Medical and Pharmaceutical Aerosols - Aerosols: Measurement, Dosimetry, and Health Effects - page 5

1.2.1.6 Biotechnological Agents, Genes, and DNA Aerosols
The most sustained effort in the area of delivery of biotechnological agents has been for the treat-
ment of cystic ibrosis. In the early 1990s, rDNase aerosols (Genetech, South San Francisco, CA)
were delivered to cleave leukocyte DNA, which was contributing to the viscosity of mucus in cystic
ibrotic lungs. Delivery of this aerosol allowed the patient to expectorate readily and clear their lungs
of mucin blockages. In combination with tobramycin to treat the bacterial infection, this appears to
have been a successful approach. However, it has long been the objective of those involved in gene
therapy to challenge their technology by expressing the gene for cystic ibrosis transport receptor
(CFTR) in the epithelium of airways cells, thereby correcting the underlying chloride ion imbal-
ance, which gives rise to thickened mucus and poor mucociliary clearance. As yet this approach has
met with limited success, but it remains the goal of a number of researchers. 26-29 Oligonucleotides
have also been used to target the adenosine A(1) receptor, a G-protein-coupled receptor (GPCR) that
plays an important role in the etiology of asthma. 30 Targeting of the Akt pathway for the suppres-
sion of lung tumorigenesis has been achieved using shRNA. 31,32 Pulmonary delivery of the siRNA
ALN-RSV01 may prove an effective antiviral treatment for respiratory syncytial virus (RSV). 33,34

1.2.2 s ysteMically a cting a gents
The lungs have been considered a route of administration for systemically acting agents for decades.
The irst systemically acting agent delivered as an aerosol product in the twentieth century was
ergotamine tartrate for the treatment of migraine headaches. 35
More recently, the focus has been on proteins and peptides. Among these, the notable candidates
to date have been insulin, 9 for the treatment of diabetes, and leuprolide acetate, a luteinizing hor-
mone releasing hormone analog 10 for the treatment of prostate cancer.
Other agents have been evaluated, including calcitonin, human growth hormone, 36 parathyroid
hormone, 37 interferons, erythropoietin, 38 and granulocyte-monocyte colony-stimulating factor
(GM-CSF), 39 but these have progressed more slowly than the candidates mentioned in the previous
paragraph. Alexza Pharmaceuticals has shown success with their Staccato ® aerosol delivery device
on a wide array of drugs. Loxapine for schizophrenia and bipolar disorders is currently awaiting
FDA approval after successful clinical trials. 40,41 Alexza also has alprazolam and prochlorperazine
in phase II clinical trials.
Recent reviews of these systemic treatments and more were written by Siekmeier and Scheuch. 42,43
There are several challenges that systemic aerosols must overcome to be suitable treatment options,
including the avoidance of the mucus layer and the prevention of protease and peptidase degrada-
tion. Typically, the larger the molecular weight of a therapeutic agent, the more dificult these barri-
ers tend to be. Yet, the beneits, such as high blood perfusion and the lack of irst-pass metabolism,
make pulmonary delivery a highly desirable delivery route. 42
Inhaled vaccines have also been explored recently. Reports indicate that the administration of
a vaccine topically to the airways has several beneits: enhanced mucosal immunity, induction of
systemic immunity and immunity at distant mucosal sites, noninvasive administration, reduction in
risk of infection spread through needle use/misuse, improved stability, and the potential of elimina-
tion of the cold-chain requirements. As such, several diseases have been the focus of inhaled vac-
cines including measles, 44,45 tuberculosis, 46 HIV, 47-49 inluenza, 50-52 and several others.

1.3 CLASSIFICATION

1.3.1 M etered d ose i nHalers
Many devices used to deliver drugs to the respiratory tract do so by producing a metered dose of
aerosolized drug that is inhaled by the patient. However, MDIs are speciically recognized as those
devices that contain a pressurized formulation that is aerosolized through an atomization nozzle.