Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 449

Oral dosage forms have more advantages over injectables, such as simple manu-
facturing processes and ease of control; as well, there are patient benefits, including
low cost, convenience of use, dose flexibility, and user compliance. However, where
the drug is not absorbed effectively by the oral route and when the onset of action
is required immediately, injectables often fulfill a significant medical need. Chronic
therapy with injection has disadvantages like rapid elimination and possible side
effects; and if they necessitate frequent administrations with a particular drug regi-
men required to most efficiently treat a given disease, they can create a barrier to
patient compliance. Although injection has served as the prime means of delivering
macromolecules, many noninvasive routes have been explored as alternatives. Topical
delivery of macromolecules through the skin offers an even less permeable boundary
than the GI tract. Consequently, using a patch, passive transdermal delivery of pro-
teins and peptides has not succeeded. For peptide and protein drugs, stability in the
GI tract, avoidance of first-pass metabolism, and the need for pulsatile delivery make
it crucial to explore novel noninvasive routes for drug delivery to the lungs. The fea-
sibility of protein delivery to the lungs to achieve local or systemic effects has been
well documented [126]. Pharmaceutical aerosols have been targeted to the lungs for
the treatment of asthma and various pulmonary infectious diseases successfully. In
recent years, attention has been given to the potential of the pulmonary route as an
alternative noninvasive means for systemic delivery of macromolecules, especially of
the therapeutic peptides and proteins [16,127,128] . Advanced pulmonary technology
provides a unique and innovative delivery of large and small molecule drugs through
inhalation into lung, an alternative to the therapies that are currently been adminis-
tered by injection or oral delivery and precipitating severe adverse effects. Pulmonary
delivery also offers the potential for better and possibly more economical treatment
or prophylaxis of respiratory and systemic diseases (e.g., viral vaccines) compared to
injections, providing an additional incentive for improved patient compliance.
The respiratory tract daily inhales 20,000l of air for gaseous exchange, which
contains a relatively large load of biological and nonbiological particulates.
Approximately 30 mg/day of inert nuisance dust is inhaled into the lung without cre-
ating any adverse effect due to the lung defense mechanisms, which make the lung
a natural portal of entry for peptides, proteins, and other small molecules that are
used to provide systemic therapy. Poorly absorbed drugs show rapid absorption kine-
tics when delivered through oral inhalation aerosols [129,130]. In a study on beagle
dogs, Adjei established that pharmaceutical aerosols, for example, leuprolide acetate,
prevent significant degradation of compounds by first-pass metabolism [131]. Also,
Ashurst concluded that the aerosol route of administration targets drugs directly to
the lungs, through the pulmonary airways, and offers the advantages of bypassing
the first-pass elimination, reducing the dosage frequency, and minimizing the extent
of adverse drug reactions. This in turn improves the therapeutic effect-toxicity
ratio. It has been found that the efficacy of drug delivery is improved by targeting
the aerosolized medication to certain areas of the lungs. The major advantages of
aerosol delivery over other routes of administration are instant access and the high
ratio of the drug deposited within the lungs noninvasively [132]. Thus, pharmaceu-
tical inhalation aerosols have become realistic alternatives for administering drugs