European Journal of Pharmaceutics and Biopharmaceutics
Review ArticleIntranasal delivery of systemic-acting drugs: Small-molecules and biomacromolecules
Graphical abstract
Introduction
The intranasal administration is widely used as the logical choice for the topic treatment of local diseases in the nose and paranasal sinuses including the allergic or infectious rhinitis, nasal polyposis and sinusitis. Nevertheless, given the nasal mucosa’s high vascularization, fairly wide absorption area, porous and thin endothelial basement membrane of the nasal epithelium, intranasal administration has also become a portal for systemic drug delivery [1], [2]. Indeed, it is today regarded as a potential alternative route for systemic delivery of small drugs that are conventionally administered by parenteral routes or that undergo extensive first-pass metabolism after oral administration [3], [4]. More recently, the interest on intranasal delivery of larger molecules not absorbed via oral route, such as peptide–protein drugs and vaccines, has also becoming a remarkable reality even though the nasal absorption of these compounds decreases with their molecular weight [5]. The nasal route is less suitable for chronic drugs that must be frequently administered daily as well as for drugs that require sustained blood levels unless they are included in pharmaceutical formulations like sustained-release dosage forms.
Underlying the wide focus on exploiting nasal cavity for systemic drugs delivery is the rapid and direct systemic absorption of compounds that circumvent gastrointestinal and hepatic first-pass metabolism, enabling a reduction of the administrated dose, a rapid achievement of relevant therapeutic blood levels, a quicker onset of pharmacological action and fewer side effects than other administration routes. However, the success of systemic drug delivery at nasal cavity is limited mainly by the mucociliary clearance which quickly clears the drug from the absorption site, reducing considerably the time available for its direct transport into the systemic bloodstream. The poor contact of formulations of small or large drugs with the nasal mucosa and particularly their low absorption when administered as simple aqueous solutions have implied the development of alternative strategies to improve the nasal bioavailability [2]. Among the most frequently alternative formulations commercially available are solution-based formulations coupled with mucoadhesive systems which may incorporate enzyme inhibitors and nasal permeation enhancers. The first diminishes the enzymatic activity at mucosa, while the latter increases the permeability of the drug, enhances the drug nasal residence time and improves the therapeutic efficacy of the systemic drugs [1], [6], [7], [8], [9], [10]. The preparation of nano- or micro-particulate systems with various polymers has also been widely tested particularly for incorporating macromolecular drugs.
Although actual general reviews summarize the anatomy and the physiology of the nasal administration and the major factors that affect the nasal drug delivery, the present updated review aims to take a step further by discussing intranasal formulation strategies and delivery systems used to optimize nasal bioavailability of systemic-acting drugs. Thus, in this paper, the critical aspects concerning the intranasal delivery of the systemic drugs will be firstly reviewed. The wide variety of small and large therapeutic agents currently marketed or under development as nasal formulations for systemic actions will be also described, presenting together the pharmacokinetic features studied in animals or/and humans as well as the most innovative methods that have been used to modulate the systemic drug exposure.
Section snippets
Anatomical, physiological and mechanistic features behind intranasal delivery of systemic-acting drugs
Researchers became interested in the nasal route for the systemic delivery of medication due to the high degree of vascularization and permeability of nasal mucosa. The nasal mucosa, unlike the skin, does not present a highly keratinized stratum corneum; instead, it forms numerous microvilli underlined with a very rich vascularity. Indeed, the main site for systemic entry of drugs is the respiratory region around the inferior turbinate and it is the largest area of the nasal cavity. The nasal
Small-molecule drugs: physicochemical properties and formulation
The awareness that the direct passage of venous blood from the nose into the systemic circulation could allow a drug to reach general circulation in few minutes after nasal administration remarkably expanded the number of systemically acting drugs marketed as nasal formulations (Table 1). This particular and recent interest in nasal administration of conventional molecules with low molecular weight may reflect the desire of the pharmaceutical companies to extend the lifespan of drugs in the
Biomacromolecular drugs
Intranasal administration also represents a promising choice for delivery of several high molecular weight therapeutic agents such as peptide-, protein- or nucleic acid-based drugs [104], [105]. Because of the higher susceptibility of biological drugs to enzymatic degradation and due to their low permeability across the epithelium via transcellular and paracellular pathway, the absorption of these biomacromolecular drugs (usually also called biologics) from mucosal sites is poor. Therefore, to
Conclusions
The valuable advantages of the intranasal route for systemic drug delivery have enhanced the number of nasal therapeutic drugs marketed over the last few years and expanded the number of drug candidates currently under clinical or preclinical development. Indeed, the improved patient compliance, avoidance of first-pass metabolism and the rapid onset of action achieved after intranasal administration allowed nasal dosage forms of small-molecule drugs to successfully be used in acute or chronic
Conflicts of interest
The authors have declared no conflicts of interest.
Acknowledgements
The authors thank to Fundação para a Ciência e Tecnologia (Portugal) for the doctoral grants (SFRH/BD/64895/2009; SFRH/BD/69378/2010). The authors also thank to POPH (Programa Operacional Potencial Humano) which is co-funded by FSE (Fundo Social Europeu), União Europeia.
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