Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degenerati
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ORIGINAL ARTICLE
Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD) Monika Yadav 1 & Nicola Schiavone 2 & Ana Isabel Guzman Aranguez 3 & Fabrizio Giansanti 2 & Laura Papucci 2 & Maria J. Perez de Lara 3 & Mandeep Singh 1 & Indu Pal Kaur 1
# Controlled Release Society 2020
Abstract Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time propose and investigate local application of atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles (SLNs), as self-administrable eye drops. Insolubility, instability, and high molecular weight > 500 of ATS, and ensuring that SLNs reach posterior eye were the challenges to be met. ATS-SLNs, developed (2339/DEL/ 2014) using suitable components, quality-by-design (QBD) approach, and scalable hot high-pressure homogenization, were characterized and evaluated comprehensively for ocular suitability. ATS-SLNs were 8 and 12 times more bioavailable (AUC) in aqueous and vitreous humor, respectively, than free ATS. Three-tier (in vitro, ex vivo, and in vivo) ocular safety, higher corneal flux (2.5-fold), and improved stability (13.62 times) including photostability of ATS on incorporation in ATS-SLNs were established. Autoclavability and aqueous nature are the other highlights of ATS-SLNs. Presence of intact fluorescein-labeled SLNs (F-SLNs) in internal eye tissues post–in vivo application as eye drops provides direct evidence of successful delivery. Perinuclear fluorescence in ARPE-19 cells confirms the effective uptake of F-SLNs. Prolonged residence, up to 7 h, was attributed to the mucus-penetrating nature of ATS-SLNs. Keywords Ocular delivery . In vivo safety . Uptake studies . Ocular pharmacokinetics . Posterior eye delivery . Statins . Nanostructured carriers
Introduction Age-related macular degeneration (AMD) is a progressive degenerative macular disease attacking the region of highest Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-020-00733-4) contains supplementary material, which is available to authorized users. * Indu Pal Kaur [email protected]; [email protected] 1
Department of Pharmaceutics, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
2
Department of Experimental and Clinical Biomedical Sciences, Section of Experimental Pathology and Oncology, Viale Morgagni 50, 50134 Florence, Italy
3
Facultad de Optica y Optometria, Dpto. Bioquimica y Biologia Molecular IV, Universidad Complutense de Madrid, C/Arcos de Jalon 118, 28037 Madrid, Spain
visual acuity, the macula. It becomes a leading cause of irreversible blindness in people over 50 years of age especially those living in industrialized countries [1, 2]. More than 30 million peo
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