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Hydrogel-forming microneedles (MN) were fabricated and evaluated for transdermal therapeutic monitoring of glucose as an endogenous biomarker model and two drugs, sodium valproate, as an anion model drug, and lithium as a cation model drug. A range of hydrogel-forming materials were characterized and evaluated to identify the most suitable formulation for fabrication of MN suitable for transdermal TM. MN contain no drugs themselves, upon insertion into skin they can rapidly imbibe ISF and undergo a transition to form discrete in situ hydrogel bulbs while maintaining their structural integrity and removed intact from the skin. Drug can thus diffuse through the swollen MN, which act as a continuous unblockable conduit between ISF and MN matrix. Hydrogel-forming MN were prepared from an optimised aqueous blend containing 11.1% w/w poly (methyl vinyl ether maleic anhydride) (Gantrez AN139), 5.6% w/w poly (ethylene glycol) (PEG 10,000). Successful transdermal extraction and detection of glucose was achieved in vitro through neonatal porcine skin and in vivo from healthy human volunteers. In vitro glucose was detected following application for 5 minutes but in vivo glucose was detected from MN applied for 1 hr. Results showed good correlation to blood glucose concentration with a lag time of 1 hr. Sodium valproate extraction was unsuccessful in vitro and was limited by the chemical nature of the drug, the MN fabrication material and the negative charge of the skin, in addition to the sensitivity of the analytical method. Finally, lithium was successfully extracted in vitro and in vivo from Sprague Dawley rats and gave a good reflection of picture of lithium serum level. In the view of these promising findings, with current work focusing on further optimisation of this technology, the future seems bright for a hydrogel-forming microneedle-based diagnostic and monitoring tool.

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During the past decade there has been a considerable increase in the number of antibiotics to which bacteria have become resistant. Dissemination of antibiotic resistance is attributed to horizontal gene transfer, principally by the process of conjugation. This investigation sought to assess the potential for dissemination by measuring the frequencies of conjugation of antibiotic resistance markers amongst micro-organisms of the gastrointestinal tract particularly gene transfer between Gram-positive and Gram-negative bacteria. Conjugation experiments utilising filter matings showed the ability. of Gram-positive plasmids pIP50 I and pRE39 to conjugally transfer and disseminate antibiotic resistance between a wider range of Gram-positive food-borne pathogens and food processing bacteria than had been reported previously. By contrast the previously reported conjugal transfer of pIP501 from Gram-positive Enterococcus faecalis to Gram-negative Escherichia coli (Kurenbach et af. 2003) could not be confirmed. However, chloramphenicol resistant colonies of E.coli were produced following attempted filter matings using Gram-positive Efaecalis as donor. Stringent analyses of these E.coli strains produced both in this study and by Kurenbach et af (2003) found no evidence for the presence of pIP50 I-derived sequences or the chloramphenicol acetyl transferase (CAT) antibiotic resistance gene product. Further investigations determined that the presence of certain chloramphenicol resistance plasmids was required in Gram-positive Efaecalis to facilitate the isolation of chloramphenicol resistant E.coli colonies. Subsequent proteomic analyses of these chloramphenicol resistant E.coli mutants revealed a change in level of expression ofTolC and Sip consistent with constitutive expression of the marRAB operon responsible for multiple antibiotic resistance due to efflux. Therefore it appears that Gram-positive bacteria may contribute to the dissemination of antibiotic resistance without the requirement for horizontal gene transfer by facilitating the induction of an intrinsic antibiotic resistance phenotype in Gram-negative bacteria.

It has been over 2000 years since the first mechanochemical reaction was recorded, and while there has been great advancement in the field, there remains a general lack of understanding of the processes at the molecular level. This thesis aims to begin to develop an understanding of these processes, by studying the mechanochemical co­crystallisation of aspirin and meloxicam, from experimental and modelling approaches. Experimentally, it is shown that contrary to the original mechanosynthesis, in which the liquid assistant chloroform was required, that the desired co-crystal can be formed under neat grinding conditions, with a grinding frequency of 25 Hz. It is then demonstrated that the addition of 0.1 mol. equiv. of chloroform to the system allows the reaction to be performed with a grinding frequency of just 10 Hz. From the perspective of computer simulation, aspirin, meloxicam and their 1:1 co-crystal are successfully simulated using both density functional theory and force field methods. This is evidenced by the accurate calculation of various physical properties of the systems, including the formation energies, assorted surface energies and the bulk moduli of aspirin and meloxicam along with the cohesive energy of the co-crystal. Then, two studies are performed using force field molecular dynamics, the first of which shows that the phenomenon of localised heating is minimal in the mechanochemical co-crystallistaion reaction. The second, shows that the relative orientation of molecules changes the efficiency of the transfer of material between the two species and that partial solvation of the system, with chloroform, does not affect the transfer efficiency. It is suggested that chloroform’s role in the reaction is performed at a later stage, i.e. after the materials have become thoroughly mixed. This work will help us to understand the processes that occur at the molecular level during a mechanochemical reaction.

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