Nanosystems in nose-to-brain drug delivery: A review of non-clinical brain targeting studies

Abstract

The treatment of neurodegenerative and psychiatric disorders remains a challenge in medical research. Several strategies have been developed over the years, either to overcome the blood-brain barrier or to achieve a safer or faster brain delivery, one of them being intranasal (IN) administration. The possibility of direct nose-to-brain transport offers enhanced targeting and reduced systemic side effects. Nevertheless, labile, low soluble, low permeant and/or less potent drugs might need a formulation other than the common solutions or suspensions. For that, the formulation of nanosystems is considered to be a promising approach, since it can protect drugs from chemical and/or metabolic degradation, enhance their solubility, or offer transport through biological membranes. However, the understanding of the factors promoting efficient brain targeting when using nanosystems through the nasal route is currently patchy and incomplete. The main purpose of the present review was to evaluate the association between brain delivery efficacy (in terms of brain targeting, brain bioavailability and time to reach the brain) and nanosystem type. For that, we performed a systematic bibliographic search and analysis. Furthermore, study designs, nanosystem properties, and reporting quality were also analyzed and discussed. It was found a high heterogeneity in how pre-clinical brain targeting studies have been conducted, analyzed and reported in scientific literature, which surely originates a significant degree of bias and data dispersion. This review attempts to provide some systematization recommendations, which may be useful for researchers entering the field, and assist in increasing the uniformity of future reports. The analysis of literature data confirmed that there is evidence of the advantage of the IN route (when compared to the intravenous route) and in using carrier nanosystems (when compared to IN solutions) for brain delivery of a large set of drugs. Among the most represented nanosystem classes, microemulsions had some of the lowest pharmacokinetic ratios values, while polymeric micelles had some of the best. Nevertheless, brain targeting efficacy comparisons between nanosystem groups had little statistical significance, and the superiority of the polymeric micelles group disappeared when nanosystems were compared to the respective IN drug solutions. In fact, some drugs reached the brain so efficiently, even as drug solutions, that further benefit from formulating them into nanosystems became less evident.

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

“…Hence, a potent drug is required for intranasal drug delivery to the brain. Moreover, it is very important for excipients in a formulation to be biocompatible and not produce any aggressive odor [217]. Additionally, the tonicity, viscosity, and pH (5.0-6.5) of the formulation also play key roles in drug development [216,218].…”

Development of Meloxicam-Human Serum Albumin Nanoparticles for Nose-to-Brain Delivery via Application of a Quality by Design Approach

“…Applying viscosity enhancers increases the contact time with the nasal mucosa but might also decrease the drug diffusion [12]. Furthermore, the volume also has limitations, only up to 200 µL can be administered IN [13].…”

Acrylated Eudragit® E PO as a novel polymeric excipient with enhanced mucoadhesive properties for application in nasal drug delivery

“…Drug delivery through mucosal routes of administration offers numerous advantages such as improved bioavailability of active pharmaceutical ingredients, ease of therapy application and in some cases the possibility of targeting particular organs (Andrews et al, 2009;Khutoryanskiy, 2011;Khutoryanskiy, 2014). In recent years, nasal administration has gained a lot of interest due to the possibility for bypassing the blood-brain barrier and targeting the brain directly through drug absorption via olfactory mucosa (Gänger et al, 2018;Pires et al, 2018;Battaglia et al, 2018;Sonvico et al, 2018). This minimally invasive route to deliver drugs directly to the brain could potentially offer new opportunities for treating various neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases (Poovaiah et al, 2018).…”