Opioids are considered the cornerstone of an analgesic regimen and are indicated for the treatment of breakthrough pain and acute, moderate to severe and chronic pain. Ideally, they must exhibit a rapid onset time and a prolonged duration of action that coincides with the episode’s time course. Although oral and parenteral solutions are generally used for treatment of the breakthrough pain, the onset effect is not achieved before 30–45 min and the maximal effect within 1 h (Tveita et al. 2008). IN administration of opioids arises hence as a hope to easily and quickly achieve pain relief and improvement of the life quality of patients.

Indeed, a wide variety of opioid drugs have been under investigation, including morphine, fentanyl and buprenorphine. Although recognised as the standard opioid for cancer pain relief, morphine has a significant intestinal and hepatic first-pass metabolism that limits its bioavailability, which is around 20–32 % (Fitzgibbon et al. 2003). Similarly, the bioavailability of morphine solutions administered intranasally rounds only 10–22 % in humans and sheep (Illum et al. 2002) probably due to its low lipophilicity. In order to increase the nasal residence time, the bioavailability and the elimination half-life time of morphine after its IN administration, a wide variety of formulations have been currently under development, including formulations containing chitosan as microspheres or in solution (formulations based on starch microspheres coupled with lysophosphatidylcholine) (Illum et al. 2002) and solutions added of oleic acid as absorption promoter (Fitzgibbon et al. 2003). One of the most relevant clinical studies consisted in assessing the pharmacokinetic profile and tolerability of Rylomine^tm composed by morphine mesylate and chitosan in 13 subjects (Stoker et al. 2008). Based on the area under the concentration–time curve (AUC) values, bioavailability of IN morphine was considerably higher when compared to the other administration routes.

In opposition to morphine, fentanyl and butorphanol can be effectively and quickly absorbed at nasal cavity without using absorption promoters due to their relative high lipophilicity and low molecular weight. Particularly, IN fentanyl is currently marketed (Table 15.1) as two distinct forms: the aqueous solution Instanyl^® and the pectin-based mucoadhesive formulation PecFent^®. In a pharmacokinetic study in 19 cancer patients with breakthrough pain, nasal spray fentanyl was quickly absorbed through the nasal mucosa, attaining peak plasma concentrations within 12–15 min when administered at 50, 100 and 200 μg (Kaasa et al. 2010). One of the most important in vivo studies within this framework consisted in a balanced, randomised, double-blind, two-way crossover study in which patients received the same fentanyl dose by IN and IV administration (Christrup et al. 2008). The time to onset of action of around 10 min and the onset and duration of analgesia were not significantly different between single doses of IN and IV fentanyl in these adults. Recent researches have also shown an improvement of the bioavailability of fentanyl when administered as IN mucoadhesive formulations (Fisher et al. 2010; Kaasa et al. 2010).

Sumatriptan and zolmitriptan are analgesic drugs particularly used for migraine and cluster headaches. They are currently available as nasal formulations that provide onset times significantly quicker than those obtained after oral dosing (Dodick et al. 2005; Gawel et al. 2005) (Table 15.1). This success is due to the high lipophilicity of sumatriptan and zolmitriptan that facilitate their systemic absorption through nasal respiratory mucosa (Uemura et al. 2005) but also due to their direct access to CNS as it is referred in Sect. 15.4.1.5.

For a long time, nasal administration has been investigated as an attractive route for administration of cardiovascular drugs such as propranolol, nifedipine, nitroglycerin and carvedilol (Costantino et al. 2007).

The IN dosing of propranolol provides a pharmacokinetic profile that is very similar to that of IV administration, specifically when regarding the onset time and bioavailability (Ahn et al. 1995).

Bioadhesive sodium alginate microspheres of metoprolol tartrate for IN systemic delivery were also investigated as an alternative therapy for the treatment of hypertension and angina pectoris (Rajinikanth et al. 2003). Promising results were found in rabbits and rats, with maximum plasma drug concentrations (C _max) clearly higher after IN administration than those after oral administration.

Nifedipine is a calcium channel blocking agent frequently used for the treatment of angina pectoris and hypertension. Kubota et al. (2001) performed a crossover clinical study in order to investigate the optimal administration method of nifedipine for rapid management of hypertension. It is interesting to highlight that although the value of C _max was clearly lower after IN administration of nifedipine than that obtained for oral administration, the mean serum concentration of nifedipine 5 min after IN administration was higher (and remained higher until after 15 min). These results sustain that IN administration of nifedipine guarantees the fastest increase of drug plasma concentrations and the most significant effect on blood pressure reduction.

More recently, IN administration of carvedilol, a non-selective β-adrenergic antagonist also used in the treatment of hypertension and stable angina pectoris (Packer et al. 2002), has been under investigation due to its significant hepatic first-pass metabolism and low absolute bioavailability (25 %). Recent investigations reported that when administered by IN route to rabbits, sodium alginate microspheres and mucoadhesive chitosan microspheres containing carvedilol, the mean residence and half-life times of the drug were at least twice of those observed after IV administration. Furthermore, the high absolute bioavailability and the low t _max achieved for carvedilol sustain that both pharmaceutical formulations are promissory to prolong the therapeutic effect of carvedilol (Patil et al. 2010, 2012).

The antiviral acyclovir is currently available as several dosage forms that present limitations. Firstly, the intestinal absorption of acyclovir is slow, variable and incomplete, with an absolute bioavailability of approximately 15–20 % which requires a frequent oral dose regimen. On the other hand, its low solubility in water and lipids hamper the administration of acyclovir by intramuscular route (Shao et al. 1994). Even when intravenously administered, acyclovir is mainly excreted unchanged through urine by glomerular filtration and tubular secretion, demanding a high dose to be administered in order to attain therapeutic drug concentrations.

Hence, the IN administration of acyclovir emerged recently as an innovative strategy that could maintain the drug for a longer time in systemic circulation within effective and non-toxic concentration ranges (Alsarra et al. 2008). Since acyclovir is also practically impermeable through the nasal mucosa, neutral mucoadhesive liposomes were formulated in order to enhance the nasal penetration and systemic absorption. In a study performed in rabbits, the absolute bioavailability of nasal liposomes with acyclovir was 60.7 % while that of free acyclovir was only around 5 %. This discrepancy was also observed for AUC values, clearly demonstrating that liposomes pass directly into systemic circulation, resulting in a considerable systemic concentration of acyclovir (Alsarra et al. 2008).

Similarly, zanamivir is another antiviral drug which, although presenting higher bioavailability when administered by IN route than orally (Cass et al. 1999), is poorly absorbed at nasal level especially due to its high hydrophilicity. Thus, similar investigations to those executed for acyclovir are expected to be soon performed for zanamivir.

The nasal delivery of drugs for the treatment of nausea and motion sickness is steadily appearing as a desirable alternative to parenteral and oral medications especially because a rapid onset of action is required in acute situations. Moreover, the gastric dysmotility associated to the pathological situation is probable to affect the intestinal drug absorption and the drug fraction that is absorbed after oral administration.

For instance, when orally administered, metoclopramide bioavailability is highly variable (32–98 %) and it has a short half-life (3–4 h) that demands an oral administration three to four times daily. The IN administration of metoclopramide is identified as a good alternative (Mahajan and Gattani 2010). There are, however, limitations related to the low permeability across the nasal mucosa and the rapid MCC of metoclopramide, and in order to overcome these features, new nasal formulations have been developed and are under investigation. They consist on aqueous solutions added of absorption enhancers to increase nasal permeability (Zaki et al. 2006) or on gel and mucoadhesive formulations to prolong the residence time at the nasal absorption local and facilitate the drug uptake (Mahajan and Gattani 2010; Tas et al. 2009). Zaki et al. (2006) demonstrated that when nasal spray solution was administered to humans, the C _max of metoclopramide was significantly higher than that observed after oral administration while values of t _max and half-life time were significantly lower (Zaki et al. 2006). However, no statistical differences were observed for the mean residence times of metoclopramide, and therefore, the same research group developed and administered gel and mucoadhesive formulations composed by gellan gum (0.4 %, w/v) and Carbopol (0.15 %, w/v) to rabbits. The superior absolute bioavailability of the nasal gel compared to the oral solution clearly indicated higher absorption of metoclopramide when administered intranasally. Favourable results were also found for gel dosage forms based on mucoadhesive polymer sodium carboxymethylcellulose for IN administration of metoclopramide to sheep (Tas et al. 2009).

Ondansetron has also been under investigation to be administered by IN route, although it is currently available in IV solutions and oral dosage forms. The low oral bioavailability of ondansetron in humans (60 %) and its administration at least 30 min prior to chemotherapy sessions (Gungor et al. 2010) propelled Hussain and collaborators (2000) to investigate for the first time the feasibility of ondansetron IN administration to rats. The plasma concentration-time profiles for IN administration were comparable to that of IV administration and the rapid absorption through the nasal mucosa allowed ondansetron to reach systemic circulation almost instantaneously. Equivalent results were also reported by Gungor et al. (2010). Nevertheless, several ondansetron formulations have been developed and demonstrated to enhance drug delivery, reduce the onset time and prolong drug effect duration in relation to the oral administration (Cho et al. 2008; Gungor et al. 2010)

Scopolamine, an antimuscarinic agent indicated for motion sickness, is another example of a drug in this area that is suitable for IN dosing as depicted by human pharmacokinetic studies developed by Ahmed et al. 2000.

Sildenafil citrate is considered a standard treatment for erectile dysfunction. It is rapidly absorbed after oral administration but only with an absolute bioavailability of 40 %, an onset of action time within 15.5 min and effect duration of approximately 40 min (Deveci et al. 2004). Recently, Elshafeey et al. (2009) attempted to take advantage of nasal administration to improve these limitations and developed a new microemulsion of sildenafil citrate composed of oleic acid/Labrasol/Transcutol/water. The research group achieved drug concentrations that were nearly twofold higher than those obtained for oral tablets. A higher bioavailability and faster onset systemic levels were also observed for IN formulation probably due to the fact that liver metabolism was bypassed.

The brain is a delicate organ that plays a set of vital functions to maintain convenient body homeostasis; therefore, its integrity is ensured by specific physiological barriers and mechanisms of defence which efficiently protect and isolate the CNS from harmful endogenous substances and external insults (e.g. xenobiotics and virus).

The BBB represents one of the strictest structural and functional barriers in segregating the brain from the systemic circulation. It is characterised by the presence of non-fenestrated capillary endothelial cells with intercellular tight junctions, a very high transendothelial electric resistance (Misra et al. 2003; Vyas et al. 2005a) and a high metabolic activity associated to the expression of numerous carrier-mediated efflux transporters (Anderson 1996; Rautio et al. 2008) that regulate the influx and efflux of a variety of compounds. Unfortunately, the CNS delivery of proficuous therapeutic agents is also frequently prevented. In the last decades, several different approaches have been attempted in order to circumvent the BBB and to deliver drugs efficiently to the brain for therapeutic or diagnostic applications (Illum 2000). For example, recent developments have generated much interest in the possibility of exploiting the IN administration as a non-invasive alternative route for delivery of drugs to the CNS. In fact, assuming the olfactory region as a unique direct connection between the nose and the brain, the IN administration has emerged as a promising approach for the delivery of therapeutic agents to the CNS bypassing the BBB (Hanson and Frey 2008; Illum 2004; Vyas et al. 2005a).

In many CNS disorders, a rapid and/or specific targeting of drugs to the brain would be beneficial. Therefore, valuable efforts have been conducted to improve brain delivery of various therapeutic agents via the IN route, in order to provide higher drug bioavailability at the biophase and consequently better therapeutic efficacy.

IN administration represents a promising choice for delivery of a variety of high molecular weight therapeutic agents such as peptide-, protein- or nucleic acid-based drugs (Csaba et al. 2009; Singh et al. 2012). Because of the higher susceptibility of biological therapies to enzymatic degradation and due to their low permeability across the epithelium via transcellular and paracellular pathways, the absorption of these biomacromolecular drugs from mucosal sites is poor. Therefore, to increase their bioavailability, they are mostly administered by parenteral routes. Over the last years, new pharmaceutical formulations and novel delivery strategies have been developed offering promising opportunities to expand the IN delivery of biomacromolecules (Ozsoy et al. 2009; Singh et al. 2012).

As the nasal mucosa is one of the most permeable and highly vascularised tissues, also avoiding gastrointestinal and hepatic first-pass metabolism, the extent of absorption of biomacromolecules may be potentiated by IN administration comparatively to that achieved through oral route. Accordingly, the nasal route has gained a great interest as an alternative and non-invasive way for systemic and/or direct brain delivery of various classes of biological therapeutic agents (Ozsoy et al. 2009; Veronesi et al. 2011).

The recent advances in the field of biotechnology have promoted the emergence of a range of biodrugs. Besides therapeutic peptides and proteins, a broad variety of other biodrugs are coming into clinical practice or moving to a greater extent into clinical research, namely, vaccines, cell or gene therapies, cytokines, tissue growth factors and monoclonal antibodies (Csaba et al. 2009; Ozsoy et al. 2009; Singh et al. 2012). Hence, it is expected that the number of biomacromolecular drugs commercially available for administration via nasal route will progressively increase.