Intranasal delivery of systemic-acting drugs: Small-molecules and biomacromolecules

Highlights

• Deep description of systemic drugs delivered by IN route.

• Description of formulations strategies employed to improve IN administration.

• IN route achieves higher plasma concentration and bioavailability than oral route.

• Rapid onset of action of systemic drugs administered by IN route is herein evidenced.

• IN route has been suitable for systemic administration of peptides and proteins.

Abstract

As a non-invasive route, intranasal administration offers patient comfort and compliance which are hurdled in parenteral drug therapy. In addition, the current recognition that the high permeability and vascularization of nasal mucosa coupled to the avoidance of the first-pass elimination and/or gastrointestinal decomposition ensure higher systemic drug absorption than oral route has contributed to the growing interest for intranasal delivery of drugs that require considerable systemic exposure to exert their therapeutic actions (systemic-acting drugs). Nevertheless, several features may hamper drug absorption through the nasal mucosa, particularly the drug molecular weight and intrinsic permeability, and, therefore, several strategies have been employed to improve it, propelling a constant challenge during nasal drug (formulation) development.

This review will firstly provide an anatomical, histological and mechanistic overview of drug systemic absorption after nasal administration and the relevant aspects of the therapeutic interest and limitations of the intranasal systemic delivery. The current studies regarding the nasal application of systemic-acting small drugs (analgesic drugs, cardiovascular drugs and antiviral drugs) and biomacromolecular drugs (peptide/protein drugs and vaccines) will also be outlined, addressing drug pharmacokinetics and pharmacodynamic improvements.

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.