Mucoadhesion; A prerequisite or a constraint in nasal drug delivery?

Abstract

Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cutoff at approximately 1000 Da and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Nasal drug administration is presently used for local therapies within the nasal cavity. Anti-allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practiced since ancient times. Nasally-administered psychotropic drugs by native Indians, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known. The use of the nasal cavity as a route for drug delivery has been an area of great interest to the pharmaceutical industry during the last few decades. This area is characterized by a high degree of maturity; a few novel chemical entities have been developed, and the focus is on improvisation of the formulations. There has also been a great interest in developing products for systemic delivery of drugs such as small molecular drugs (e.g. sumatriptan), peptides (e.g. desmopressin) and proteins (e.g. insulin) that are not easily administered via routes other than injection or where a rapid onset of action is required. The use of the nasal cavity for vaccination has also been an area of interest. Nasal drug delivery has now been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. Nasal drug delivery offers many attractive possibilities, such as systemic delivery of drugs with avoidance of first-pass metabolism, easy administration, rapid onset of effect and the possibility to circumvent the blood-brain barrier. It also offers both systemic and local vaccine response and of course avoidance of adverse systemic effects when treating local nasal ailments. Not surprisingly, nasal administration has therefore attracted great interest from both the industry and academia. The widespread interest in the intranasal route for therapeutic purposes other than the topically administered nasal drug delivery arises from the particular anatomical, physiological and histological characteristics of the nasal cavity, which provides potential for rapid systemic drug absorption and quick onset of action. In addition, intranasal absorption avoids the gastrointestinal and hepatic presystemic metabolism, enhancing drug bioavailability in comparison with that obtained after gastrointestinal absorption. On the other hand, intranasal administration also offers several practical advantages either from the viewpoint of patients (non-invasiveness, essentially painless, ease drug delivery and favourable tolerability profile) or pharmaceutical industry (unnecessary sterilization of nasal preparations). Hence, bearing in mind the intrinsic value of the intranasal route to overcome patient compliance concerns together with its pharmacokinetic advantages, it appears to be an appropriate route for the treatment of not only acute or chronic nasal diseases, but also for a range of acute or chronic conditions requiring considerable systemic drug exposure. Despite the potential of nasal drug delivery, it has a number of limitations. One problem with nasal administration is the rapid removal of mucus from the nasal cavity, resulting in a clearance half-life of about 15 min for ordinary formulations. Mucoadhesion, allowing prolonged retention time, is therefore often considered a prerequisite for effective nasal administration. Over the last few decades, the application of mucoadhesive polymers in nasal drug delivery systems has gained interest among pharmaceutical scientists as a means of promoting dosage form residence time in the nasal cavity as well as improving intimacy of contact with the absorptive membranes of the biological system. In addition, the enhanced paracellular absorption following the swelling of the mucoadhesive polymers on the nasal membranes provides an important way for the absorption of the macromolecules through the nasal cavity. It has been demonstrated that low absorption of drugs can be countered by using absorption enhancers or increasing the drug residence time in the nasal cavity, and that some mucoadhesive polymers can serve both functions. Mucoadhesion is where two surfaces, one of which is a mucous membrane, adhere to each other. This has been of interest in the pharmaceutical sciences in order to enhance localized drug delivery, or to deliver 'difficult' molecules (proteins and oligonucleotides) into the systemic circulation. Mucoadhesive materials are hydrophilic macromolecules containing numerous hydrogen bond-forming groups, the carbomers and chitosans being two well-known examples. The mechanism by which mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the establishment of the adhesive interactions). The relative importance of each stage will depend on the individual application. For example, adsorption is a key stage if the dosage form cannot be applied directly to the mucosa of interest, while consolidation is important if the formulation is exposed to significant dislodging stresses. Adhesive joint failure will inevitably occur as a result of over-hydration of a dosage form, or as a result of epithelia or mucus turnover. New mucoadhesive materials with optimal adhesive properties are now being developed, and these should enhance the potential applications of this technology. The mucoadhesive polymers have enormous potential for the delivery of therapeutic macromolecules, genes, and vaccines through the nasal cavity with high drug bioavailability. Guest Editorial [Downloaded free from http://www