Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 463

systems for the pulmonary system. In 2005, Yamamoto prepared elcatonin loaded sur-
face-modified DL -lactide/glycolide copolymer (PLGA) nanospheres with chitosan for
pulmonary delivery of peptide and aerosolized nanosphere suspension with a nebu-
lizer in guinea pigs and concluded that chitosan-modified PLGA nanospheres loaded
with elcatonin reduced blood calcium levels to 80% of the initial calcium concentra-
tion and prolonged the pharmacological action to 24 h, which was a significantly lon-
ger duration of action than that by chitosan-unmodified nanospheres [116].

9.6.2.5 Thyroid-Stimulating Hormone, Follicle-Stimulating Hormone,
Parathyroid Hormone, and Somatostatin

Human parathyroid hormone is an 84-aminoacid protein that is involved in control

of calcium and phosphorus homeostasis and control of bone growth and density.
Pulmonary delivery of parathyroid hormone (PTH) 1-84 and 1-34, thyroid-stimulating
hormone (TSH), follicle-stimulating hormone (FSH), and somatostatin have been
investigated [230,231] . Bioavailabilities following pulmonary administration by instil-
lation using silicone tubing or catheters were as follows: somatostatin 1%, TSH and

FSH delivered in solution of neutral pH were 2.5% and 2.3%, respectively. The bio-
availabilities of TSH and FSH in alkaline conditions were 2-30 times greater than those
in neutral pH conditions. On the other hand, the bioavailabilities of TSH and FSH,
when given intratracheally as dry powder, were 1.6% and 0.6%, respectively. Low
et al. fused a and b subunits of FSH to the Fc domain of IgG 1 either in a single chain
or a heterodimer format and studied the absorption through the epithelium in lung and
intestine by neonatal Fc receptor (FcRn)-mediated transcytosis [232] . Both FSH-Fc
fusion proteins were absorbed after oral dosing of newborn rats with long terminal
half-lives of 60 h, and pulmonary delivery in cynomolgus monkeys with long terminal
half-lives between 55 and 210 h. The study suggested that Fc fusion proteins offer the
potential for oral and pulmonary delivery of FSH.

9.6.2.6 Recombinant-Methionyl Human Granulocyte
Colony-Stimulating Factor

The pharmacokinetics of rhG-CSF has been extensively studied in preclinical and

clinical studies [233,234], which were carried out to elicit the pharmacokinetics fol-
lowing intravenous injection in hamsters and human volunteers. The original demon-
stration of efficacy via the inhaled route was conducted by Robert Platz and colleagues
at SRI in Palo Alto. Using hamsters in an Intox nose-only exposure unit, they were
able to demonstrate that aerosols (solid and liquid) of rhG-CSF are systemically active
and serum levels of the human protein are detectable after aerosol exposure [235].
However, no formal pharmacokinetic studies were performed. Subsequent work by
Niven and coworkers using hamsters has confirmed the observations of Platz and col-
leagues. Systemic delivery of r-huG-CSF readily induces an increase in circulating
levels of natural granulocyte colony-stimulating factor to approximately 3-5 times
greater than baseline. Niven et al. showed that r-huG-CSF induced systemic response
after delivery by aerosol in hamsters [236]. The absorption from the lung was rapid,