Marc Brown

Look at the drug discovery calendar and you will find many conferences on alternative drug delivery methods. Nasal delivery figures prominently, both in dedicated events and with other 'hot' areas such as transdermal drug delivery. Nasal delivery is not new, but to date it has been mainly limited to topical steroids and decongestants. Even in relation to allergy and congestion, where nasal administration is apparently successful, numerous patients fail to realize optimum clinical benefit from nasally-administered drugs because of poor localization of the active within specific areas of the nasal cavity. Now however, because of recent advances in nasal drug delivery technology, there is much optimism about the possible use of the nose for systemic treatments. Pain and osteoporosis management are two areas under serious investigation. Vaccines are being mentioned and there is the tantalizing possibility of being able to deliver via the nose directly to the brain for treating neurodegenerative diseases.  

The attraction of nasal administered therapeutic agents is obvious, including faster onset of action, increased compliance and avoiding degradation during first pass metabolism. The latter, of course, opens the way to lower dosages. However, the challenges in nasal delivery are also numerous. First, actual delivery devices have to be designed for correct actuation in varying conditions by differing age groups. Obvious as it may seem, they also have to be designed to ensure delivery to the correct site; that is, the respiratory region for systemic delivery and the olfactory region for the brain. However, because the nose is an elegantly-designed, highly-effective filter, just reaching the sinuses effectively by achieving a constant flow over the moving cilia is not easy. Irritation caused by both the actual molecule and the essential accompanying excipients is another major issue. Formulation experts also face the problem that a limited number of excipients are FDA approved for nasal drug delivery. Droplet size is key — too small and we risk lung deposition, too large and they could be swallowed; spray pattern and plume geometry are also crucial. Other formulation issues include finding better mucoadhesives, penetration enhancers and preservatives. 

Insulin is a drug often mentioned as a candidate for nasal delivery. Initial attempts floundered on the above mentioned problems of accurate site targeting and irritation. New formulations are being investigated, but the focus now appears to be pulmonary or even oral drug delivery. Vaccines are another area of research for nasal delivery and could remove the need for needles, but this requires further investigation. However, the huge investments in vaccines spurred by biodefence requirements could lead to an early answer. Sexual health is another favourite amongst nasal advocates. Vaccines are again seen as a possibility because antibody production in the nose is often matched by similar titers in other mucosal tissue such as the vagina. Equally the idea of a Viagra spray is often touted and may help to overcome the delayed onset of action associated with the oral dosage form. 

Despite playing devil's advocate and questioning the real potential for nasal delivery in the face of advances in other areas of delivery, I am genuinely excited by the prospects of nose-to-brain delivery. Research into neurodegenerative disease is throwing up a whole range of candidate molecules and there is growing expectancy among the public that this will soon lead to the availability of drugs for dementia and Alzheimers. Delivery will be a major challenge with fast onset of action for what are certain to be expensive medications initially expected. Nasal delivery could be a real option. One approach that seems to offer real potential is bidirectional delivery, which has shown the ability to deliver to the all important olfactory region. Users blow into a mouthpiece to release drug, which is then delivered via a sealing nozzle into the nose. Blowing into the mouthpiece causes an automatic physical reaction that closes the soft palate at the back of the mouth and thus prevents lung deposition. A breath actuation mechanism releases the drug into the airflow and is blown up one nasal cavity allowing a controlled and targeted deposition. One company sees applications for single and multidose delivery of a range of liquid and powder drugs, as well as vaccines. We are currently collaborating with them on a generic sedative, which will not only test the general efficacy of the method in reaching the olfactory region, but also whether drugs can be delivered directly to the brain.  

In summary, progress has been nowhere near as far in nasal delivery as the attendant publicity may lead you to believe. Nevertheless, it should not be dismissed. We could be on the verge of significant breakthroughs, and after all who would have thought transdermal and pulmonary delivery would be so successful only a few years ago?  

 is CTO at MedPharm Ltd, UK, and senior lecturer in pharmaceutics, King's College London, UK. 

Articles

The attraction of nasal administered therapeutic agents is obvious, including faster onset of action, increased compliance and avoiding degradation during first pass metabolism.