Don’t turn your nose up at nasal delivery!

A survey carried out in 2003 by the Institute for Biomedical and Pharmaceutical Research in Nuremberg found that over 90% of Euro banknotes showed traces of cocaine. In 2009, the University of Massachusetts reported similar findings for US banknotes. In both cases, the use of rolled-up banknotes to ‘snort’ lines of cocaine was given as the root cause for this contamination, though both studies acknowledged that transfer between notes in cash dispensing or note counting machines had exaggerated the extent of this ‘recreational’ use of currency.

Although this variant of nasal delivery does not appear in any of the established pharmacopeia, these studies are a reminder that the nose is recognised as a very convenient portal of administration for medications, whether or not formally prescribed. The indigenous peoples of North and South America were using nasal delivery for tobacco snuff and a variety of psychotropic herbal concoctions centuries ago. Indian and Persian records show that physicians and apothecaries were making widespread use of the nose to treat a range of conditions back in medieval times.

In Europe and the USA, nasal delivery experienced a surge in interest from the 1980s onwards; as a result, over the past three decades some excellent research, together with very innovative development in formulations and devices, has revealed significant opportunities in nasal delivery thereby generating substantial market growth by the turn of the century. Depending on which survey you read, the global nasal drug delivery market is now estimated at around $8.5 Bn. Market growth for nasal products was running at around 20% annually at the turn of the century, though it is presently closer to 6%. Nasal delivery still has great promise, but we should also remain aware that nasal delivery is not without its challenges.

Why, what, where and how?

Back in the early 1990s, I remember a senior figure from a major pharmaco roundly dismissing nasal delivery as “something for a runny nose and little else”. Given that Team were developing a successful nasal device for a hormone-based systemic therapy at the time, and had previously worked on a number of other innovative nasally-delivered therapies, I was somewhat indignant. However, for anyone operating outside those fields in which the nose presented a promising delivery route, the view expressed was perhaps understandable. Today there is a greater awareness of device-based drug delivery in general, and specifically of nasal delivery. So where are the focal points where nasal delivery has something to offer and why might it be any better than alternative, perhaps better understood routes of administration?

– Let’s start with why

The nose presents a large area of highly vascularised, accessible mucosa. Delivery is non-invasive and avoids first-pass hepatic metabolism, with excellent bioavailability and rapid onset of action in many cases. Recognition of these attributes was a major factor in the rapid growth of nasally delivered drugs, especially in systemic applications, in the 1980s and 90s.

– So what conditions and therapies are suited to the nasal route?

Runny noses are still a nuisance and to no great surprise, OTC decongestants and prescription allergy therapies still account for between 70 – 80% of the nasal market by value. Predominantly, this segment is about large volumes of low-priced products. The remainder of the market is comprised almost entirely of a range of prescription systemic therapies, with lower sales volumes but significantly higher priced products. Drugs and conditions treated include the following:

  • Vaccines: The nasal mucosal lining provides an excellent site for vaccination. ‘FluMist®/Fluenz’ for influenza is licensed in the EU and USA and vaccines for a number of other diseases are under development, including influenza H1N1, Norovirus, and West Nile virus.
  • Hormones: There is significant interest in nasal delivery of a range of hormones including parathyroid hormone (PTH), for treatment of osteoporosis, and human growth hormone (HGH). Results comparable to injected delivery are claimed for intranasal HGH.
  • CNS: Sumatriptan, for migraine relief, was first introduced as a nasal spray by Glaxo in 1997, providing a rapid acting, needle-free alternative to injection. AstraZeneca introduced a nasal spray version of their Zolmitriptan migraine treatment in 2002.
  • Breakthrough cancer pain: PecFent® was launched by Archimedes Pharma in 2010 as a nasally delivered spray of Fentanyl, a powerful opioid analgesic, formulated to gel in contact with the nasal mucosa, from where it is rapidly absorbed to provide relief.
  • Rescue medication: Nasally delivered Midazolam for treating epileptic seizures is simple, quick, involves no needles and has a very rapid onset. Results are encouraging and approval in the EU is expected shortly. Alternative delivery routes (IV or IM injection or rectal) involve needles, may be awkward to use, and have delayed onset.
  • Heroin overdose: Another area for rescue treatment is that of heroin overdose. Naloxone, an opioid antagonist that reverses the effects of opioid overdose, has proved highly effective in a nasally delivered format, with similar advantages to those found in seizure rescue treatment.

As a generalisation, lipophilic drugs are more readily suited to nasal absorption than hydrophilic drugs, though formulations have been developed to compensate for poor absorption of the latter. Also, in terms of molecular weight, 1kDa is generally regarded as a practical cut-off, but once again, innovative formulations and enhancers have been developed to allow for delivery of larger molecules such as PTH, for instance, with a molecular weight of 4.18 kDa.

– As to where?

Sure, we stick the medicine up the nose – is that it? Well no, not really. The nose is a complex organ. The anterior portion (the visible part) is largely lined with non-ciliated, squamous epithelium and is not the preferred site for drug delivery. For most systemic applications, the turbinates or concha, scroll-like features along the sides of the nasal passageways and covered with ciliated mucosal tissue, are where absorption mainly takes place. The olfactory region, in the ‘roof’ of the nasal cavity, is of key interest for CNS delivery; nerve fibres from the olfactory bulb (within the frontal brain) extend through a thin, perforated portion of the skull (the cribriform plate) to present a high density of olfactory receptor cells within the nasal cavity. These form a connection from nose to brain, bypassing the blood-brain barrier.

– Finally, how

User technique and device design for maximum usability are one aspect of this topic, while getting the formulation right is the other. It is always best to consider formulation and device design at the same time, early on in the development of any combination product, but this is especially so in the case of nasal delivery. The range of devices and formulations available is extensive, so here are just a few top-level observations, principally relating to nasal sprays (the most common format compared to drops or gels):

User technique and device design are not readily separated:

Ideally, spray performance should be operator independent – operating mechanisms which ‘trigger and deliver’ at a set force threshold are beneficial. Location within the nostril is clearly important – designs which encourage correct engagement in the nostril and maintain device position during actuation aid consistency. Innovative device technologies such as the Aerogen nasal mesh nebuliser, OptiNose Bi-directional nasal delivery system or Impel Neuropharma Precision Olfactory Delivery (POD) claim improved targeting of key areas in the nasal cavity. A good device technology can make a big difference. However we shouldn’t forget that reading a well-prepared instruction for use (IFU) – and following it – can genuinely improve outcomes. Bad habits are readily learnt with OTC products as many of us simply throw the IFU away. Simple ideas can be effective; the ‘contralateral’ technique (left hand, right nostril and vice-versa) directs spray away from the septum and towards the turbinates.

A liquid dose above 100μl per nostril will generally result in wastage (down the throat, or onto the upper lip). Even at or below 100μl, the nasal cilia clear mucus rapidly and continuously so a slowly absorbed drug may be cleared (ending up in the stomach) before absorption, resulting in poor efficacy. Formulations which enhance absorption, or which encourage adhesion to the mucosa to allow controlled absorption (such as PecFent®, see above) have proved effective. Powder formulations, rather than liquids, are another response to the ‘100μl’ challenge, although mucociliary clearance still has to be dealt with. Preservative-free formulations have become increasingly common and are better for the patient in many ways, but multi-dose products do require device design changes in order to avoid contamination of device contents, given that these devices are regularly inserted into the nose.

The device is the drug-to-patient interface, so it must be reliable and effective, but easy to use correctly. To be therapeutically effective, the formulation must enable the active ingredient to be taken up by the target tissue. Get all this right and you can get excellent results – a piecemeal approach may be less than satisfactory.

Nothing’s ever straightforward though…

And so it is with nasal drug delivery. Some problems have been encountered including:
Damage to the nasal septum, especially with frequent use of OTC decongestants. Without doubt, damage – ranging from crusting and soreness up to (very rare) instances of perforation – can arise. However IFUs generally stipulate that these products should not be used for longer than three to five days, whereas most instances of septum damage occur after extended periods of use. Quite apart from issues of septum injury, ‘rebound congestion’ – where the decongestant becomes ineffective with excessive use – means that ignoring IFU is pointless as well as potentially harmful.

An increased risk of cancer has been associated with the long-term use of nasal calcitonin in the treatment of osteoporosis. As a result, calcitonin nasal sprays were withdrawn from the European market in August 2012, in the US from March 2013 and Canada from October 2013. That said, it is worth adding that injected calcitonin also now carries warnings regarding long term use and increased cancer risk.

In October 2000, a newly licensed nasal inactivated influenza vaccine was used in Switzerland, but 46 instances of Bell’s Palsy were reported amongst those treated. Subsequent investigations indicated that this could have been associated with the specific adjuvant used yet the vaccine was withdrawn. Despite this, nasal vaccination continues to be widely accepted by regulatory authorities.

Just like any other drug or combination product, complications and issues may arise. So whilst every effort is made to identify problems prior to release, occasionally there are adverse reactions, sometimes leading to product withdrawal.

What next?

Nasal delivery is not a universal panacea, but then neither is any other route of administration. Nasal delivery can do some things very well, however, and has some advantages including elimination of sharps, relative ease of use, and patient acceptability. Nasal delivery has already been used to re-purpose several existing drugs and we can probably expect more ‘life cycle management’ applications of nasal delivery going forward. But if we look further toward the horizon, what then?

Delivery of biologic drugs to treat CNS conditions such as Parkinson’s, Alzheimer’s and stroke has been a mission for many years. Both OptiNose and Impel claim improved access to the olfactory region and in April 2013, Impel Neuropharma published results showing that their POD device was able to deposit a radiolabelled tripeptide into the deep nasal cavity with subsequent rapid and significant delivery to the CNS.

There is also interest in the possibility of delivering cell-based therapies to cure neurodegenerative disorders, such as Parkinson’s disease. A very interesting study, led by the University Hospital of Tübingen in 2011, indicated that Meschenchymal stem cells, delivered to the brains of rats via the nasal olfactory region, resulted in substantial restoration of neurodegenerative damage and of motor function.

These are just a couple of examples and it is too early to suggest that a nasal spray can reverse the effects of a stroke or a similar human condition in the near term. But the progress made in the last 30 years deserves recognition. And in areas such as pain relief, emergency therapies, hormone delivery and vaccination, nasal delivery still has much to offer – providing we maintain a common focus upon the drug, the formulation, the delivery device and the patient.


Statistics for nasal delivery tend to get bundled with those for inhaled delivery, despite the fact that in general, the only common factor is association with the respiratory tract. As a result, it is difficult to extract specific figures for the nasal drug market. Team would therefore like to thank Dr René Bommer for his permission to use nasal drug market data researched and published by pharmAccel Consulting and also for his helpful advice and useful observations regarding the nasal drug delivery landscape.

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