Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

1. Nasal drug delivery
1.4 Nose to brain-transport
The blood-brain barrier provides an efficient diffusion barrier especially for polar drugs. Hence,
limitations are evident in the treatment of diseases of the central nerve system, such as
Parkinson’s and Alzheimer’s disease. It has been suggested that after intranasal administration,
some drugs reach the targeted brain structures, circumventing the blood-brain barrier. Lipophilic
compounds may be transported by neuronal transport of nervus olfactorius. Extend of neuronal
transport is highly dependent on the physicochemical properties of the drugs, namely the molecular
weight and the lipophilicity [Illum 2004]. The existence of the olfactory-pathway has been proven for
some compounds in animal models, but not in human [Illum 2000].
Since central nervous bioavailability of drugs, transported by the olfactory-pathway is estimated to
be 0.01% to 0.1%, only very potent drugs may reach therapeutic levels at the central nervous side
of action by nose to brain-transport.
Pre-estimating the contribution of the olfactory pathway in drug transport to the brain, the
differences between the species in respect to localization and extend of the olfactory epithelium
has to be considered. Furthermore, Graff and Pollak suggested efflux transporters to impair drug
concentration in the brain after transmucosal nasal administration [Graff and Pollack 2003].
In human the olfactory epithelium is situated in the superior conchae and therefore hardly
moistened by common nasal sprays. To ensure the delivery of a drug to the olfactory epithelium
some authors propose specially developed delivery devices or application techniques [Dhanda et
al., 2005].
Assuming the existence of an olfactory-pathway to the brain in human, it remains unclear to what
extent it contributes to central nervous availability of a nasally administered drug.
Katja Suter-Zimmermann Page 15 of 188 University of Basel, 2008