Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 462

radioimmunoassay. In February 2000, Alkermes and Lilly signed a broad, mutually
exclusive agreement to develop an inhaled formulation of hGH based on Alkermes'
AIR pulmonary drug delivery system for diseases such as growth hormone deficiency,
hypopituitarism, which may be idiopathic and attributed to a prenatal insult, possibly
due to hypothalamic dysfunction. The Phase I clinical trial was designed to assess the
safety and tolerability, while evaluating the pharmacokinetic profile, of hGH powder
for inhalation. The trial was a randomized crossover comparison to subcutaneous hGH
study in 12 healthy volunteers. The results of the trial showed that concentration-time
profiles for pulmonary inhalation of hGH were similar to those following subcutane-
ous injection and concluded that delivery of up to 92 mg of the air formulation of hGH
was well tolerated with no clinically significant changes in vital signs and pulmonary
function observed in study participants. Phase 1 trials were completed by 2003 and
the details were patented [222,223] . A modified growth hormone - releasing factor
(GRF; TH9507), a 44-amino-acid peptide analogue of natural human GRF, is being
developed for the treatment of age-associated conditions resulting from diminished
growth hormone secretion. A study carried out in dogs to investigate the absorption
of TH9507 following intratracheal dry powder insufflation and subcutaneous injec-
tion at doses of approximately 375 and 38

g/kg, respectively [224], indicates that the
delivery of TH9507 by the inhalation route may provide a suitable alternative to sub-
cutaneous injection.

μ

9.6.2.4 Calcitonin
Very few attempts have been made to deliver calcitonin through the lung. Intratracheal

instillation of both human and salmon calcitonin (sCT), using catheters in rats, has
shown an absolute bioavailability of approximately 17% [225]. Pulmonary absorption
of sCT by intratracheal administration of sCT in the form of dry powder (using dif-
ferent absorption enhancers) and liquid (solution) preparations to rats suggested that
the pulmonary absorption of peptides and proteins is greatly improved by absorption
enhancer [226 - 228] . Kobayashi further studied the effects of protease inhibitors, like
chymostatin, bacitracin, potato carboxypeptidase inhibitor, and phosphoramidon (pro-
tease inhibitors), and absorption enhancers on the absorption of sCT after intratracheal
coadministration to rats, using the plasma calcium level as an index. A good corre-
lation between the in vitro activity of protease inhibitors and the in vivo - enhancing
effect on sCT activity suggested that membrane enzymes are responsible for the
inactivation of sCT and concluded that metabolic degradation and low permeability
of sCT may be possible barriers to the absorption of sCT. Morimoto [229] prepared
negatively and positively charged gelatin microspheres for pulmonary delivery of
sCT, characterized for particle size and examined for their stability in pH 7.0 PBS
and BALF. The release studies showed that sCT was rapidly released from positively
charged gelatin microspheres within 2 h (85% of cumulative release) and the release
profiles were not influenced by particle size. The pharmacokinetic study showed that
pharmacological availability after administration of sCT in positively charged gelatin
microspheres was significantly higher than that in negatively charged gelatin micro-
spheres and concluded that gelatin microspheres are novel candidates as delivery