Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 458

the respiratory ELF in a dose-dependent fashion. Alveolar macrophages, but not
blood monocytes, were found to be activated. Repeated lung function testing did not
reveal any abnormality after inhalation therapy. Natural IFN-

, in patients with lung
or pleural cancer (mesothelioma), seemed to be tolerated even better than IFN-

β

α and

1 0 6 IU),

possibly also better than IFN- γ when inhaled at varying doses (3 to 100

and no IFN- could be detected in the serum. Occasional side effects consisted of

a rise in body temperature and decline of FEV [186]. IFN-

β

is extremely well tol-
erated, and only after high-dose inhalation (5.4 mg) were detectable levels of IFN
found in the serum [187]. This study also showed that the oxygen radical production
of alveolar macrophages as measured by lucigenin-enhanced chemiluminescence to
opsonized particles was augmented by inhalation of IFN-

γ

. Except for the highest
dose (5.4 mg) inhaled, all IFN was cleared from the bronchoalveolar epithelium in
27 h. In 2001, Phase II studies were carried out by the National Institute of Allergy
and Infectious Diseases (NIAID) for evaluating IFN-

γ

for aerosol for the treatment
of mycobacterium avium-intracellulare complex (MAC) infection with the dos-
age regimen of 500

γ

-1b three times a week for 48 weeks by inhalation in
patients with MAC infection [188]. In 2007, Phase I studies were carried out by the
National Center for Research Resources (NCRR) for evaluating IFN-

μ g of IFN γ

for aerosol
for the treatment of pulmonary fibrosis with the dosage regimen of aerosol IFN

γ

γ -1b

100 g given via nebulizer three times weekly for 1 year in patients with mild-to-

moderate idiopathic pulmonary fibrosis [189].

μ

9.6.1.3 Deoxyribonuclease
Deoxyribonuclease (DNase) is an enzyme that breaks up extracellular DNA found in

the purulent sputum during respiratory infections. A single exposure of rodents and
monkeys with high doses of rhDNase indicated bioavailability of the doses inhaled
of

2%, respectively. Inhalation of aqueous solutions of certain composi-
tions may cause broncho-constriction and coughing [190,191]. Solutions for inhala-
tion should be preferably isotonic [192]. These considerations lead to the following
final formulation: isotonic aqueous solution, pH

15% and

0.7, 1 mg/ml rhDNase,
150 mM NaC1 and 1 mM CaCl 2 2.5 ml of this formulation (pulmozyme) is filled and
packaged in single-dose vials. Phase I clinical studies showed that rhDNase aerosols
were well tolerated during short-term treatments with escalating doses in normal and
cystic fibrosis subjects [193]. There was also an indication of efficacy in terms of
improvement in lung function in these studies. A dose-ranging study (Phase II, in the
USA) was carried out over 10 days [194] in outpatients, using a randomized, placebo-
controlled parallel design with varying dose levels of 0.6, 2.5, or 10 mg of rhDNase,
or placebo with the aid of a jet nebulizer and compressor. The study showed that the
highest improvement was found with the 2.5 and 10 mg doses. Fine powders of rhD-
Nase suitable for inhalation by aerosol solvent extraction system (ASES) found that
the fine particle mass of rhDNase powders generated using the gas-energizing nozzle
was 33%, and the biochemical integrity of the rhDNase powder is a function of the
antisolvent and the operating temperature [195]. DNase (dornase alpha) inhalation is
available under the brand name Pulmozyme.

6.3