Schools of pharmacy are not only teaching institutions. Their teaching work is underpinned by basic and applied research in the pharmaceutical sciences. The Royal Pharmaceutical Society's chief scientist describes some of this research
Much of the research in schools of pharmacy is aimed at producing new medicines and these capture the public's attention because patients can see the direct benefits to them that the new medicines will bring. The success of academic projects that end in new products is easy to see because they can be measured by patient take up, professional acknowledgement and sales. However, it should be remembered that there is also exciting research that increases knowledge in the pharmaceutical sciences that is not so newsworthy and may be missed by the casual observer. This article gives some examples of the research performed by schools of pharmacy that has ended with products being brought to market and concludes with examples of advances in pharmaceutical technology that have added significantly to our knowledge.
One huge success was the development of atracurium at the University of Strathclyde by a group of medicinal chemists led by Professor John Stenlake and Professor Roger Waigh. Previously, muscle relaxation for surgery with tubocurarine had some undesirable side effects and complications in post-surgical care. Working closely with pharmacologists at the then Wellcome Laboratories, the medicinal chemists at Strathclyde designed a molecule to limit the drug's duration of effect and then fine-tuned the structure to give a drug with high potency and an almost complete absence of side effects.
Christened atracurium, it was successfully marketed in the 1980s as Tracrium, reaching annual sales exceeding £100m. It remains one of the two most widely used muscle relaxants because of its predictable action.
A more modern example is the antitumour drug temozolomide which has been licensed for use in 16 markets throughout the world for the treatment of brain tumours and is expected to be approved soon in Europe for use in malignant melanomas.
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The molecular structure of temozolomide, which was found to have antitumour activity |
Research into a new generation of phosphate binders has been led by Professor Bob Hider at King's College, London. One of the results of chronic renal disease is the retention of phosphate which can lead to an imbalance of calcium. High levels of calcium and phosphate in the body give rise to muscle cramps, generalised bone damage and bone disease. Thus, phosphate binders are administered where a low phosphate diet or dialysis is insufficient to remove the phosphate. The novel class of binding agents is based on high molecular weight polyguanidine-containing compounds and they are currently in various stages of clinical trials. The examination of guanidine compounds followed the observation that mellitin (the major component in bee venom) is stabilised in an inactive tetrameric form by phosphate due to the formation of stable bridges with guanidine functions in the molecule. Thus, knowledge in one field of research in the pharmaceutical sciences gave birth to successful ideas in a totally different area.
The delivery of anticancer drugs has been markedly improved by the use of novel drug delivery systems to improve their effectiveness and decrease toxicity. Polymers may be covalently bound to drug molecules to target anticancer drugs to tumours. An example is polymer platinate which was developed by Professor Ruth Duncan of the School of Pharmacy, University of London. In preclinical studies, polymer platinate was less toxic and allowed a 15-fold increase in platinum dosage to be administered which delivered greater than 60 times more platinum to the tumour sight compared to cisplatin. Platinum compounds are one of the most popular classes of chemotherapeutic agent,s with an estimated £500m annual sales and the correct delivery is crucial to its efficacy.
Another successful polymer-drug conjugate produced by Professor Duncan is a copolymer with the cytotoxic drug doxorubicin which is used to treat leukaemias, lymphomas, and a variety of solid tumours. This is currently undergoing Phase I/II evaluation.
The use of microspheres and liposomes to deliver drugs has been the subject of study at many schools. Professor Ian Kellaway's group at Cardiff is making significant advances in the development of mucoadhesive polymers. These materials incorporate drugs and are used to coat mucosal surfaces such as the lung, nose, etc, as well as the eye so that the formulation sticks to the surface and releases the drug over a period of time, rather than being washed away as with conventional formulations.
The fast-acting, long-duration percutaneous anaesthetic Ametop gel (amethocaine) was developed by Professor David Woolfson and Dr Dermot McCafferty at the Queen's University of Belfast. The need for such a product came from a clinician who was concerned at the pain caused to young children who had frequent venepuncture as part of their treatment. Although there were products available over-the-counter at that time, they were intended for application to mucosal surfaces or broken or abraded skin. What was needed was a preparation that delivered the anaesthetic through skin where the stratum corneum remained intact. The solution was to develop an amethocaine phase-change system to allow the free base to be absorbed by the skin.
Although the development took some 15 years, the most difficult part of the project turned out to be convincing an industrial partner that it would be a commercial success. The eventual commercial partner proved to be the UK multinational health care group Smith & Nephew. The success in converting the pharmaceutical development to a final product is a very good example of technology transfer (the finding of a commercial partner to take forward the results of academic research).
Pharmaceutical analysis
Moving analyses from the laboratory to the factory, where they may be performed by relatively unskilled staff, has been studied by Professor Fred Rowell's group at Sunderland.
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Professor Rowell's team has developed simple tests for plant validation |
While much research activity is concerned with the chemistry of drug molecules, their crystalline characteristics and physical characteristics are also of vital concern. It is these that determine whether powders will flow and whether they can be compressed into tablets and also affects the dissolution rate of an active ingredient from a finished formulation.
Professor Peter York at the University of Bradford and his colleagues have developed an entirely new technology to control the manufacture of particles based on the use of supercritical fluids (gases compressed to the point of liquifaction). The drug is dissolved in the supercritical fluid and sprayed in an unpressurised, enclosed, oxygen-free and light-free atmosphere to form uniform particles.
The outcome is batch-to-batch consistency in the physical form of the drug, which allows close control over particle size, shape and polymorphic form. This ability to engineer particles of constant physical properties benefits fine chemical manufacture, formulation and product development, and also reduces the need for large quantities of chemical solvents which often leave impurities in the product.
Bradford Particle Design Ltd was founded in 1995 to continue this pioneering work and to undertake contract work for the pharmaceutical industry.
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Scanning electron micrographs of particles of nicotinic acid (vitamin B) before (left) and after (right) going through Bradford Particle Design's SEDS (solution enhanced dispersion by supercritical fluids) process |
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A chemical pancreas (PJ, February 7, 1998, p187) has been developed by Dr Joan Taylor at Leicester's De Montford University to control blood levels of insulin in diabetics. The system holds a reservoir of insulin that is released in response to changing glucose levels through a barrier membrane made from a glucose-sensitive gel. The device can be implanted intraperitoneally and needs refilling only every three months. It has the potential of being refilled from the outside via a valve. Thus the peaks and troughs in glucose levels that lead to the long-term effects of diabetes may be controlled even with diabetic patients treated with insulin injections.
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Standard testing of sputum samples for the presence of tuberculosis can take 12 weeks to produce results, but a new test being developed by Professor Stephen Denyer's group at Brighton school of pharmacy is designed to produce results in 10 hours without any need for expensive equipment. The new method is called BioPhAB and uses a technique called phage amplification. When samples are pre-treated with various anti-tuberculosis drugs, the susceptibility of the patient's strain of bacteria to those drugs can be determined so that the most appropriate treatment may be chosen. The method also has the advantage that it kills the tuberculosis bacteria during the process of the test. |
The school of pharmacy at Brighton university has developed the BioPhAb phage amplification process which is used to detect tuberculosis bacilli in sputum samples. The test produces results within 10 hours and kills the infective organism |
The University of Brighton also helped develop another cheap and simple test that came to market. This was for the detection of neuroblastoma in children, which affects about 100 children a year in the United Kingdom. Dr Gerard Gallacher, working with St Bartholomew's Hospital, London, and Cambridge Life Sciences invented a new way of using artificial antibodies to identify chemical changes in blood and urine samples to detect the cancer in children at an early stage. It had not previously been usually detectable until children were older, by which time it was also usually untreatable.
Schools of pharmacy have recognised over the years that they can make commercial gain from some of their discoveries. While they may sell or license their intellectual property to the pharmaceutical industry, many schools are setting up separate companies to turn their scientific concepts into commercially viable products and services.
Nottingham is one of the leaders in this area with three separate companies. Danbiosyst was founded by Professor Bob Davies and Professor Lisbeth Illum in 1987 as a specialist drug delivery company. It develops formulations for challenging drug molecules such as peptides, proteins, DNA and oligonucleotides for products such as medicines, vaccines and diagnostic tests and was sold to the West Corporation in 1998. Pharmaceutical Profiles was also founded by Professor Davies in 1987 to investigate drug absorption and distribution by using the non-invasive technique of gamma scintigraphy. This method has the great advantage that a drugs progress can be followed as it moves down the gastrointestinal tract without any pain to the patient. In 1998, Molecular Profiles grew out of the work carried out by Professors Martyn Davies and Saul Tendler in their biophysics and surface analysis laboratory. The company provides state of the art applications of surface biophysical tools to understand biomolecular interactions important in disease and in the development of novel biomaterials.
Other commercial companies have been spun off from schools of pharmacy, some of which have gained awards from the Department of Trade and Industry. They provide services mainly for the pharmaceutical industry and include:
Thus, it can be seen that the output of Britain's schools of pharmacy is much more diverse than might be expected from institutions whose raison d'être is to train pharmacists. The same members of staff that are responsible for training new members of the profession are also original thinkers who can be relied upon to inspire new generations of pharmacists to leave a lasting impact behind them.