denotes statistically significant difference between (NTM-PNLC-GEL and NTM-PNLC) and (NTM-PNLC-GEL and Natacyn) at P < 0.05, respectively; (n = 3, data represented as mean ± standard error).

FIG. 5.

NTM concentrations (μg/g) in cornea, ICB, AH, and VH from NTM-PNLC-GEL (dose: 0.3 mg; instillation volume: 100 μL), NTM-PNLC (dose: 0.3 mg; instillation volume: 100 μL), and Natacyn (dose: 5 mg; instillation volume: 100 μL) obtained after instillation every 3 and 4 h for a 9- and an 8-h study, respectively. *Denotes statistically significant difference at P < 0.05 (n = 3, data represented as mean ± standard error). AH, aqueous humors; ICB, iris-ciliary bodies; VH, vitreous humors.