Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 440

and peptidase inhibitors like bacitracin, amastatin, boroleucin, and puromycin [63]
have been reported to improve nasal absorption of LH-RH peptides, leucin-enkephalin,
and hGHs.
9.5.3.1.3 Transporters and Efflux Systems
In the human nasal respiratory and olfactory mucosa, researchers have identified multi-
drug resistance transporters that influence the transport of a wide variety of hydropho-
bic and amphiphilic drugs across the nasal mucosa [64] . Pgp, an ATP dependent efflux
transporter, exists in the submucosal vessels of the human olfactory region and in the
apical area of ciliated epithelial cells [65] . Various studies revealed that Pgp plays an
important role in preventing active influx of drugs from the nasal mucosa [65-68] .
9.5.3.1.4 Physiological Factors
9.5.3.1.4.1 Site of Deposition Deposit of the formulation in the anterior por-
tion of the nose provides a longer nasal residence time than in the posterior portion.
The anterior portion of the nose is an area of low permeability, whereas the posterior
portion of the nose is an area of high permeability. As discussed earlier, the particle
size of a liquid or solid formulation is an important factor affecting absorption in the
administration of droplets or powder to the site of deposition [69,70] . Depending on
the size, particles may deposit in the nasal cavity or in the respiratory tract or may be
cleared from the nasal cavity.
9.5.3.1.4.2 Nasal Blood Supply and Neuronal Regulation The nasal cavity is
highly vascularized as it is important for the heating and humidification of inspired
air and nasal resistance. Nasal cycles of congestion (increased blood supply) on para-
sympathetic stimulation, and relaxation (decreased blood supply) on sympathetic
stimulation, regulate the amount of drug absorbed.
9.5.3.1.4.3 Nasal Secretions Various mucosal and submucosal glands
secrete nasal mucus that forms a continuous layer of 5 m on the nasal mucosa.
Approximately 1.5-2 L of mucus is produced daily. Both the composition and the
viscosity of nasal secretions affect intranasal drug absorption. A drug needs to be
solubilized before it permeates. The use of water-soluble analogues of investigational
drugs via the nasal route has shown to increase drug absorption.
9.5.3.1.4.4 Nasal Cycle Various studies revealed that circardian rhythms affect
both the frequency of the nasal cycle and the secretion and clearance rates of nasal
mucus. The frequency of the nasal cycle and production and clearance rates of the
nasal secretions is reported to be high in the daytime compared with that in the early
morning and at night.
9.5.3.1.4.5 pH of Nasal Secretions The pH of nasal secretions varies between 5.5
and 6.5 in adults and 5.0 and 6.7 in infants [71-74] . A drug will be absorbed better
when the nasal mucus pH is lower than the drug's p K a as the drug will be present pre-
dominantly in a unionized form. Thus, a change in the pH of nasal secretions affects
the drug ionization, altering the amount of drug absorbed.