The lung is an excellent target for the delivery of drugs that treat local and systemic disorders because of its large surface
area, good vascularization, thin alveolar epithelium, and capacity for solute exchange. The surface area of the lung is between
80 and 140 m2 . In peripheral pulmonary regions, the thickness of the alveolar epithelium is only 0.1–0.2 Ám (1). In the deep lung (peripheral
or alveolar region), the distance between the epithelial surface and the blood is 0.5–1.0 Ám, which is much less than in the
bronchial regions, where the distance between the mucus surface and blood is 30–40 Ám (2). Thus, pharmaceuticals deposited
in the peripheral region of the lung can be absorbed rapidly and are not subject to hepatic first-pass metabolic effects after
The ability to consistently manufacture inhalation powders with customized particle size and aerodynamic properties is crucial
to the advancement of effective medications that treat local pulmonary diseases, and to the delivery of systemic medications
through the lung. To target deposition in various regions of the respiratory tract, including the deep lung, inhalation powders
must have the appropriate particle size and aerodynamic characteristics, be therapeutically effective, be chemically and physically
stable, and be compatible with current modes for pulmonary delivery. The ideal particle size for deposition into the deep
lung is 1–3 Ám (3–5). Particles with diameters of 4–5 Ám typically deposit in the upper airways, regardless of whether they
are dry particles or droplets, as nebulized formulations are (6, 7). For inhalation powders, particle size is not the only
characteristic that guides deposition to a particular region of the lung. The mass median aerodynamic diameter (MMAD) has
a greater influence on the deposition profile than particle size because it accounts for particle density and shape.
Current particle-size reduction technologies typically yield particles with MMADs in the range of 3–5 Ám. However, the ability
to create particles in the 1–3-Ám range that target the peripheral lung provides opportunities to improve medications for
diseases such as asthma and chronic obstructive pulmonary disease. Particle-size reduction techniques generally are categorized
as milling from larger particles (i.e., top-down) or precipitation from solution (i.e., bottom-up).
Milling has been the traditional method for particle-size reduction. Various models such as ball mills, colloid mills, hammer
mills, and jet or fluid-energy mills have been studied, but the majority of inhalation powders are prepared with jet mills.
Jet milling has disadvantages that include the lack of control over parameters such as size, shape, morphology, and surface
properties of the milled particles. In addition, the high energy input can promote chemical degradation and often damages
the crystal surface, thus yielding highly charged and cohesive particles.
Precipitation techniques include spray drying, spray freeze-drying, supercritical-fluid extraction, and microcrystallization.
Spray drying is a widely accepted pharmaceutical process that forces a fluid through a nozzle, thus generating a mist that
is dried to produce a fine powder. Spray drying has been adapted to employ various nozzles that use ultrasound or air-jet
shear to nebulize drug suspensions. Supercritical-fluid extraction uses a supercritical fluid, generally carbon dioxide, to
extract a solvent from a drug emulsion or solution, thus leaving behind a suspension of drug particles. Both spray drying
and supercritical-fluid extraction often use cosolvents to improve drying, require large amounts of excipients to stabilize
the drug and powder properties, and require high shear rates that can denature proteins. The two processes typically have
low yield efficiencies for particles smaller than 3 Ám. Generally, these techniques produce inhalation powders that are blended
with excipients or a carrier such as lactose.
Spray drying generates particles of an appropriate size for pulmonary delivery (8). Recently, spray-dried porous nanoparticle-aggregate
particles (PNAPs), which are composed of a shell of nanoparticles and excipients, have exhibited an aerodynamic size of about
2 Ám. Scientists have studied PNAPs for a range of applications from needle-free vaccine delivery to the delivery of antituberculosis
compounds through the inhalation route (9, 10).