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

Abstract

Nanotherapeutics based on biocompatible lipid matrices allow for enhanced solubility of poorly soluble compounds in the treatment of ophthalmic diseases, overcoming the anatomical and physiological barriers present in the eye, which, despite the ease of access, remains strongly protected. Micro-/nanoemulsions, solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) combine liquid and/or solid lipids with surfactants, improving drug stability and ocular bioavailability. Current research and development approaches based on try-and-error methodologies are unable to easily fine-tune nanoparticle populations in order to overcome the numerous constraints of ocular administration routes, which is believed to hamper easy approval from regulatory agencies for these systems. The predictable quality and specifications of the product can be achieved through quality-by-design (QbD) implementation in both research and industrial environments, in contrast to the current quality-by-testing (QbT) framework. Mathematical modelling of the expected final nanoparticle characteristics by variation of operator-controllable variables of the process can be achieved through adequate statistical design-of-experiments (DoE) application. This multivariate approach allows for optimisation of drug delivery platforms, reducing research costs and time, while maximising the understanding of the production process. This review aims to highlight the latest efforts in implementing the design of experiments to produce optimised lipid-based nanocarriers intended for ophthalmic administration. A useful background and an overview of the different possible approaches are presented, serving as a starting point to introduce the design of experiments in current nanoparticle research.

Development of Lactoferrin-Loaded Liposomes for the Management of Dry Eye Disease and Ocular Inflammation

“…The addition of HA produced a slight increase in average size and PI and a slight ZP reduction, maintaining a strongly positive potential that favours the stability of the system through repulsion by electrostatic forces between particles [ 56 ]. Optimized bLF-LIP were characterized morphologically by imaging using cryo-TEM ( Figure 2 a).…”

“…This technique allows predicting the instability courses of liposomes earlier than detected by other methods [ 28 ]. Furthermore, several authors have reported that liposomal particle size bellow 90 nm allows for better stability of the colloidal dispersion because gravitational phase partition is avoided by Brownian motion [ 56 ]. Moreover, the high value of ZP, over +20 mV, avoids electrostatic interaction between particles and the consequent phenomena of instability [ 61 ].…”

“…This fact confirms its controlled bLF release from liposomes, providing a longer anti-inflammatory activity and enhancing its bioavailability. The presence of a cationic surface charge in the lipidic nanocarrier, may increase the residence time by interaction with the negatively charged corneal epithelium and the mucins from tears fluid and conjunctiva [ 56 ]. Moreover, statistically significant differences were observed between the positive inflammation control and the group treated with free bLF, displaying its anti-inflammatory activity [ 19 ].…”

Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease

“…However, the work of Pinto et al observed both an increase and a decrease, depending on the ratio of solid to liquid lipid and they highlight the importance of the ratio of saturated to unsaturated fatty acids [ 39 ]. Such differing results between experimental reports demonstrate the importance of careful design when specific properties are required but that varying the lipids, the ratios and the surfactant will all have an effect that can best be determined by a carefully executed DOE [ 32 , 40 , 41 ].…”

Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study

“…In fact, reaching the eye, especially the inner part, is a challenge both through topical and systemic administration. Topical administration is limited by eye physiological barriers, such as the cornea, which limit the access of xenobiotics [14], but also by some protection mechanisms, like blinking, tearing, and drainage, which promote a quick clearance of the drug [15]. On the other hand, it is equally difficult to make a drug reach the eye from the inside, due to the blood-aqueous barrier, which works similarly to the blood-brain barrier, preventing drug diffusion from blood to retina, through the intervention of uveal capillary endothelia and ciliary epithelia.…”