4th United Kingdom-Ireland Controlled Release Society Symposium on:

"Continuous v Discontinuous therapy -
Current Perspectives"

6th January 1998, School of Pharmacy, University of London

Professor Sandy Florence welcomed around seventy delegates to the 4th UKICRS National Meeting which despite severe storms off the south west coast, gales preventing ferry sailings from Ireland and a snow fall in the Midlands took place in almost balmy weather conditions in the capital. Professor Clive Wilson, chairman of UKICRS delivered the opening address, outlining the broad aims of the society to link academia and industry, to provide interesting scientific meetings and funds for young scientists to attend conferences in the UK and abroad. An important goal, achieved in 1997, was the linking of Ireland to UKCRS to form a new UK-Ireland local chapter. Dr Anne Brindley, the meeting organiser, then thanked committee members, Peter Scholes, Hiep Huatan and Saghir Akhtar for assistance in particular and acknowledged the generous sponsorship of Astra Charnwood, 3M Healthcare, Pfizer Central Research, Jago Pharma AG, Polymer Laboratories, Faulding Pharmaceuticals and Bristol Myers Squib.


Dr John Devane, from Elan Pharmaceutical Technologies opened the scientific proceedings with a talk on Continuous versus Discontinuous Therapy : Drug Delivery and Therapeutic Issues. The central tenet settled on the growing recognition, through the study of chronotherapeutics, that variable or mixed drug exposure was optimal. Intensive study of natural biological patterns had revealed strong links over a 24 hour period with the pattern of activity and associated symptomatology of the diseased state. The combination of chronotherapeutics with chronopharmacokinetics (variation of drug kinetics with the time of day it is administered) and chronopharmacodynamics (variation of biological responses with the time of day) has resulted in the ability to define optimal drug exposure/time profiles. This in turn has created major challenges but also opportunities for drug delivery to meet new and complex therapeutic regimens. One intriguing response involves the integration of biosensor technology and feedback drug delivery technology to produce individualised 'smart pills' .


Dr Rob Horne, senior lecturer in Health Psychology and Pharmacy Practice at Brighton quickly grabbed attention when he revealed that £2 billion of UK health resources is wasted per year due to unused medication. This is occasioned by a 30-50% non-compliance rate with most patients being non-compliant some of the time. Psychological research has shown that patients form their own 'common sense' models of their illness and evaluate health advice in a 'risk-benefit' analysis before responding to recommended treatment. In a significant number of patients, beliefs that medicines were oversubscribed or were essentially harmful and addictive presented barriers to taking medication. Thus non-compliance may be a logical attempt to moderate the perceived risks by taking less. Compliance may be improved if patient and doctor engage in a more open dialogue about the nature of the illness and treatment to lower 'motivational barriers' alongside making the regime simple and convenient to follow.


Professor Peter Redfern from the School of Pharmacy and Pharmacology at Bath returned to the subject of chronotherapy - the influence of time of day on drug response - with a talk on circadian rhythms (CR) in physiological processes. Rhythms in blood pressure, temperature, and hepatic metabolism for example respond both to the biological clock residing in the suprachiasmatic nuclei of the hypothalmus and the 24 hour day-night pattern of the environment. Circadian periodicity can influence the 1) symptomatology of the disease process over 24 hours 2) the pharmacokinetics of drugs (eg due to the variations in physiological processes responsible for absorption) 3) altered afficacy. Thus we should aim to deliver drugs such as cytotoxic agents according to the rhythmic variation in biological processes (the principles of chronotherapeutics). Difficulties in applying this strategy include a deficiency of knowledge of circadian periodicity in physiological processes, an often small amplitude of the CR, significant inter-individual variation and alteration of the normal CR by disease. A major challenge to drug delivery technology lies in provision of a delivery profile which varies reliably and reproducibly over 24 hours.


Lunch provided attendees with the opportunity to view the poster exhibition, renew aquaintances and establish new contacts. Nineteen posters were submitted all being automatically entered in the competition for two prizes of £500 which are awarded annually to the winning post graduate students to help attend the CRS international meeting.


The first talk of the afternoon session was given by Professor Philip Home of the Human Diabetes Research Institute, University of Newcastle on the subject of 'Restoring Physiological Insulin Delivery'. Professor Horne's first salient point was that insulin is still injected 75 years after its discovery. A tendency for the peptide to hexamerise, its acid solubility and surface adsorption coupled with a widely varying physiological requirement, slow and erratic absorption from the subcutaneous site and poor bioavailability (insulin has a half-life of approximately 5 minutes in the circulation) underline the challenges inherent in delivering insulin effectively. Control of insulin delivery via glucose sensors is desirable but indwelling sensors present biocompatibility problems. Implanted insulin pumps have suffered from long-term incompatibility of insulin with pump surfaces. Promising advances have however been achieved in design of insulin molecules to prevent hexamer formation and improve absorption rate or to prolong absorption time to mimic basal insulin delivery between meals. Not surprisingly, Professor Horne's specification of an ideal insulin delivery device : diameter 10µm, 107 per person, multiple inputs, fast response, no calibration, lifespan 70 years, powered by the measured (glucose) molecule fitted the Islet B-cells of the pancreas and turned attention once more to the potential of cell encapsulation technology.


Dr David Chaplin from the Gray Laboratory, Cancer Research Trust described the opportunities for targeting tumour epithelium so as to cause shut-down of the tumour vascular function leading to secondary tumour cell death. Significant selectivity between tumour and normal tissue response is the key to effective targeting. Combretastatin (A-4 disodium phosphate) was found to cause vascular shut-down at 1/10 the maximum tolerated dose and short in vitro drug exposure resulted in long-term anti-proliferative/cytotoxic effects against proliferating but not quiescent endothelial cells. The potency of combretastatin A-4 was convincingly illustrated by an impressive video recording of progressive vascular shut-down and tumour necrosis in vivo in experimental models.


The coffee break provided valuable extra minutes for Dr Friederick Rudenbekke to reach the lecture theatre after flying in from Germany as a late replacement for Dr DeGrande of 3M. The talk on novel transmucosal (TMD) and buccal drug delivery systems centred on the advantages of 3Ms 'Cydot' adhesive patch devices which are positioned on the gingiva of the gum. The system has been used to deliver melatonine, buprenorphine and low Mw heparin and can provide rapid or sustained delivery, good dose response and reproducibility. Other advantages include low inter-subject variability and avoidance of first pass liver metabolism. An intriguing future prospect raised by Dr Rudenbekke involved TMD of therapeutic proteins and peptides.


The scientific session was brought to a close by Dr Glynn Wilson of Access Pharmaceuticals who described some of the challenges facing the development of novel polymer therapeutics. In particular, polymer conjugates as pro-drugs or as components of particulate systems had been shown to provide a number of opportunities for improving drug efficacy by exploiting disease-related physiological changes (eg 'leaky' tumour endothelium) and specific drug release mechanisms. However the successful translation of innovative research into commercial products necessitated integration of basic research with essential development activities. These included detailed safety assessments, patent protection, pre-clinical and clinical testing and education of industry and clinicians.


An extremely interesting meeting, notable for the high level of audience participation through enthusiastic questioning of the speakers, was closed by Professor Wilson. The two winners of the £500 prizes for best posters were Aminul Islam from the Dept. of Pharmaceutical and Biological Sciences at Aston for 'Studies on uptake and sub-cellular trafficking of antisense oligodeoxynucleotides using self assembling cationic lipids as delivery systems' and Alison Potts from the Dept. Of Pharmaceutical Sciences, University of Strathclyde for ' In vivo determination of the oesophageal retention of smart hydrogels'.


It remains for the chairman and committee members of UK-Ireland CRS to wish Aminul and Alison bon voyage and good luck in Vegas!

A. Coombes

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