Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 762

(i.t.) administration which bypasses the nose and throat, making it easier to
precisely quantify the delivered dose. This is in contrast to MDI or DPI inhalers
and/or nebulizers in animal studies, which filter the aerosol through the nasophar-
ynx, are prone to inter subject variability and are not capable of targeting a desired,
predetermined area of the lungs.
A limited number of substances are approved by drug regulatory agencies
worldwide for use in inhalation therapy. Excipients may be categorized according
to the type of inhalation technique. For nebulization solutions, excipients are typi-
cally the same as used in injectables or large-volume parenterals for pH and osmo-
larity control, preservation or solubilization and wettability. MDI require the use of
propellant. Currently, hydrofluoroalkanes are used as propellants, since the elimi-
nation of chlorofluorocarbons. Lipids, phospholipids or surfactants are often pres-
ent in the MDI formulations. DPI often avoids excipients if the shape and size of
dry particles is sufficient for ensuring respirability of the formulation. In some
cases, sugars, amino acids or soluble polymers are used as particle shapers. These
excipients are employed for constructing respirable particles with techniques such
as spray drying. Sustained-release polymers, such as poly lactic acid (PLA), PLGA
or other polyesters, polyacrylates, albumin, chitosan or alginates are studied for
extending the lung residence time of compounds. The goal is to increase efficacy
and allow safer low doses to be effective. For highly potent anti-tuberculosis agents
(e.g. siRNA), when the dose is very low, lactose may be used as a 'carrier' for
constructing ordered mixtures. It is important to stress that lactose intended for use
in pulmonary delivery is a large-sized powder used for flow and packing improve-
ment. During aerosolization, micronized drug particles are detached and lactose
particles are deposited in the mouth (Misra et al. 2010 ). Hypoallergenic materials
such as lactose, mannitol, sodium citrate dihydrate, glycine, lysine, leucine, etc. are
generally used in inhalation products. Such material is 'generally regarded as
safe' and is not known to modify immune response to the inhalant in the lung
(Chimote and Banerjee 2009 ).
To date, most studies have focused on developments of nanoparticles adminis-
tered by DPIs and nebulizers and not by MDI (Azarmi et al. 2008 ; Bharatwaj et al.
2010 ). MDIs are of great technological relevance as they are the least expensive
oral inhalation devices. Moreover, they are portable, easy to use and have high
compliance, making MDIs the most widely used devices for administration of
therapeutics to the pulmonary tract (Laube 2005 ). Compared to DPIs and
nebulizers, however, there is yet an additional challenge in the development of
polymeric nanoparticles-based MDIs: it has been shown to be difficult to stabilize
particle dispersions in the low dielectric hydrofluoroalkane propellants (Rogueda
2005 ). The particles for MDIs thus need not only to be within the desired size
range, but must also have an appropriate surface chemistry-one that is well-solvated
by the propellant so as to prevent particle aggregation, which may otherwise
negatively impact the aerosol characteristics of the formulation (Bharatwaj et al.
2010 ; Rogueda 2005 ).
Pulmonary delivery of nanoparticles intended for macrophage targeting
should be easily recognized and phagocytosed by infected alveolar macrophages.