Page 224 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioTechnology

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Encyclopedia of Physical Science and Technology EN011J-141 July 31, 2001 15:14

Pharmaceuticals, Controlled Release of 801

skin-impermeable. Under the action of a small voltage a more readily absorbed form. Most nasal devices deliver
gradient, the skin permeation rate of the drug increases the drug as a fine liquid or solid spray; the average par-
10- to 100-fold. Another advantage of iontophoresis is ticle size significantly affects the rate of drug absorption.
that the voltage driving force can be easily regulated; this Intranasal delivery of systemic drugs requires sophisti-
allows pulsatile drug delivery or variable delivery accord- cated delivery devices to ensure accurate, repeatable dos-
ing to the patient’s needs. This control is useful in the ing and minimal irritation. Dosing accuracy is particularly
delivery of analgesics such as fentanyl for the control of important for delivery of potent and expensive drugs such
pain. Despite the many patents in this field, no commercial as the new generation of peptide and protein products.
products have yet reached the market. Long-term nasal delivery may also require dose-counters
The main advantages of transdermal over oral drug de- and lock-out systems to prevent overdosing as, for exam-
livery are the ability to maintain constant plasma lev- ple, in the pain relief area.
els with short-half-life drugs and to avoid the hostile Prior to 1985, chlorofluorocarbons were widely used as
conditions of the gastrointestinal tract and consequent inert nontoxic inhaler propellants; these compounds are
drug deactivation because of the hepatic first-pass effect. now all but banned. Consequently, much recent research
Moreover, patient compliance tends to increase, reducing has centered on the development of dry powder inhalers,
the number of administrations required. Patches are now which deliver the active ingredient as ultrafine particles di-
available for once-a-day, twice-a-week, and once-a-week rectly to the lungs with minimal deposition in the mouth
treatment. and trachea. Some of these devices are activated directly
by the inspiration of the patient without the need to coor-
C. Nasal Spray/Inhalers dinate activation and inspiration.
Although dry powder inhalers have a number of ther-
Drug delivery by inhalation has a long history and is an apeutic benefits, they also have problems. For example,
obvious method of administering agents that act on the contact of the powder formulation with moisture can lead
respiratory system. However, it is now being used in- to agglomeration and inaccurate dosing, and dose unifor-
creasingly to deliver systemically active drugs. The first mity is hard to achieve. The potential for nasal delivery is
hand-held, pressurized, metered inhaler was launched in greatest in two areas: local delivery to the lung for respi-
1960; several other products have been introduced since. ratory treatment diseases and systemic delivery of a broad
Intranasal delivery is currently employed in treatments variety of drugs via the alveoli, which have highly absorp-
for migraine, smoking cessation, acute pain relief, noc- tive properties. Its greater long-term potential is in the de-
turnal enuresis, osteoporosis, and vitamin B 12 deficiency. livery of macromolecules, but further research is needed to
In 1999, Aviron’s intranasal influenza vaccine, FluMist, determine the long-term immunogenicity, reproducibility,
was filed with the FDA, and several other vaccines are and stability of the delivery systems.
being considered for nasal administration. Other applica-
tions for nasal delivery under development include cancer
D. Targeted Drug Delivery
therapy, epilepsy control, antiemetics, and treatment of
insulin-dependent diabetes. Targeted or directed drug delivery is a relatively new
The advantages of the nasal cavity over other drug ad- method of delivering drugs. The objective is to alter the ef-
ministration routes are rapid, direct access to the sys- fectiveness of drugs by targeting their delivery directly to
temic circulation and complete avoidance of first-pass the site needing drug action. Promising techniques include
metabolism. The nasal cavity is also a far less aggressive the use of liposomes, polyethylene glycol (PEG)-coated
environment than the gastrointestinal tract, and so is par- molecules, blood–brain barrier transfer agents, and several
ticularly useful for the delivery of peptides and proteins, antibody conjugate approaches.
which are easily degraded in the stomach. Patient compli- The most advanced targeted delivery technology uses
ance is also improved, particularly if the alternative treat- liposomes, which are ultrafine water/oil/water emulsions
ment is intravenous injection. However, the nasal route is in which the emulsion droplets consist of lipid vesicles
not without its problems. Issues that need to be considered containing an aqueous drug solution. The surface of the
are the rate of drug absorption through the nasal mucosa, vesicles is sometimes modified to promote targeting of the
the residence time of the formulation at the site of delivery, lipid-drug-containing vesicle to selected tissues. The first
local toxicity and tolerability, and degradation of the drug liposomes were developed in 1965 as a model of biologi-
in the nasal cavity. The rate of absorption of the drug can be cal membranes. Their potential as a drug delivery system
controlled by including carriers and enhancers to modify was recognized later; now, after many years of gestation,
permeation, or by chemical modification of the drug into liposomes are finally being introduced in commercial