Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 452

Also, excessive mucus secretion, for example, in the case of cystic fibrosis, limits the
uptake of aerosol particles by the bronchial epithelium. Inflammation also increases
clearance of the delivered formulations by the macrophages. Another important
parameter is the aerosol characteristics that determine the distribution of the inhaled
particles in the airways. The mass median aerodynamic diameter (MMAD) of the
aerosol particle states that a spherical aqueous particle has a density of 1 g/cc. In
warm and humid environment of the airways, inhaled aqueous droplets expand from
1 to 2

m size, delivered from
an aerosol device, impact and deposit in the oropharyngeal and upper airway tract
[158] . Particles in the size range 1 - 2

μ m in diameter to about 4.5 μ m. Particles above 3 μ

m deposit into distal and terminal airways due
to sedimentation. Because they are in random Brownian motion, small-size aerosol
particles, generally less than 1

μ

m size, diffuse into the alveolar spaces and do not
contribute to the therapeutically effective fraction. The flow velocity of the aerosol-
ized particles also has an impact on the deposition profile, with higher velocity lead-
ing to uptake in the tracheobronchial tract.

μ

9.5.8 Aerosolization of Pharmaceutical Particles
Noninvasive local as well as systemic drug delivery by inhalation aerosols should be

well tolerated by patients. For most peptide and protein drugs (e.g., deoxyribonucleases
for the treatment of cystic fibrosis and leuprolide for the treatment of endometriosis)
the route of administration is only by injection. Administration through aerosoliza-
tion by MDI or DPI offers the clinical benefit of self-administration to the patient.
Pulmonary drug delivery systems are divided into three principal categories: MDIs,
nebulizers, and DPIs (Fig. 9.3). Each device has its unique strengths and weaknesses.
pMDIs are small, portable devices and the most popular method among all
devices used for pulmonary drug delivery. Typically, a pMDI formulation contains an
active ingredient, generally in solution or suspension, along with inactive excipients
like solvent, surfactant, suspending agents, protective agents, and propellants. These
systems are tamperproof and deliver an accurate and reproducible dose of aerosol-
ized drugs to the lung but suffer from the limitation of problems associated with
chlorofluorocarbon (trichlorofluoromethane (CFC-11)-, dichlorodifluoromethane
(CFC-112)-, and dichlorotetrafluoromethane (CFC-114))-based propellants, low lung
deposition, and high oropharyngeal deposition resulting from high velocity delivery.
However, with the evolution of hydrofluroalkane (tetrafluoroethane (HFC-134a) and
heptafluoropropane (HFC-227))-based pMDIs and the development of new designs
at the drug and device level, the pMDIs have gone through a process of revival within
the last few years, with encouraging results.
Nebulizers use ultrasound or compressed gas to produce aerosol droplets in the

respirable size range from aqueous solutions of drugs containing cosolvents and phar-
maceutical aids to ensure physical and chemical stability of a drug. They are widely
used to deliver 2 -agonists, corticosteroids, antiallergics, anticholinergics, antibiotics,

mucolytics, and other therapeutic agents to the respiratory tract [159]. An important
use of nebulizers is for aerosol delivery of gene therapy formulations as it delivers a
relatively large volume (up to 10-fold) of drug solutions and suspensions as compared

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