Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)

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.

Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation

“…The presented research on lipid-based nanocarriers has also shown that one optimisation problem can be approached following different experimental designs, still arriving, in any case, at valid polynomials [97]. For instance, the same formulation problem regarding solid lipid nanoparticles has been optimised by a three-level full factorial, central composite, Box-Behnken or Taguchi designs [120,125,134,155]. It is important to underline that one single experimental design will in most cases not offer all the responses and that meticulous planification and statistical analysis are more important than experimental work.…”

“…Several examples of CCDs applied to lipid nanoparticle optimisation found in the literature are reported in Table 3 . Particularly, Yadav and colleagues [ 125 ] recently proposed a new approach for the treatment of age-related macular degeneration based on atorvastatin-loaded solid lipid nanoparticles intended to be topically administered. Preliminary studies allowed them to demonstrate that the concentration of all the four formulation components (lipid matrices and co-/surfactants) affected the responses under study.…”

Preparation of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Drug Delivery and the Effects of Preparation Parameters of Solvent Injection Method

“…SLNs were investigated in a potential self-administrable eye drop formulation for the management of age-related macular degeneration. They were found to increase bioavailability in aqueous and vitreous humor and to be more stable than free atorvastatin [ 54 ]. On the other hand, hot HPH has its limitations, which include temperature-induced drug degradation and drug loss to the aqueous phase during homogenization [ 55 ].…”

Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

“…Nano-sized drug delivery systems may become useful in enhancing the therapeutic potential of statins [ 202 , 203 ]. Just recently, Yadav et al investigated for the first time the effects of topically applied atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles as self-administrable eye drops [ 204 ]. The authors proposed that topical application of statins as eye drops will achieve high ocular concentration resulting in a consistent therapeutic effect [ 204 ].…”