Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 453

to MDI or DPI [160,161]. Another advantage is that there is minimal GI absorption
because a majority of the aerosol deposits in the lungs, as opposed to the deposi-
tion with MDIs and DPIs. Nebulizers may be inhaled during normal tidal breathing
through a mouthpiece or facemask, and hence they are used to deliver aerosolized
drugs to patients such as children, the elderly, and patients with arthritis, who have
difficulties using other devices. The nebulizer requires proper setting of the flow rate
of compressed air and an appropriate volume of solution in order to optimize drug
delivery. The quantity of the drug reaching the lung is a characteristic of the type
of nebulizer used. Drug delivery dose by nebulizers used to be time-consuming and
relatively expensive, and they were bulky and nonportable. These various limitations
of jet nebulizers have been resolved with new technological advances and improved
designs. In the new devices, vibrating mesh or an aperture plate (VM/AP) for the gen-
eration of therapeutic aerosols is employed, and these were found to produce aerosols
with increased efficiency, fine particle fractions, low residuals, and the ability to neb-
ulize even microliter volumes. Current VM/AP devices in clinical use are the Omron
MicroAir, the Nektar Aeroneb, and the Parie Flow. Some devices are approved for
use only with specific medications [162]. Another device is the Respimat Soft Mist
Inhaler, a multidose, handheld, liquid inhaler that generates a higher fraction of fine
particles [163] .
DPIs are breath-actuated propellant-free devices used for delivering a dry powder
formulation of an active drug locally or systemically via the pulmonary route. DPIs
have been alternatives developed to overcome the limitations of pMDIs and nebuliz-
ers and to facilitate the delivery of macromolecules, protein, peptides, and products
of biotechnology. DPIs are usually formulated as one-phase, solid-particle blends of
therapeutic agent, formulated with lactose as the carrier [164]. Dry powders are at
a lower energy state reducing the rate of chemical degradation and the likelihood
of reaction with contact surfaces. DPIs are very compact in nature, breath actuated,
patient-friendly, easy to use, stable, and efficient systems that do not require spacers
[165]; they have a high capacity for carrying a drug dose, high lung deposition (from
50% to 70%), and minimal extrapulmonary loss of drug, due to low oropharyngeal
deposition, low device retention, and low exhaled loss. DPIs are subject to strict
pharmaceutical and manufacturing standards by regulatory bodies, especially with
delivered dose uniformity, the most challenging demonstration of device reliability
[166]. One major drawback with DPIs is coordination between patient inhalation and
actuation. Patients with chronic airway disease and impaired pulmonary function find
DPIs hard to operate. Production of dry powder from liquid droplets by spray drying
involves hot air resulting in particles suitable for inhalation [167]. However, powders
of therapeutic proteins prepared by spray drying are often found unstable when dried
alone. During spray drying, owing to the relatively large surface area of the atomized
droplets and the high drying temperatures and mechanical stress, the integrity of the
protein may be adversely affected. Protein degradation is minimized by cospray dry-
ing the protein with excipients, as has been reported for recombinant human deoxy-
ribose nuclease (rhDNase) for inhalation [168,169] . Optimal formulation for powder
aerosol performance and protein stability requires individual characterization of each
protein and excipient system.