The Pharmaceutical Journal Vol 267 No 7168 p470-481
6 October 2001

BPC 2001 summary

Explorations in drug delivery: soft matter, small spheres

The GSK International Achievement award is made to an individual who has demonstrated through published work substantial advances in pharmaceutical knowledge. Presenting the award, Dr Rosemary Leak, vice-president, inhalation product development, said that at the School of Pharmacy, Professor Florence had capitalised on the interdisciplinary nature of his staff collaborating with medicinal chemists, toxicologists, protein chemists and microbiologists.

Professor Florence said that the first part of the title of his lecture “Explorations in drug delivery: soft matter, small spheres” covered the uncertainty of scientific research. The work of his PhD at the University of Strathclyde had been on surfactants, which had become much more relevant in pharmacy than they seemed to be at the time. “We were working in this area without really knowing what the potential value would be,” he said. Professor Florence used examples from his laboratory work to illustrate the theme of unexpected ramifications of research work.

The “soft matter” part of the title reflected his work with surfactants which form “soft” rather than solid, condensed or rigid structures. Surfactants have a dual structure and they assemble into membranes, micelles, vesicles and liquid crystals. “Liquid crystals have structure but are malleable. It is this that gives them their intrigue — the ability to take a self-forming structure and turn it into something else,” he said. For example, liquid crystals might have structure over a short distance but could flow under certain conditions.

Research often moved from one subject to another and sometimes in circles. Professor Florence had started his career studying surfactants, moved to thin films, then emulsions, microcapsules and eventually to nanoparticles. Then, in order to get smaller systems to go further into the body, he had tried to synthesise precise spherical polymers or dendrimers. “Then from dendrimers to particle dendrimers and, lo and behold, many of these had turned out to be surfactants,” he said. “So one often goes in a loop.” The “small spheres” part of the title reflected his work with nanoparticles.

Movement of vesicles

Professor Florence had examined the flow of vesicles and discovered that it was possible to extrude vesicles into interesting shapes. This had applications in examining the behaviour of carrier systems in blood capillaries and the movement of particles through tissues (eg, to a tumour). Professor Florence also began to look at what happens to nanoparticles when they are taken up by the gut. In addition to solutions, bacteria, viruses and small particles are taken up in the gut. Some of the ramifications of the work included a better understanding of:

• Oral vaccinations “It is the goal of many companies and research groups to find adequate means of carrying antigen intact across the gut,” he said. The mechanism of particulate uptake could be used to find suitable oral vaccines.
• Prion uptake The tissues that allow particulate uptake in the gut have been implicated in the way that prion proteins are taken up from the gut into the circulation and eventually into the central nervous system.
• Drug delivery Particulate uptake by the gut also had applications in nanoparticulate drug and toxin uptake.

Niosomes

“It was the L’Oreal company that first got us interested in niosomes (non-ionic surfactant vesicles) which were supposed to carry anti-ageing materials to the skin. We laughed at that concept a while ago but we now know that you can transport materials across the skin in small vesicles,” he said.

Geodesic niosomes are complex niosomes involving multiple niosomes conglomerated around a central core. “These were discovered eight years ago and they still intrigue us,” he said. “We are trying to work out how to remove individual parts of them which may form the basis of a pulsatile drug delivery system.” A pulsatile delivery system would be an ideal biomimetic system. “Nature has so much to offer: if we could harness some of the natural processes in our body that release drugs to particular targets we could get more effective drug delivery systems,” he said.

Based on this, Professor Florence examined a capillary system in which vesicles were pulsed out. The vesicles were either released slowly or the system burst.

In reality, it was possible to get spherical vesicles to pulse out but often they aggregated. Solid particles and vesicles would pulse out intact. Drugs incorporated in the vesicles could be pulsed out in some sort of similarity with a biological system.

When he tried to extrude polyhedral vesicles, which are not spherical, the result was unexpected. The vesicles conglomerated and formed a continuous, lipid surfactant tubule. This led to an interest in what could be done with lipid structures and work on manipulating shape which was of value because size and shape are important factors in drug delivery. Shape determines flow patterns and size the final destination of the drug, Professor Florence explained.

The gut probably interests researchers most in drug delivery. Particles are taken up by specialised tissue on the gut. From there, they are taken into the lymphatic system and to the lymph node. Particles of a certain size might block capillaries and accumulate in the lymph nodes, something that might be wanted, for example with vaccinations or HIV drugs. The destination depends on particle size. This was difficult to study in vivo so models were needed to understand the complex processes.

Professor Florence also discussed dendrimers. Side chains can be added to a central core of dendrimers. The arms are regularly spaced, which is important in trying to target particular sites in the GI tract. Particular ligands can be attached to interact with biological ligands. “This provides a more complex biological targeting method as long as we know what the molecules are that we are targeting: this is the realm of molecular pharmaceutics,” he said.

Ideal delivery

Professor Florence said that the components of the ideal delivery vector of the future were a reservoir, recognition ligands on the surface, a biosensor, for example to measure blood glucose levels or hormones, a pump and a controlling valve. “Bit by bit, different groups are learning different parts to this model,” he said. “But will we get there? I’m not particularly sure, but if we can combine things like tethering a non-ionic vesicle with some of the other work that is going on, then we might be able to do what is considered the impossible.”

The UK had experienced an obsession with the differentiation between pure and applied research, said Professor Florence. Drug delivery research is considered to be applied — to produce a new system — but this is too rigid a criterion. Organic chemists, for example, can produce an exotic, highly toxic but useless molecule that contributes to the fundamental understanding of organic chemistry. “The same spirit should be applied to drug delivery research. I hope that the fundamental nature of things will be studied for its own sake and for the unknown advantage that might occur.” He added: “We should inform our students that what is relevant today might not be relevant tomorrow.”

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