Oral delivery systems

Oral delivery is usually the preferred system for drug delivery, owing to its convenience and the high level of associated patient compliance generally attained. Biopharmaceutical delivery via this route has proven problematic for a number of reasons:

• 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.

• Inactivation due to digestive proteases. Therapeutic proteins would represent potential targets for digestive proteases such as pepsin, trypsin and chymotrypsin.

• Their (relatively) large size and hydrophilic nature renders difficult the passage of intact biop-harmaceuticals across the intestinal mucosa.

• Orally absorbed drugs are subjected to first-pass metabolism. Upon entry into the bloodstream, the first organ encountered is the liver, which usually removes a significant proportion of absorbed drugs from circulation.

Given such difficulties, 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 substances, including cellulose, polyvinyl alcohol, polymethylacrylates and polystyrene. Delivery systems 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 absorption 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-specific (charge-based) interactions can be achieved by the use of polyacrylic acid, whereas more biospecific interactions 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.

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