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.
Highlights
Intranasal administration is most commonly used for the treatment of local affections, such as nasal congestion, rhinitis or sinusitis, symptoms that are generally related to allergies or upper respiratory tract infections [1]
The intranasal route has proven to be better accepted by adults and adolescents than the rectal route, and it can be an alternative for patients for whom the oral and buccal routes are not suitable, such as in conditions associated with vomiting, with regard to jurisdictional claims in published maps and institutional affiliations
Brain drug levels were not determined, the results showed that the resveratrol concentration in plasma after intranasal administration of the transfersome hydrogel was significantly higher at all time points, when compared to the oral suspension, with plasma Cmax increasing by 2-fold and AUC by more than 20-fold
Summary
Intranasal administration is most commonly used for the treatment of local affections, such as nasal congestion, rhinitis or sinusitis, symptoms that are generally related to allergies or upper respiratory tract infections [1]. Having a large surface areato-volume ratio and high vascularization, the nasal cavity is favorable for systemic drug absorption and has proven useful for therapeutic systemic effects, having several potential advantages when compared to other routes [2,3] One of these advantages is its non-invasiveness and ease of administration, not requiring trained professionals or in-hospital setting. Of the administration route, it is difficult to formulate drugs that have low water solubility at high strength without having to use substantial amounts of cosolvents or surfactants, which are potentially toxic excipients This is an even bigger problem in intranasal delivery, since the drug has to be administered in a small volume, as mentioned before, and even higher drug strengths are required [2,3]. The purpose of this work was to review the strategies that have been used to increase drug solubility/strength in formulations intended to be administered intranasally, to treat central nervous system disorders
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