Clarithromycin Solid Lipid Nanoparticles for Topical Ocular Therapy: Optimization, Evaluation and In Vivo Studies.

Anroop Nair,Shery Jacob,Pottathil Shinu,Sumeet Gupta,Mohamed Morsy,Katharigatta Venugopala,Bandar Al-Dhubiab,Nagaraja Sreeharsha,Snehal Patel,Jigar Shah,Mahesh Attimarad

doi:10.3390/pharmaceutics13040523

Abstract

Solid lipid nanoparticles (SLNs) are being extensively exploited as topical ocular carrier systems to enhance the bioavailability of drugs. This study investigated the prospects of drug-loaded SLNs to increase the ocular permeation and improve the therapeutic potential of clarithromycin in topical ocular therapy. SLNs were formulated by high-speed stirring and the ultra-sonication method. Solubility studies were carried out to select stearic acid as lipid former, Tween 80 as surfactant, and Transcutol P as cosurfactant. Clarithromycin-loaded SLN were optimized by fractional factorial screening and 32 full factorial designs. Optimized SLNs (CL10) were evaluated for stability, morphology, permeation, irritation, and ocular pharmacokinetics in rabbits. Fractional factorial screening design signifies that the sonication time and amount of lipid affect the SLN formulation. A 32 full factorial design established that both factors had significant influences on particle size, percent entrapment efficiency, and percent drug loading of SLNs. The release profile of SLNs (CL9) showed ~80% drug release in 8 h and followed Weibull model kinetics. Optimized SLNs (CL10) showed significantly higher permeation (30.45 μg/cm2/h; p < 0.0001) as compared to control (solution). CL10 showed spherical shape and good stability and was found non-irritant for ocular administration. Pharmacokinetics data demonstrated significant improvement of clarithromycin bioavailability (p < 0.0001) from CL10, as evidenced by a 150% increase in Cmax (~1066 ng/mL) and a 2.8-fold improvement in AUC (5736 ng h/mL) (p < 0.0001) as compared to control solution (Cmax; 655 ng/mL and AUC; 2067 ng h/mL). In summary, the data observed here demonstrate the potential of developed SLNs to improve the ocular permeation and enhance the therapeutic potential of clarithromycin, and hence could be a viable drug delivery approach to treat endophthalmitis.

Highlights

Ophthalmic drug delivery continues to pose challenges to formulation scientists due to the complex biochemical, anatomical, and physiological ocular barriers
Stearic acid has been widely used in ophthalmic drug delivery systems, and in particular in formulating solid lipid nanoparticles (SLNs) [39]
Initial fractional factorial design suggests that the sonication time and amount of lipid significantly influence the SLN formulation

Summary

Introduction

Ophthalmic drug delivery continues to pose challenges to formulation scientists due to the complex biochemical, anatomical, and physiological ocular barriers. Delivering the drug molecules to the posterior segment of the eye is challenging primarily due to the long diffusion pathway and the cellular characteristics of the vitreous humor [3]. Endophthalmitis is a severe intraocular inflammatory infection that affects the vitreous and aqueous fluids within the anterior and posterior region of eye [5]. It is the infection generally caused due to organisms such as bacteria, fungi, or parasites that enter the eye through the blood stream, surgery in the eye or other parts near the eye, or sepsis [6]. Chitosan nanoparticles containing daptomycin were developed in ocular treatment of bacterial endophthalmitis

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