Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 433

tissue and intravenous-like pharmacokinetics when these compounds are delivered to
the peripheral lungs [14] . Because drugs absorbed into pulmonary circulation enter
directly into the systemic circulation via pulmonary vein, left ventricle, and cardiac
output, this avoids first-pass metabolism of the administered drugs [15,16] . These
reasons make inhalation a promising noninvasive route for the systemic delivery of
drugs that are otherwise not well absorbed via conventional routes of administra-
tion, for example, peptides and proteins. The complex geometry of the respiratory
pathway, the biophysically unfriendly pathway for inhaled particles, and the natu-
ral filtration mechanism are some critical factors that have an impact on deposition,
absorption, and bioavailability of pulmonary-delivered peptide and protein drugs.
9.3.6.1 Absorption of Peptides and Proteins
Because of thinner alveolar walls (i.e., about 0.1-1 m) compared to capillary walls
(approximately 7 m) [17] and the large absorptive surface of alveolar walls, a prop-
erly inhaled drug dose covers the entire lung surface in a few seconds and is absorbed
rapidly [18] .
9.3.6.1.1 Factors Affecting Pulmonary Absorption
Pulmonary absorption of peptide drugs usually correlates well with partition coef-
ficient and molecular weight. The tight junction pores in the lung have a larger
diameter than the molecular size of most peptide and protein drugs [19,20] . Other
physicochemical factors, for example, formulation pH, ionic strength, drug solubil-
ity, concentration, charge, and device system, have a significant impact on the extent
of peptide absorption from the lung. A number of proteases, such as elastase and
collagenase [21] , chymotrypsin, prolyl endopeptidase, aminopeptidase P, some spe-
cies of carboxypeptidase, angiotensin-converting enzyme, neutral endopeptidase
(enkephatinase), and cathepsin, have been reported in bronchoalveolar lavage fluids
(BALF). These findings suggest that lung uptake of therapeutic peptides and pro-
teins is affected to varying degrees depending upon the impact and exposure of the
aerosolized drug to these ubiquitous enzymatic systems. The approach of incorporat-
ing enzyme inhibitors is limited by considerations concerning long-term safety of the
product and morphological damage to lung tissue.
9.3.6.1.2 Factors Affecting Pulmonary Deposition
Drug absorption from pulmonary epithelia occurs only after inhaled drug deposits in
the lung and undeposited aerosolized particles clear out of the lung in expired air.
Depending upon the type of inhalation technology, only about 20-50% of the pulmo-
nary-delivered dose is deposited in the peripheral lung. The particle size of inhaled
substances will affect the absorption of the inhaled drug to systemic circulation.
Particles 8 m in aerodynamic diameter deposit in the central and conducting air-
ways by inertial impaction, whereas fine particles, those 3 m in diameter, deposit
primarily in the respiratory regions of the peripheral lung by diffusion. Particles
between 3 and 8 m in diameter largely deposit in the transitional zones of the lung