Pharmaceutical Manufacturing Handbook: Production and

FACTORS INFLUENCING NASAL DRUG ABSORPTION 597
excessive nasal secretion may wash away a nasally administered drug before it can
be absorbed [24] . Nasal drug absorption and distribution are also infl uenced by the
presence of nasal polyps and blockage. Several studies however have suggested that
the presence of nasal pathological conditions do not affect nasally administered
peptide drugs. For example, buserelin and desmopressin absorption studies have
shown similar nasal absorption profi les in normal subjects and in those suffering
from colds or rhinitis [25, 26] .
5.6.3.4 Dose Volume and Site of Deposition
A dose of 25 – 200 μ L per nostril is what can be maximally accommodated by the
human nose. A dose higher than this will be drained off and hence shows lower
absorption. Some studies have reported that a 100 - μ L volume resulted in a larger
deposition area. Hence, taking into account the volume of administration becomes
very important for manufacturers of nasal drug delivery systems. The site of deposition
of the nasal formulation may also affect the nasal absorption of drugs since the
anterior part of the nose provides greater contact between the nasal epithelium and
drug, but the mucociliary clearance mechanism of the posterior tends to remove
drug more rapidly [27] . It has been found that the permeability of the posterior area
is greater than that of the anterior portion, and hence, based on the formulation,
drugs may be administered in either the anterior or posterior parts of the nose. The
nasal adapter ’ s spray - cone angle defi nes the width of the nasal spray pattern and
thus plays an important role in determining the site of deposition in the nasal cavity.
Changes in the cone angle of the adapter from 60 ° to 35 ° or 30 ° can produce a larger
and more posterior deposition and therefore higher drug deposition in the ciliated
area [10] .
5.6.3.5 Physicochemical Properties of Drugs
The absorption of a drug across the nasal mucosa is a function of its physicochemical
properties, such as molecular weight, lipophilicity, and water solubility, as seen with
most of the mucosal routes of delivery. The majority of studies on the effects of drug
lipophilicity on nasal absorption are rather confl icting. The effect of lipophilicity on
the nasal absorption of barbituric acids has been investigated. It was found that drug
absorption through the nasal mucosa increases with an increase in the partition
coeffi cient. Interestingly, there was only a fourfold increase in absorption between
phenobarbital and barbital despite the fact that the partition coeffi cient of phenobarbital
was 40 - fold higher than that of barbital [28] . Similarly, increases in nasal
absorption have been seen for hydrocortisone, testosterone, and progesterone with
increases in the partition coeffi cient. However, a hyperbolic — rather than a linear —
relationship was observed between the in vivo nasal bioavailability of a series of
progesterone derivatives and their octanol – water partition coeffi cients [29] . In contrast
to this, Kimura et al. [30] showed that, for a series of quaternary ammonium
compounds structurally related to tetraethylammonium chloride, nasal absorption
was inversely related to the partition coeffi cient. All these studies suggest that a
drug ’ s lipophilicity may not be an appropriate indicator of the extent of its nasal
absorption. Besides the drug lipophilicity another important factor most studied for
its infl uence on nasal absorption is the aqueous solubility of a drug. This is because