Research and Development of a New Safe Form of Drugs - Aerosols: Measurement, Dosimetry, and Health Effects - page 250

11.1 PART I. PHYSICAL-CHEMICAL AND TOXIC-PHARMACOLOGICAL

CHARACTERISTICS OF AEROSOLS FORM OF DRUGS

T.G. Tolstikova, A.A. Onischuk, I.V. Sorokina, A.M. Baklanov,
V.V. Karasev, V.V. Boldyrev, and V.M. Fomin

11.1.1 i ntroduction
It is expected that the use of nanoparticulate materials will be of high importance in future science and
technology. There is increasing optimism that nanotechnology, as applied to medicine, will bring sig-
niicant advances in the treatment of disease. The administration of drugs directly into the respiratory
tract has been used in a number of therapeutic areas. The ield of aerosolized drug application includes
treatment of lung diseases, like asthma, chronic obstructive pulmonary disease, cystic ibrosis, and
lung cancer (Hickey, 2004). Aerosol delivery has also expanded into the ield of systemic drug delivery
(Laube, 2005). The optimal target in the lungs for delivery of drugs to the systemic circulation is the
alveolar region. For rapid delivery, alveolar drug administration has a number of advantages including
large absorptive surface area, easy permeability of the alveolar walls resulting in the fast passage from
the alveolar airspace to the pulmonary capillary bed, and a direct connection between the pulmonary
circulation and the systemic circulation. Aerosol delivery is much more eficient than the peroral admin-
istration because of low oral bioavailability for some drugs such as zanamivir (Fenton et al., 1977) or
amantadine hydrochloride (Skyler, 2007). In the case of systemic targeting, the advantages of aerosol
delivery with respect to peroral treatment include the possibility of avoiding losses in the gastrointesti-
nal tract as well as metabolic destruction in the liver. In contrast to injection therapy, inhalation therapy
is noninvasive, and so it is a more convenient and safe route leading to an improved treatment outcome.
On the other hand, the aerosol treatment has no limitations for the use of water-insoluble drugs giving
evident advantage with respect to injection therapy. Approximately one third of the modern drugs are
water-insoluble or poorly water-soluble. Many currently available injectable formulations of such drugs
can cause side effects that originate from the detergents and other agents used for their solubilization.
Besides, water-solubility problems delay or completely block the development of many new drugs and
other biologically useful compounds. Thus, the lung deposition route can be a good alternative for the
administration of poorly soluble substances.
The modern devices which are available on the market for therapeutic aerosol delivery systems
can be subdivided into three groups: nebulizers, dose-metering inhaler systems, and dry powder
inhalers (Baron and Willeke, 2001; Hickey, 2004). All these inhalers have evident shortcomings
(Hickey, 2004). One of the main problems of jet nebulizers is their limited portability due to the
need for compressed gas supply. Besides, it is important that the nebulizer solutions not be stored in
nebulizer reservoirs due to the possible growth of bacteria. The disadvantages of pressurized dose-
metering inhaler systems include high aerosol velocity (which results in substantial oropharyngeal
deposition), limited single dose etc. Different facilities including extension tubes and spacers were
applied to overcome some of these problems; however, new problems have appeared such as large
spacer volume and particle electric charge (Rubin and Fink, 2005). One of the problems of dry
powder inhalers is that the dry powder formulation should be appropriately prepared. The powder
properties are shelf life dependent. The crucial question is hygroscopicity. Thus, aerosol properties
and the lung deposition eficiency can be functions of the powder storage time.
A more serious problem related to traditional inhalers is that all these devices are able to generate
the particles as small as a few microns in diameter. However, the alveolar deposition eficiency is a
strong function of the particle size. Particles 10-20 nm in size deposit in the alveolar region about
four times more eficiently than those several microns in diameter (Hinds, 1999; Hickey, 2004;
Oberdörster et al., 2005; Wong, 2007). Moreover, the nanoparticles are easily transported across the