A combination of the structure and function of the nasal mucosa as a barrier to absorption, the properties of the active drug and the formulation within which it is contained will affect the extent to which a compound is absorbed nasally. The following factors are commonly reported as significantly influencing the extent of nasal absorption.
Generally, drugs which are in solution will be rapidly absorbed nasally (31), although it appears that hydrophilic compounds are not readily absorbed above around 1000 Da (32,33), as they are thought to be absorbed via aqueous channels in the nasal mucosa (34), and so absorption decreases as molecular weight increases.
The absorption of lipophilic drugs is thought to occur via an alternative pathway to aqueous channels, namely the transcellular route. The extent of absorption is linked to lipophilicity, and the partition coefficient between the nasal mucosa and any buffer solution used (4,35), allowing the drug to partition into the lipid cell membrane (36).
The pH of the nasal surface is 7.39 (37) and nasal secretions in the adult have a pH in the range of 5.5-6.5 (38). The effect of pH can be variable, but can generally be linked to how the pH would affect the ionization or structure of the molecule (4,6) , as drugs are generally more likely to be absorbed in the unionized state. For example, midazolam (pKa 6.1) absorption in rats was found to be dependant on a pH greater than 4, when it existed in at least 1% of the unionized form (39). Given the relative sensitivity of the nasal mucosa however, nasal formulations should be adjusted to a pH in a range close to that of the nasal surface, which may lead to difficulty where drug physicochemistry is not amenable to this range. For example, some other increases of absorption at low pH are thought to be a result of damage to the nasal mucosa (40,41), rather than physicochemical effects.
Osmolarity has been reported to play a role in nasal absorption, although accounts are conflicting. A group of researchers (42) found that hypertonic solutions promoted absorption of secretin in rats, thought to be a result of the observed shrinkage of cells in the mucosa, allowing more drug to permeate. It was found elsewhere that addition of osmotic agents to adhesive gels containing insulin resulted in further decreases in plasma glucose concentrations in rats (43). The finding that hypertonic solutions promote absorption would appear to agree with the theory that some polymers promote absorption via uptake of water and subsequent shrinkage of epithelial cells, resulting in a widening of tight junctions between the cells as shown by (44). However, contrary to these results it has been reported that in rats only very hypoosmotic solutions led to significant absorption of midazolam (39). The authors suggested that a resultant swelling of the mucosa aided paracellular diffusion of midazolam, however it was also indicated that pH effects may also have influenced the results, showing that the complex number of determining factors involved in nasal absorption can result in difficulty in discerning the precise mode of action.
Drug absorption can be affected by the condition of nasal mucosa. Disease states such as allergic rhinitis, sinusitis, the common cold or nasal infection can result in increased nasal secretions. Such conditions may also result in increased or decreased viscosity of the mucus layer, and the resultant outcome for any of the above occurrences will be reduced absorption, either due to rapid clearance from the nasal cavity or the increased physical barrier between drug and mucosa. Physical abnormalities such as a deviated septum or nasal polyps may also affect the dynamics of mucociliary clearance and therefore drug absorption.
Individual administration devices and technique can result in different sites of deposition within the nasal cavity, influencing absorption and clearance. Harris et al. (45), found that administration of a nasal pump spray resulted in deposition on the non-absorptive anterior region of the nasal cavity, and Soane et al. (46) reported that nasal formulations were deposited in either the anterior or turbinate region, depending on the administration technique of the volunteer. Ideally, the drug would be deposited in the turbinate site for predictable absorption (12).
When a drug is administered as a solution the volume applied at one time is of consequence, and is also inherently restricted due to the size of the nasal cavity (12). Optimal volumes appear to be between 50 and 100 mL, with improved absorption obtained by halving the dose and administering twice if the volume is too large (6). This effect was demonstrated in a study by Harris et al. (47) who reported that administration of desmopressin as a 2 x 50 mL dose gave significantly higher peak plasma and area under the curve (AUC) values than either a 1 x 50 or 1 x 100 mL dose.
Cytochrome P450 enzymes are thought to be responsible for the metabolism of many therapeutic compounds in the nasal mucosa. A further barrier to the absorption of peptide drugs such as insulin nasally may be degradation of the peptide by the various enzymes present in the nasal cavity. For example, research by Hirai et al. (48) has shown a high level of insulin degradation on exposure to rat nasal enzyme homogenates.
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