Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

Abstract

Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.

Formulation and characterization of lamotrigine nasal insert targeted brain for enhanced epilepsy treatment

“…They are slightly shifted from the accepted range. The pH of the prepared formulations should be close to the nasal mucosa’s (5.0 to 6.5) to avoid causing sensations of discomfort, irritation or toxicity in the nasal epithelium and/or enhanced mucociliary clearance (Pires et al., 2022 ). The mucoadhesion force of the prepared nasal inserts was ranged from 7063.2 ± 2.06 to 9319.5 ± 2.02 dyne/cm2 ( Table 6 ).…”

Fabrication and Characterization of Clozapine Nanoemulsion Sol–Gel for Intranasal Administration

“…Drug absorption and bioavailability of clozapine administered using the nasal route may be limited by its poor solubility. , Large, undissolved drug particles may cause nasal irritation and trigger the mucociliary clearance of the nasal cavity . In this study, the clozapine-encapsulated nanoemulsion sol–gel (CLZ-NESG) was developed using the aqueous titration method to determine the oil, surfactant, and cosurfactant with the highest drug solubility, followed by sonication.…”

Antipsychotics-Loaded Nanometric Emulsions for Brain Delivery

“…There are several types of nanosystems, with the main categories being: polymeric nanosystems (polymeric nanoparticles, polymeric micelles), lipid nanoparticles (solid lipid nanoparticles, nanostructured lipid carriers), liposomes and related nanosystems (transfersomes, cubosomes, ethosomes), and nanometric emulsions [ 11 ]. Nevertheless, most of these systems have been reported to have short/low physical stability, low encapsulation efficiency, and non-biocompatible components, while requiring complex preparation methods, that are time- and resource-consuming, and that frequently use toxic organic solvents [ 12 , 13 , 14 ]. Yet, nanometric emulsions, which consist of colloidal liquid-in-liquid dispersions, can form spontaneously, evidencing the great advantage of having straightforward methods of preparation, that are not quite common.…”