Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 459

9.6.1.4 Vasoactive Intestinal Peptide
VIP is deficient in idiopathic pulmonary arterial hypertension, which leads to an
increased right ventricular workload, cardiac failure, and death. VIP exerts a relaxing
action on tracheal smooth muscle, which is mediated through interaction with VIP
receptors. The deficiency of VIP in the airways has been implicated in the patho-
genesis of asthma. However, the therapeutic application of VIP is largely limited by
its rapid degradation; in addition, there are systemic adverse effects due to the wide
distribution of VIP receptors. Inhalation of VIP was suggested as a noninvasive route
of administration, and attempts were made to increase the stability of this peptide in
the airways by novel delivery systems and by synthesizing VIP analogues. The sta-
bilized VIP analogue synthesized and topical administration method has been devel-
oped for respiratory system organs such as the trachea, bronchus, and lung [196,197].
Unilamellar nanosized VIP-loaded liposomes (VLL) were developed to improve VIP
inhalation therapy by providing a dispersible peptide depot in the bronchi [198].

9.6.2 Systemic Delivery of Peptides and Proteins
Drug delivery to the systemic circulation through the respiration system is highly
challenging due to complex biophysical and biochemical factors of the aerosolized
particles and results in significant reduction in lower airway drug deposition. The
lung route appears to have a number of significant advantages for systemic delivery
of peptides and protein drugs such as rapid onset of drug absorption, comparatively
lower enzymatic activity of the peripheral lung, and avoidance of the hepatic first-
pass effect; other advantages include device-related factors such as aerosol devices,
which present attractive patient-related features, for example, noninvasive drug deliv-
ery, compact packaging, tamperproof packaging, and user-friendliness, especially for
patients in ambulatory care.

9.6.2.1 Insulin
Insulin has been employed in the therapy of diabetes mellitus for over 70 years by

invasive methods like the subcutaneous route. Intranasal delivery of insulin shows
low bioavailability ( 10%) relative to subcutaneous administration [199]. But the use

of bioadhesive formulations may lead to prolonged mucosal retention of insulin, by
providing the time necessary for improving the extent of nasal absorption [200]. Oral
inhalation provides access to a much larger absorptive surface area than nasal insuf-
flation. Different methods of drug delivery to the pulmonary system like direct intra-
tracheal instillation in rabbit and aerosolization of insulin in rabbit; and evaluation
methods like plasma glucose level study and pharmacoscintigraphy (a combination
of gamma scintigraphy and pharmacokinetic monitoring) were reported and showed
that insulin is efficiently absorbed from the lungs [201 - 203] . The effects of oligo-
merization and liposomal entrapment on pulmonary insulin absorption in rats, using
an intratracheal instillation method, indicated that both dimeric and hexameric insu-
lins are rapidly absorbed into the systemic circulation and intratracheal administration
of insulin liposomes led to facilitated pulmonary uptake of insulin and enhanced the