Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 442

mucosa, with a considerable amount of drug being cleared away by mucociliary
clearance [85] .
9.5.3.2.1.5 pH, p K a, and Partition Coefficient As per the pH partition theory,
unionized species are absorbed better compared to ionized species, and the same holds
true in the case of nasal absorption. Ohwaki et al. found that absorption of salicylic acid
was much higher with pH lower than 4.79, maximum at pH 3, and minimum at above
pH 7. Corbo et al. demonstrated a linear relationship between the lipophilicity and
absorption rate constant of progesterone, with absorption increasing linearly with an
increase in partition coefficient [86] . In another study by Shao et al. on rats with
acyclovir and its 2-ester prodrugs, nasal absorption was found to increase with the
lipophilicity of the drug [87] . All these observations demonstrated that the partition
coefficient is a major factor in determining the transnasal absorption of drugs.
9.5.3.2.1.6 Polymorphism In nasal drug product development, polymorphic
forms of drugs should be considered when the drug is to be administered in a par-
ticulate form. Polymorphism is known to affect the dissolution rate and solubility of
drugs and thus their absorption through biological membranes [88-90] . It is therefore
advisable to study the polymorphic stability and purity of drugs for nasal powders
and/or suspensions.
9.5.3.2.1.7 Chemical State and Charge The chemical form of a drug also affects
its transnasal absorption. For example, conversion of a drug into a salt or an ester
form alters its absorption. Huang et al. reported that in situ nasal absorption of car-
boxylic acid esters of L-tyrosine was significantly greater than that of unmodified
L-tyrosine [91] . Esterification of the drug results in more favorable partition coef-
ficients and so better drug transport through the nasal membrane. Also, because of
high esterase activity, these ester linkages are cleaved either in the nasal mucosa or in
the blood to deliver the parent drug, for example, L-dopa, acyclovir, and 5-iodo-2-
deoxyuridine [92,93] . Also, small, uncharged particles pass easily through the mucus
layer, whereas large or charged particles do not transverse easily. Mucin, the principal
protein in the mucus, binds with charged solutes, which in turn hinders diffusion.
9.5.3.2.2 Physicochemical Properties of Formulation
The following physicochemical properties of the formulation also affect the absorp-
tion of a drug across the nasal cavity.
9.5.3.2.2.1 pH of Formulation pH of the formulation is an important fac-
tor influencing transnasal absorption, as it determines the extent of drug ionization
and thereby its mucosal absorption. Nasal irritation is minimized when the products
delivered have a pH in the range of 4.5-6.5. This physiological pH of the nasal cavity
may neutralize the pH of the formulation by its buffering capacity, and affects micro-
environmental pH surrounding the drug molecules during the absorption process.
9.5.3.2.2.2 Osmolarity of Formulation/Tonicity Ohwaki et al. studied the effect
of formulation osmolarity on the nasal absorption of secretin in rats. They found that
the nasal absorption of secretin changed with changing concentrations of sodium