The Pharmaceutical Journal
Vol 269 No 7211 p232
17 August 2002

Society summary

Welsh Executive:
How "sticky and fluffy stuff" helps protein drug delivery

The use of "sticky and fluffy stuff" to aid the absorption of peptides and proteins from the gut was described to the Welsh AGM by Professor Hans E. Junginger (head of the department for pharmaceutical technology at the Leiden/Amsterdam centre for drug research and scientific secretary to the International Pharmaceutical Federation).

Giving the annual Welsh Executive lecture, Professor Junginger said that the safe and reliable absorption of peptides and proteins was one of the major challenges in oral drug delivery, and the development of suitable systems could not keep pace with the availability of therapeutic agents. These hydrophilic macromolecules were too large, too labile and too polar for straightforward administration by the oral route. They had to face the defence mechanisms of the mucous blanket, intestinal enzymes and lipophilic barrier, which excluded and degraded foreign proteins.

One approach to the problem was to develop delivery systems that employed functional excipients to overcome these barriers by locally modifying intestinal conditions. The concept was to stick the delivery system to the mucosa, ensuring localised release of excipient and drug. By limiting the area over which conditions needed to be modified, this approach reduced excipient requirements and reduced the risks associated with disrupting the defence mechanisms.

Professor Junginger described research on delivery systems using polyacrylic acid derivatives, polycarbophil and carbomer. These mucoadhesive hydrogels increased permeability by opening the tight junctions between epithelial cells — through their affinity for calcium ions. They also inhibited proteolytic activity, primarily that of trypsin. Effective blood levels, but only 2 per cent absorption, of buserelin had been achieved in rats with 0.5 per cent carbomer.

Better results were expected for chitosan derivatives. Chitosan was adhesive, it deactivated the important enzymes and it bound calcium ions, increasing the concentration gradient and opening the tight junctions. It had many advantages, being biocompatible, biodegradable and available in a range of molecular weights. It was a cheap, plentiful waste product from shells.

A 25 per cent absorption of a 10mg octreotide dose had been achieved using 10 per cent N-trimethyl chitosan chloride (TMC) at pH 7.4 in pigs. This was the wrong pH and impractical, as it was necessary to open the gut and apply the suspension.

The principle of using functional excipients had been established but achieving direct contact with the mucosa remained a problem. The solution was oral administration of novel delivery systems based on superporous hydrogels with a double phase time-controlled release profile. Superporous hydrogels rapidly swelled in water; polymerisation with simultaneous carbon dioxide production achieved a porous structure and a 200-fold expansion. The aim was to clog the intestine for a few hours, bringing gel surface into contact with the mucosa at a sufficient pressure for successful localised modification of conditions.

Enteric coating delayed the release of enhancers and enzyme inhibitors and then swelling provided a time lag before a burst release of the drug. Drug microparticles were retained by a soluble plug within the superporous hydrogel outer layer or drug minitablets were embedded in the surface of the superporous hydrogel.

Studies with octreotide had confirmed that superporous hydrogels and composites were viable candidates for oral delivery systems. In pigs, a 16 per cent absolute bioavailability had been achieved for octreotide formulated with TMC as a penetration enhancer. The gel became mechanically weaker with time and then disintegrated.