Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 443

chloride in the formulation. With 0.462 M concentration, the absorption reached a
maximum, with concomitant shrinkage of nasal mucosal cells.
9.5.3.2.2.3 Buffer Capacity Nasal formulations are generally administered in
small volumes ranging from 25 to 200 l. Because nasal secretions may alter the pH
of the administrated dose, an adequate formulation buffer capacity may be required
to maintain the pH of formulation in situ .
9.5.3.2.2.4 Viscosity Pennington et al . and Harris et al. examined whether an
increase in solution viscosity would increase retention of the nasal formulation in the
nasal cavity, thereby enhancing its therapeutic effect by virtue of enhancing rate and
extent of drug absorption [94,95] . Suzuki et al. showed that a drug carrier such as
hydroxypropyl cellulose was effective for improving the absorption of low-molecu-
lar-weight drugs but did not produce the same effect for high-molecular-weight pep-
tides [96] .
9.5.3.2.2.5 Drug Concentration, Dose, and Administered Volume Drug con-
centration, dose, and volume of administration are three interrelated parameters that
impact the performance of the nasal delivery system. Nasal absorption of 1-tyrosyl-
L-tyrosine was shown to increase with drug concentration in nasal perfusion exper-
iments [91,97] . The effect of drug dose on nasal absorption has been reported by
numerous studies based on molecules like calcitonin [98] , GnRH agonist [99] , des-
mopressin [100,101] , and secretin [102-104] . All studies conclude that by increasing
the drug dose, greater transnasal absorption was achieved. The optimal formulation
volume for nasal administration is 25-200 l per nostril. More than this volume can
lead to anterior leakage or postnasal dripping of the formulation.
9.5.3.2.2.6 Excipients Used Stability of the formulation largely depends on the com-
position of the product and devices used to deliver the product. For this reason, variations
in critical parameters of the actuator, valves, and product excipients require careful con-
sideration with respect to compatibility, stability, and shelf life of the product.
(i) Solubilizers: The aqueous solubility of a drug is always a limitation for nasal
drug delivery. Conventional solvents or cosolvents such as glycols, small quantities
of alcohol, transcutol (diethylene glycol monoethyl ether), medium chain glycerides,
and labrasol (saturated polyglycolyzed C8-C10 glyceride) are used to enhance the
solubility of drugs. Other options include the use of surfactants [105] or cyclodextrins
such as hydroxypropyl--cyclodextrin [106] that serve as biocompatible solubilizers
[107,108] .
(ii) Preservatives: Most nasal formulations are aqueous-based and therefore
require preservatives to protect them from microbial contamination. Parabens, ben-
zalkonium chloride, phenyl ethyl alcohol, EDTA, and benzyl alcohol are some of the
commonly used preservatives in nasal formulations. Proteins are generally not stabi-
lized well in the presence of preservatives.
(iii) Antioxidants: A small quantity of antioxidants may be required to prevent
drug degradation by oxidation. Commonly used antioxidants are sodium metabisulfite,
sodium bisulfite, butylated hydroxyl toluene, and tocopherol. Generally, antioxidants do
not affect drug absorption or cause nasal irritation. But chemical or physical interaction