Novel methods intended to improve drug delivery via the eye, lung, gut and buccal cavity were explored on September 14 and 15
This was a major symposium, run in conjunction with the UK and Ireland Controlled Release Society. It occupied the whole of Tuesday and the Wednesday morning.
The first session was chaired by Dr A. d'Emanuele (University of Manchester). It started with an account, given by Professor C. G. WILSON (University of Strathclyde) of some unexpected phenomena in the passage of dosage forms through, and their absorption within, the gastrointestinal (GI) tract.
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In the various subdivisions of the GI tract, the availability of water varied widely - a fact that had a considerable bearing on therapy. The most frequent accident in hospitals was falling out of bed, but the second was that a tablet or capsule got stuck in a patient's oesophagus. To examine this phenomenon, specimens of both capsules and tablets were radiolabelled. The capsules were labelled by the inclusion of Technetium-99m beads, and the tablets by drilling a hole, inserting a tiny cylinder of ion-exchange resin containing Tc-99m and holding it in place with a dab of bone cement. The passage through the body after ingestion could then be followed by gamma-ray scintigraphy.
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Gamma ray scintigraphy: the passage of radiolabelled tablets and capsules through the body can be followed using this method |
The common concept of food being reduced to an almost liquid consistency by mastication and swallowing was also far from the truth. Typically, a sandwich arrived in the stomach as a hydrogel-like bolus, and both it and any contained dosage form could be trapped in the lesser curvature of the stomach, halfway up the wall of the organ. Caps and bodies of capsules that were designed to separate in the colon had also been radiolabelled so that the fate of both cap and body could be followed. Although the capsule would swell in the ascending colon after the cap had separated, the contents did not hydrate or disperse because there was a shortage of water. Even a highly water-soluble drug, if released at a point in the colon, did not spread. Fluid only entered from the small intestine some two to four hours after a meal and traffic across the transverse colon was strictly one-way. Enemas did not pass the first colonic flexure, so it could be seen that local colonic dosing was not easy.
Novel delivery methods for proteins Dr E. PROSSER (Trinity College, Dublin) gave an update on the oral delivery of protein and polypeptide drugs. He pointed out that there were 38 peptides in the top 100 drugs, but only one oral delivery form was on the market. However, the GI tract did not distinguish between food and drug proteins, and the half-life in the stomach might be as short as 5 minutes. As if the enzymes in the lumen were not enough, there were intracellular proteases as well.
Counting buccal absorption as a kind of oral delivery, there were a number of companies at present with new preparations under development. Theratech had a glucagon-like model peptide that had been tested in dogs, and had reached the stage of a 24-subject human volunteer study; 3M had a low molecular weight heparin in a buccal patch, containing penetration enhancers; Generex had a zinc-based transmucosal oral insulin - Oralin - that should reach the Phase II trial stage in October, and Cortecs had an oil-based, stable emulsion oral insulin that had completed Phase I.
Dr Prosser said the best hope for successful oral delivery was perhaps that being developed by the author's pharmaceutical technology group - Elan - attached to Trinity College. Elan, along with Endorex, another company, had manufactured, polymerised (and therefore stabilised) liposomes intended to deliver human growth hormone by entrapment in the villi of the small intestine. The liposomes had ligands on their outer surface to guide them to the target site, which they were capable of reaching without degradation in the gut. These "Orasomes" had not yet been tested in humans. There had been progress with penetration enhancers, which were accepted for transdermal and nasal use. At the University of Maryland, a 45kDa polypeptide, called Zot (Zonula occludens toxin) was capable of opening the paracellular pathway through mucosal membranes, and could be used as a nasal dosage form adjuvant. Unigene had a patent on the oral delivery of calcitonin (in Phase I trials with Warner-Lambert) that contained a penetration enhancer, and Amarillo Biosciences had a low-dose oral mucosal delivery system for interferon.
Drug release in the GI tract Dr J. T. FELL (University of Manchester) followed along the path sketched out by Professor Wilson, with an account of how dosage forms could be persuaded either to remain in, or release their contents at, specific sites in the GI tract. The most helpful technique in all such investigations had been gamma-ray scintigraphy, since it allowed the location of a suitably radio-labelled drug to be determined non-invasively as a function of time. In order to retain material in the stomach, a useful tool to employ was buoyancy. Resin beads could be loaded with bicarbonate and coated with ethylcellulose. In the stomach, the coating, was insoluble but permeable, so that water got in, carbon dioxide was liberated and the beads floated. Another approach was to use alginate beads, made by dropping an alginate solution into calcium chloride solution. Oven drying then produced beads that were denser than water, while freeze-drying gave light beads that would float. In vivo scintigraphic studies showed that dense beads left the stomach after 30 to 50 minutes, while the floating ones remained in the stomach for some three hours, although they moved down slowly. When the next meal arrived, they rose again and remained in the upper part of the stomach for as long as another eight hours.
Colonic delivery could be obtained in several ways. The use of pH change along the GI tract was unreliable, as the changes were not great and might vary. However, blends of different Eudragit coatings allowed the transit time through the small intestine to be utilised as a release parameter. Better still was to use an amylose or pectin coating (or a blend of the two), possibly with the addition of ethylcellulose, which could allow release either on a time basis, or could be attacked by the resident colonic flora.
The Tuesday afternoon session was chaired by Professor D. Q. M. Craig (Queen's University, Belfast), who introduced as the first speaker his colleague from the same university, Professor S. GORMAN, whose subject was medical implants.
At present, three million people in the UK were host to an implant of some kind and the market was worth £23bn per annum. The down side was that there were 250,000 device-related infections per year, which translated into a cost of £100m in terms of lengthened hospital stay.
The infection difficulty stemmed mainly from the fact that any installed device - the author's principal line of study had been the uteral stent - would be colonised by bacteria within two hours of insertion. After 12 hours, the organisms would have formed a complete film and would have begun to secrete a protective slime layer that would confer resistance to antibiotics. The degree of viable adherence could be markedly reduced by the incorporation of hexetidine into the plastic tubing from which the stent was made. A promising new technique was to coat the surface of plastic with vapour-deposited diamond-like carbon, which greatly improved biocompatibility.
In the case of hip replacement, a phenomenon called aseptic loosening was a recognised occurrence, needing surgical intervention. However, improved techniques of examining newly-removed prostheses had shown that the loosening might be far from aseptic, with bacterial DNA being recognisable in as many as 70 per cent of cases. Although the bone cement used had gentamycin as an additive, many gentamycin-resistant organisms were found.
Polymer properties that help drug design Having chaired the first session, Dr A. d'EMANUELE reappeared to describe some properties of polymers that might help in the design of drug delivery systems that could respond to a physiological need. For example, glucose levels fluctuated under insulin treatment much more than they did under natural control because insulin had a half-life of about 25 minutes. This might be improved by using a different form of delivery. Vaccines could usefully be delivered in degradable microspheres that would release their contents at, say, 14 days, 3 months and 12 months, which would avoid the need for booster injections. In the new field of chronotherapy, it was known that a constant rate of infusion of 5-fluorouracil gave a peak serum level at 11am and a trough at 11pm. Thus, it would be an improvement if the drug were to be supplied at a rate that would counter the effects of the circadian rhythm.
There were various physico-chemical principles upon which the required dosage design might be based. These included the use of sepharose beads, which could be polymer coated and loaded with insulin. When the blood glucose concentration rose, insulin would be released from these beads. Polymer beads containing ferritic particles and drug could be formulated, so that release occurred when a magnetic field was applied. Release could also be induced from dosage forms using electrophoresis. Here, the voltage and power required would be very low, and it had already been shown that propranolol would pass in this manner through polyHEMA. Tablet disintegration and dissolution could be greatly speeded up by a focused beam of ultrasound, largely because of the formation and collapse of cavitation bubbles adjacent to the tablet surface, disrupting the boundary layer. Poly-(N-isopropylacrylamide) nanospheres could be made that would shrink and expel water (and dissolved drug) from their hydrogel structure in response to temperature variations. This was an emerging technology that was dealt with more fully in a later contribution to the symposium.
Advances in ophthalmology A consultant ophthalmologist, Dr B. DHILLON (University of Edinburgh), showed a series of slides that brought home to the audience the rapid advances that had taken place in the field of cataract treatment.
Not very long ago, this was a traumatic operation, needing a 6mm long incision in the eyeball. With the advent of foldable plastic lenses, an incision only half that length became sufficient to sonicate and remove the defective lens, and to replace it. Even more recently, a newer hydrophilic lens had been developed that could be installed through a cut as small as 1.6mm.
Eye infections, particularly in AIDs patients, were difficult to treat. Direct injections into the eye were possible, but any drug was cleared from the eye within a week. The latest method was to insert a 4mg pellet of, for example, gancyclovir in a small PVA pouch, through an incision, and hold it in position on the inside of the eyeball with a small stitch.
Mimicking natural polymers Biomimesis was the art of examining a biological system and synthesising a functionally similar analogue from a smart polymer. Dr S. TONGE (Aston University) explained that lipids were transported in the body by apoproteins. These had a series of a-helices surrounding a central pore in a doughnut arrangement. This was hydrophilic on the outside and hydrophobic on the inside.
To mimic this, using commonly available polymers, the Aston group used an alternating copolymer of maleic acid and styrene. By varying the degree of charge on the pendant carboxylic acid groups, the overall shape of the molecule could be controlled. The shape that was of particular value was one in which, at a specific charge level, the molecule partially collapsed and rearranged itself into microdomains.
In these microdomains, the hydrophilic and hydrophobic components were separated, the whole arrangement being an asymmetric, coiled structure that was like the amphipathic apoproteins that were to be imitated. The synthetic polymer had an extremely good solubilisation capability. In addition, it readily formed a pH-governed association with, for example, phospholipids, in a microstructure with a far higher degree of surface activity than the polymer itself.
The combination had potential value for delivery to the deep lung and for the solubilisation of lipoid molecules in general.
The third session was chaired by Dr M. J. Lawrence (King's College, London) and the first presentation was by Professor R. H. MULLER (The Free University of Berlin, Germany). He described the production and use of solid lipid nanoparticles. These were an alternative to traditional drug carriers, such as oil in water emulsions or liposomes. Since the particles were solid, they offered the possibility of controlled release. A big advantage was that they could readily be manufactured on a large scale, by either hot or cold homogenisation. This could be done relatively cheaply - a 50kg double homogeniser batch set-up cost in the region of £100,000. A 150 kg unit was under construction. High loading capacities could be achieved - up to 25 per cent for a coenzyme - beyond this, the slow-release capability might be compromised. Release times could be controlled from periods of a few minutes to as long as five weeks.
Applications for nanoparticles As mentioned earlier, poly-(N-isopropylacrylamide) had some interesting and useful properties, which were described by Dr M. SNOWDEN (University of Greenwich, London). It could be prepared in a highly monodisperse microgel form by a one-pot polymerisation reaction. The nanoparticles were spherical, with an open structure and a typical diameter of 500nm. However, when the temperature was raised from 25 to 50C, they contracted in diameter to around 100nm, squeezing out the water that was initially inside their hydrogel structure. The five-fold reduction in diameter, it should be noted, corresponded to a 125-fold reduction in volume, so that any contained solute in the water would be almost completely expelled. The change was almost instantaneous and was reversible. It could also be brought about by changing the pH, or by changing the electrolyte concentration in the continuous phase.
By adding potassium persulphate in the polymerisation reaction, the polymer could be prepared with sulphate groups on its surface. Adding 4,4¢-azo-biscyanovaleric acid put in carboxylic acid groups, and 2,2¢-azo-bis(2-amidinopropane) would make amino groups predominate on the surface of the molecule. More complex additives were possible. For example, the incorporation of 1 per cent 1-vinylamidazole in the microgel gave rise to the capability of binding haematin, and this complex would then take up carbon monoxide. The nanoparticles were very stable and monomer did not emerge, so there appeared to be no toxicity problems, and there were a variety of uses being investigated, such as synthetic blood. They were also capable of picking up specific metal ions at one pH, and giving them up at another, so they had potential as water-purifying devices. The author's particular example was the removal of lead, which the nanoparticles could hold at a level of 500mg per gram at pH8, falling towards zero at pH3.5.
Mimicking secretory vesicles A similar expanding and contracting nanoparticle delivery system was described by Professor D. NEEDHAM (Duke University, North Carolina, US). It was specifically designed as a result of the elucidation of the operation of the vesicles/granules that occured in the types of cell that produced secretions in the body. These secretory granules filled up within the cytoplasm, then released their accumulated contents in a burst when appropriately triggered. A heparin proteoglycan (molecular weight 100kDa) capable of forming a hydrogel that would collapse and contract under the influence of calcium ions was loaded with doxorubicin to as high a level as 2M. It was then converted into nanoparticles and collapsed to the small-diameter form before being coated with a lipid bilayer. As a dosage form, it could then be triggered by any convenient mechanism to expand, break the coating and produce a burst release of the drug.
The author showed a microphotographic film clip of a gel droplet protruding from the end of a horizontal 3mm diameter capillary tube, surrounded by an aqueous medium. A micromanipulator held a second, slightly larger, tube that could be moved past the droplet, from which emerged a solution capable of acting as a trigger. The droplet diameter changed in as little as 300milliseconds, recovering equally quickly when the triggering solution supply was moved away. For pH triggering, the drop was in the condensed state at pH3, and was expanded at pH6. The degree of swelling was controllable by altering the cross-linking of the original polymer. Other triggers included the use of ultrasound, and a process known as electroporation, in which the particles were subjected to an electric field. The membrane became porous when a potential difference of 1-3V was applied across it, but to achieve this for such tiny particle dispersions meant that a field strength of 4.5kV per centimetre must be applied to the suspension. A more useful triggering mechanism for therapeutic use would appear to be the equivalent of haemolysis, breaking down the membrane enzymatically. To this end, work was being carried out to incorporate suitable ligands into the membrane to facilitate attack by body enzymes. However, the main current problem was that, in the manufacture of the particles, there was only a 20 per cent efficiency of coating.
Inhalation technology The final paper of the symposium had the title "Inhale smarter not harder". It was given by Dr G. TAYLOR (University of Wales, Cardiff). In anaesthesia, which was a lung delivery system, there was always monitoring and feedback to ensure control, but in the delivery of powdered drugs from inhalers there was not. Admittedly, with the b-agonists there was feedback in the form of achieved relief, but with steroids even this was missing, so reliance must be placed on the delivered dose. Half of the inhalers in service were misused, particularly as most asthmatics were often poor coordinators of inhalation and firing. Breath-actuated devices had greatly improved this, with asthmatics typically increasing their therapeutically active dose from 7 per cent to 20 per cent by moving to the Autohaler. The Smartmist (Aradigm) got over many of the difficulties. It had a chip that could arrange firing at any point in the inspiration cycle and an LED to give the patient a visual confirmation of function. It included a measurement of peak flow rate. However, it was expensive.
Dry powder inhalers were effective, particularly if breath-actuated, but they used the inspirational effort to resuspend the drug, so the delivered dose was flow rate-dependent. With the Turbohaler, a 10-volunteer study showed that the quantity of drug reaching the lung was virtually doubled when the inspirational flow rate increased from 30 to 60L /minute.
Nebulisers were only convenient for stationary administration at home or in hospital, but they, too, had benefited from technological improvement. The Halolite Medic-Aid (Brighton) was an adaptive aerosol delivery device. It monitored the first three breaths taken, and then monitored on a rolling average of the next three. It administered the required dose as a pulse at the best point in the breathing cycle, and logged the quantity.
There was, the author concluded, room for improvement in all departments of aerosol technology.