10th United Kingdom-Ireland Controlled Release Society Symposium on:
"Macromolecular Drug Delivery: Big Molecules, Big Problems"

January 13th 2004, GSK House, Brentford

This was a joint one day meeting between the RSC and SCI Colloid Group and the United Kingdom and Ireland Chapter of the Controlled Release Society (UKICRS) entitled ‘Macromolecular Drug Delivery: Big Molecules, Big Problems'. The aim of the day was to discuss the problems associated with the formulation of macromolecular drugs such as antibodies and heparin. The meeting, of 65 delegates, was generously hosted by the Pharmaceutical Company, GlaxoSmithKline (GSK) in their new corporate headquarters in Brentford, Middlesex.
 
The morning session commenced with Professor Randy Mrsny (University of Cardiff) describing his research groups attempts to modulate the barrier properties of the intestinal membrane by selectively opening up gaps between the cells constituting the membrane in a controlled and reversible manner. If this goal proves to achievable then it opens up a whole new avenue for drug delivery as it may then be possible to deliver realistic amounts of drug encapsulated in a colloidal vehicle across the small intestine; the major site of drug absorption after oral administration.  

Professor Mrsny was followed by Professor Sandy Florence (School of Pharmacy, University of London) who detailed efforts that have been made to date to use colloidal particles (particularly those in the 5-500nm size range) as oral drug delivery vehicles. A whole plethora of colloidal systems have been studied including dendrimers, microemulsions and hydrophobic nanoparticles but with varying degrees of success. It is now generally accepted that it is only possible to deliver very low levels of therapeutic molecules across the intestine using colloidal carriers, such as those suitable for vaccine delivery. However this may change if Professor Mrsny's approach is successful. Realising the fact that many of the barriers facing the successful formulation of drugs for oral delivery are colloidal in nature, Professor Florence called upon colloid and surface chemists to become involved in the drug delivery process. Professor Florence also highlighted that many of the macromolecular drugs available are themselves small colloidal particles and may be able to act as their own delivery vehicle.

The final speaker of the morning, Dr Giuliano Siligardi (King's College London) told the audience about his work successfully exploiting the naturally-occurring blood colloid, human serum albumin (HSA) as a drug delivery vehicle. This is achieved by utilising the natural ability of HSA to bind fatty acids. By modifying a drug molecule to contain a fatty acid it is possible to get up to 9 drug molecules binding to HSA. The use of HSA as a delivery vehicle offers a number of advantages, including increasing both the plasma half-life and safety margin of the drug, and acting as a solubiliser of the drug. This novel technology is now being commercially developed.

After an excellent lunch during which the audience were able to view the posters and small scientific exhibition, Dr Marianne Ashford (AstraZeneca) gave a personal view of the need to identify potential drugs with a view to fitting into a particular drug delivery system, rather than developing supposedly 'universal' drug delivery vehicles. Recent advances in high throughput screening and combinatorial chemistry meant that many thousands of putative drugs are being identified, many of which however exhibit physico-chemical properties that make them difficult, if not impossible, to formulate successfully using conventional methods. In order to successfully develop new medicines therefore Dr Ashford argued, that the selection procedure should not be based solely on consideration of therapeutic activity of the drug but also its ability to be incorporated into existing drug delivery vehicles.

Professor Bob Laughlin (Cinncinati, USA) then detailed his work concerned with development of a vaginal controlled release between-period contraceptive technology. This technology consists of a silicone diaphragm-like device from which it is possible to control the release of the spermicidal nonionic surfactant, C10E5. This novel contraceptive device offers the advantage that the spermicidal C10E5 is non-hormonal and is released at its intended site of action and consequently should not produce any major side effects and it was well accepted by patients in a clinical trial. Unfortunately due to Company policy this exciting technology was not commercialised.

The final two sessions of the day outlined the development of physico-chemical techniques to characterise antibodies. Antibodies are potentially very important therapeutic molecules and recent advances in biotechnology mean that it is now possible to manufacture them at a cost that makes them realistic candidates as drugs. In his paper Professor Tudor Arvinte (University of Geneva) showed how he has successfully combined the use of quantitative electron microscopy with a wide variety of spectroscopic techniques including fluorescence and circular dichroism to determine subtle changes in antibody conformation. Of particular interest was his work showing how these techniques could be used to explain the inactivity of an antibody preparation after freeze drying.

The final presentation of the day was by Professor Steve Harding (University of Nottingham) who showed the audience how analytical ultracentrifugation techniques can be successfully combined with molecular modelling to determine the solution conformation of a whole range of antibodies. Ultracentrifugation is the one of the best ways to determine antibody structure in solution as antibodies are currently too large to be successfully studied using high resolution NMR. The only other technique employed to successfully look at antibody solution structure is neutron scattering (again in combination with X-ray structure determination and molecular modelling), but this technique is not currently widely accessible, requiring the use of national facilities and deuterated molecules.

After the scientific part of the meeting was concluded, delegates were taken on a short tour of the new GSK headquarters.