Pharmaceutical Manufacturing Handbook: Production and

706 AEROSOL DRUG DELIVERY
of the clinical pharmacokinetics and pharmacodynamics of inhaled insulin [240] . In
patients with type I diabetes, Exubera should be used in regimens that include a
longer acting insulin [241] . In patients with type II diabetes, Exubera can be used
as monotherapy or in combination with oral agents or longer acting insulins [242 –
244] . Studies revealed that the same level of blood sugar control was achieved following
inhalation compared to subcutaneous injection, although different nominal
doses were required due to lung bioavailability issues [245] . The therapeutic effi cacy
and safety of inhaled insulin appears to have been proven, although there are a
signifi cant number of issues with its administration via this route [246] . It has been
noted that asthmatics absorb less insulin from the lungs than nonasthmatics. In
addition, smokers absorb more insulin than nonsmokers. Small and reversible
changes in pulmonary lung function have been observed in some studies with
inhaled insulin. Each of these issues has led to the development of specifi c prescribing
guidelines and an intensive physician/patient education program for the inhaled
insulin product. The Exubera insulin formulation is a spray - dried, amorphous insulin
powder containing 60% insulin in a buffered, sugar - based matrix [175] .
Other pharmaceutical companies are also continuing to develop their own inhalation
insulin products. Aradigm and NovoNordisk are using a liquid insulin formulation
in combination with the AERx IDMS inhaler [247 – 251] . Alkermes and Lily
are developing an insulin product derived from their research on geometrically
large, low - density particles that are formed by a spray drying process incorporating
a natural phospholipid. MannKind is using its Technosphere technology to produce
low - density porous insulin particles. This formulation is delivered using the MedTone
inhaler. Other companies working in this area include Kos Pharmaceuticals, Mircodose
Technologies, Coremed, and Biosante.
5.8.7
NEBULIZERS
Nebulization of liquid formulations has long been established as an effective, if not
effi cient, means of pulmonary drug delivery. The basic principle of nebulizer aerosol
generation has remained unchanged; however, a number of technological advances
have been made which have improved effi ciency and reduced variability. Aerosols
that were previously delivered in a continuous inhalation mode over 5 – 15 min are
now delivered only during the inspiratory cycle, thus reducing drug waste. In general,
nebulizers convert a liquid into a fi ne droplet mist, either by means of a compressed
gas (jet nebulizer) or by high - frequency sound (ultrasonic nebulizer) [252] . Ultrasonic
nebulizers use a piezoelectric source within the formulation reservoir to
induce waves at the surface of the nebulizer formulation. Interference of these
waves induces the formation of droplets which are then carried in a fl owing air
stream that is passed over the formulation. These devices are not suitable for the
nebulization of suspension formulations [253] . Rau (2002) also observed that ultrasonic
nebulizers can increase the solution reservoir temperature and may cause drug
degradation [254] . In the case of the jet nebulizer, an aerosol is produced by forcing
compressed air through a narrow orifi ce which is positioned at the end of a capillary
tube. The negative pressure created by the expanding jet causes formulation to be
drawn up to the capillary tube from the reservoir in which it is immersed. As the
liquid emerges from the tip of the capillary, it is drawn into the air stream and