Design and Development of Solid Lipid Nanoparticles for Ocular Delivery of Acyclovir

Abstract

Background and aim: Ocular infections caused by Herpes keratitis remain the leading cause of infectious blindness in the developed world and there is a need for the development of a novel drug delivery system to improve treatment options. The complex structure of the eye poses several challenges which ocular drug delivery methods seek to address. The aim of this thesis was to improve the ocular bioavailability of acyclovir (ACV) by incorporating it into solid lipid nanoparticles (SLNs) and nano-structured lipid carriers (NLCs). Methods: SLNs and NLCs were prepared by a hot microemulsion technique. Nanoparticles were characterised by laser diffraction size measurements, zeta potential, scanning electron microscopy (SEM), x-ray diffraction (XRD), Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC). The drug was quantified by high performance liquid chromatography (HPLC) for the measurement of entrapment efficiency, drug loading, in vitro and ex vivo drug release studies. ACV-β-cyclodextrin (ACV-βCD) inclusion complexes were prepared by lyophilisation. Nanoparticles were coated with the biodegradable, cationic and bioadhesive polymer, chitosan and were characterised for cytotoxicity, cellular uptake, antiviral efficiency and stability. Finally, the chosen chitosan coated NLCs formulation was subjected to an in vivo animal ocular pharmacokinetic study. Results: The prepared nanoparticles were spherical and within the size range suitable for ocular drug delivery. The incorporation of liquid oils in the structure of SLNs resulted in the formation of NLCs with higher entrapment efficiency (91.64%) compared to that of SLNs (11.14%). The complexation of ACV with βCD led to the formation of inclusion complexes with higher solubility. Incorporation of complexes in NLCs resulted in a sustained drug release profile, increased stability and increased ex vivo corneal permeability. Coating nanoparticles with chitosan inverted the zeta potential from -25.5 ± 1.65 to +28.1 ± 0.72, increased stability, prolonged corneal residence time, sustained the drug release and increased ex vivo corneal permeation of ACV. Finally, the chitosan coated formulation was selected for in vivo animal studies and showed a 4.5 times increase in ocular bioavailability in comparison with the marketed ophthalmic ACV ointment. Conclusion: The findings of this thesis demonstrated the suitability of lipid based novel drug delivery systems for ocular administration and their capability to increase the ocular bioavailability and therefore antiviral efficacy of ACV.