Pharmaceutical Manufacturing Handbook: Production and

598 NASAL DELIVERY OF PEPTIDE AND NONPEPTIDE DRUGS
the nasal mucosa is constantly kept moist by the nasal secretions and is well perfused
with blood vessels. In addition to limiting drug absorption, it also is a limiting factor
for the formulation of the drug. Further it is also important to understand the relation
between the saturation solubility of the drug and drug absorption. However,
the infl uence of drug solubility on absorption of drugs via the nasal route has not
been signifi cantly explored and needs much more attention. The relative effectiveness
of nasal atropine and hyoscine was compared by Tonndorf et al. [31] by measuring
each drug ’ s capacity to arrest salivary secretion; they found that 0.65 mg of
hyoscine, 40 times more soluble in water than atropine, is equivalent to 2 mg of
atropine. Some authors have suggested that the aqueous pores in the nasal mucosa
play a major role in absorption of hydrophilic drugs [32] . When nasal formulations
are administered as inhaled powders or suspensions, drug dissolution rate becomes
an important factor. Formulations deposited in the nostrils require proper dissolution
for better absorption. Nasal mucociliary clearance may remove the drug if it
remains undissolved in the nostrils. The size and shape of a drug molecule can affect
its nasal absorption. Molecules with an average molecular weight less than 1000 Da
are better absorbed nasally than higher molecular weight drugs whereas linear
molecules are less effectively absorbed than compact ones [33] . The nasal and oral
absorption of polyethylene glycol 600, 1000, and 2000 have been studied by Donovan
et al. [34] in relation to molecular weight; they found that the greater the molecular
weight, the less effective the absorption. This pattern of absorption was seen in the
case of both the nasal and oral routes. The effect of water - soluble compounds such
as 4 - oxo - 4 H - 1 - benzopyran - 2 - carboxylic acid, p - aminohippuric acid, sodium cromoglycate,
inulin, and dextran showing different molecular weights on the nasal absorption
was studied by Fisher et al. [35] . A 43 - fold decrease in the nasal absorption of
the these compounds was observed with a 368 - fold increase in the molecular weight
[9] . Similarly, studies with 13 di - iodo - l - tyrosine - labeled dextran showed an inverse
relationship between the percentage absorbed after nasal administration and the
weight of the molecule; in fact, a 36 - fold increase in molecular weight produced an
88 - fold reduction in nasal absorption [36] . The effect of molecular weight on the
nasal absorption of fl uorescein isothiocyanate and diethylaminoethyl dextrans has
been studied by Maitani et al. [37] . It was found that an inverse relationship between
absorption and molecular weight existed for these compounds. However, since the
nasal absorption of these compounds was low, enhancers were used; hence it is diffi
cult to rule out the infl uence of the enhancers used on the extent of absorption
obtained. The absorption of a drug after nasal administration is also infl uenced by
the pH of a drug formulation as well as that of the nasal cavity — along with the p Ka
of the drug substance. Biological membranes form a major barrier to the transport
of drugs into the bloodstream. There are a number of transport mechanisms by
which drugs are transported across the biological membranes. These include transcellular,
paracellular, and carrier - mediated transport mechanisms. The most important
factors that infl uence the above - mentioned mechanisms are the pH, p Ka , and
partition coeffi cient of the drug. The pH of a nasal formulation should be in the
range of 4.5 – 6.5 in order to minimize nasal irritation. However, the drug ’ s p Ka must
also be taken into account so as to maximize the drug ’ s concentration in un - ionized
form. The effect of pH on the nasal absorption of benzoic acid was studied by
Hussain et al. [28] , who showed that the absorption of benzoic acid is pH
dependent.