Biomedical Engineering Reference
In-Depth Information
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Inactivation due to stomach acid. Prior to consumption of a meal, stomach pH is usually
below 2.0. Although the buffering action of food can increase the pH to neutrality, the
associated stimulation of stomach acid secretion subsequently reduces the ambient pH back
down to 3.0-3.5. Virtually all biopharmaceuticals are acid labile and are inactivated at low
pH values.
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Inactivation due to digestive proteases. Therapeutic proteins would represent potential targets
for digestive proteases such as pepsin, trypsin and chymotrypsin.
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Their (relatively) large size and hydrophilic nature renders diffi cult the passage of intact biop-
harmaceuticals across the intestinal mucosa.
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Orally absorbed drugs are subjected to fi rst-pass metabolism. Upon entry into the bloodstream,
the fi rst organ encountered is the liver, which usually removes a signifi cant proportion of ab-
sorbed drugs from circulation.
Given such diffi culties, it is not unsurprising that bioavailabilities below 1 per cent are often
recorded in the context of oral biopharmaceutical drug delivery. Strategies pursued to improve
bioavailability include physically protecting the drug via encapsulation and formulation as
microemulsions/microparticulates, as well as inclusion of protease inhibitors and permeability
enhancers.
Encapsulation within an enteric coat (resistant to low pH values) protects the product during
stomach transit. Microcapsules/spheres utilized have been made from various polymeric sub-
stances, including cellulose, polyvinyl alcohol, polymethylacrylates and polystyrene. Delivery sys-
tems based upon the use of liposomes and cyclodextrin-protective coats have also been developed.
Included in some such systems also are protease inhibitors, such as aprotinin and ovomucoids.
Permeation enhancers employed are usually detergent-based substances, which can enhance ab-
sorption through the gastrointestinal lining.
More recently, increasing research attention has focused upon the use of 'mucoadhe-
sive delivery systems' in which the biopharmaceutical is formulated with/encapsulated in
molecules that interact with the intestinal mucosa membranes. The strategy is obviously to
retain the drug at the absorbing surface for a prolonged period. Non-specifi c (charge-based)
interactions can be achieved by the use of polyacrylic acid, whereas more biospecifi c interac-
tions are achieved by using selected lectins or bacterial adhesion proteins. Despite intensive
efforts, however, the successful delivery of biopharmaceuticals via the oral route remains some
way off.
4.10.2 Pulmonary delivery
Pulmonary delivery currently represents the most promising alternative to parenteral delivery
systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality
in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the
lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), mac-
romolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary
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