Randomised controlled trials (RCTs) play a fundamental role in the development and marketing activities of pharmaceutical companies. They are the primary means of evaluating the tolerability, safety and efficacy of a drug, and for providing information relevant for pricing and reimbursement decisions and clinical decision-making. RCTs require a substantial investment by pharmaceutical companies and the financial consequences of poorly or sub-optimally designed trials are potentially substantial. Revenue does not materialise unless a licence to market a product is granted and sales may be restricted if a trial fails to provide evidence of sufficient strength or relevance for those involved in product adoption decisions. From a pharmaceutical company's perspective, the value of RCTs can therefore be judged on the contribution they make to the performance of a drug in the market and hence on their contribution to the performance of the firm. Consequently the design choices made in the planning of RCTs are effectively investment appraisal decisions. However, the application of investment appraisal techniques to RCT design has not previously been proposed. The purpose of this thesis is to consider how private sector investment appraisal methods might be applied to RCT design decision-making and to explore aspects of the practicalities of application. A general investment appraisal model is presented and its application to determine profit maximising RCT designs is illustrated. Considering the cost side of the investment appraisal equation, it is shown how decision-makers' requirements for cost-effectiveness evidence derived from trials could have a significant impact on the major determinants of cost (sample size and study duration) depending on their specific preferences for evidence defined over key components of RCT design. Considering the revenue side of the investment appraisal equation, it is shown how discrete choice analysis could be used to incorporate decision-makers' preferences for RCT designs into the planning of studies. Specifically, it is shown how the predicted probabilities derived from the application of this technique could be used within an investment appraisal framework. Directions for future research into the application of investment appraisal to RCT design are proposed.

The importance of communication skills for pharmacists has been widely acknowledged. Research has shown that the use of good communication skills can improve patient health outcomes but little research has focussed on communication within new consultation based roles of pharmacists. This study aimed to explore the communication between pharmacists and patients in clinic style consultations and to investigate participant perceptions of communication and consultations. Eleven pharmacists were recruited to the study and were responsible for the recruitment of patients from their own practice; five pharmacists recruited a total of 18 patients. A semi-structured interview was conducted with each pharmacist and with each patient before and after their consultation. Consultations were audio-recorded and observed and all recordings were transcribed verbatim. Thematic analysis based on the principles of grounded theory was conducted. Consultations were additionally coded according to the Calgary–Cambridge guide. NHS Ethics and local research and development approvals were obtained. The data show that patient reports of communication skills during consultations can lack detail, indicating that actual consultation data is required in order to assess communication skills. Pharmacists reported a lack of communication skills training and stated that additional training would need to be focussed on specific, relevant skills and should involve underpinning theory combined with observation of practice and personalised feedback. Pharmacists observed in this study used of a variety of methods for structuring consultations including official computerised or paper based forms, rehearsed segments of speech, and mental checklists. Some difficulties in using computers in a way that did not interfere with communication were identified. Further training may help pharmacists to more effectively structure their consultations. The participants reported that location has important effects on the communication within consultations. Both pharmacists and patients valued privacy in enabling open and honest consultations, particularly in community pharmacy. While it was reported that infrequent use of consultation rooms can lead to stigma being associated with private consultations, the data suggest that having a dedicated space for pharmacist-patient consultations is important. Application of the Calgary-Cambridge guide to recorded consultations showed good usage of many of the skills by the study pharmacists but skills linked to creating a patient centred consultation were under-represented. Some data did not correspond to a specific skill within the guide. Analysis showed the key theme of social conversation, which is essential for relationship building, was present in the non-coded data. Building up a relationship was reported by both pharmacists and patients as important in facilitating communication and that trust in particular played an important part in achieving successful consultations. The study methods enabled collection of rich data about pharmacist-patient communication. The data show that many factors can influence communication within consultations including pharmacist training, location, relationships, structure and use of computers. Pharmacists may need to think widely when aiming to achieve effective consultations. The data suggest that pharmacists made good use of communication skills during consultations but could improve use of the skills that create patient-centred consultations. The Calgary-Cambridge guide could be used to focus both training and research in this area.

This study has investigated the drug release mechanisms from hydroxypropyl methylcellulose (HPMC) hydrophilic matrices. A hypothesis was developed from interpretation of a previous study that drug surface activity has an influence on drug liberation. The validity of the hypothesis was tested by studying the interactions between HPMC and the two non-steroidal anti-inflammatory drugs diclofenac Na and meclofenamate Na, using tensiometry, rheology, NMR, neutron scattering and turbimetry. Meclofenamate Na was found to interact with HPMC, resulting in detectable changes in drug diffusion coefficients and polymer structure in solution. There were increases in HPMC solution solubility and changes in viscoelasticity, which suggested drug solubilisation of the methoxyl-rich regions of the polymer chains. Diclofenac Na did not show evidence of an interaction and exhibited changes consistent with a 'salting out' of the polymer. A confocal microscopy technique was used to image the drug effects on early gel layer development. The presence of drugs affected gel layer development, depending on the level of drug in the matrix and the concentration of sodium chloride in the hydration medium. Diclofenac Na matrices became increasingly susceptible to disintegration, while meclofenamate Na matrices exhibited resistance to the effects of sodium chloride. The influence of incorporated diluents on the gel layer was also investigated and it was found that lactose had a disruptive effect, whereas microcrystalline cellulose was relatively benign. When co-formulating drugs and diluents in the matrix, lactose acted to antagonise the effect of meclofenamate, but acted synergistically with diclofenac to reduce gel layer integrity and accelerate matrix disintegration. In contrast, MCC was found to have a relatively neutral effect on drug-mediated effects. HPMC particle swelling and coalescence are critical processes in gel layer formation extending drug release. Drug surface activity and capability of interacting with HPMC appears to influence particle swelling processes, affecting gel layer formation and provides a mechanistic explanation for the differing release profiles of diclofenac and meclofenamate Na.

The aim of this project was to characterize the surface properties of materials used in tablet formulations with sub-micron resolution by the techniques of Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), Scanning Thermal Microscopy (SThM), Nano-TA system, Differential Scanning Calorimeter (DSC), Attenuated Total Reflectance Infrared (ATR-IR), Near-Infrared Spectroscopy (NIR) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). In particular, the work aimed to develop new AFM based methodologies to advance this method both in terms of quantification and mapping. AFM was employed to investigate properties of solid materials such as surface free energy, Young’s modulus, melting point and phase transition temperatures from pharmaceutical materials in blend mixtures with the nanoscale resolution. These approaches developed here provide new tools to understand the process induced changes and stability issues in solid dosage forms such as tablets and inhalation formulations from minute amounts of materials. The surface free energy values of solid materials obtained from AFM adhesion force measurements were described in Chapter 3. The adhesion forces obtained with AFM in low relative humidity environments were used to derive the surface free energy values using the Hertzian and JKR based models. The surface free energy was proposed to be close to the so called dispersion surface free energy since the adhesion forces at low relative humidity mainly resulted from van der Waals forces in the systems studied here. The comparison of surface free energy between AFM and those derived from a contact angle method showed that the dispersion surface free energy values derived from the contact angle method were generally higher than those from AFM. For example, the surface free energy value derived from AFM adhesion force measurements for lactose monohydrate was 33.0 mJ/m2, while from contact angle method the value was 46.8 mJ/m2. Whilst in reasonable agreement, the variation was believed to result from the differences in probe substance (liquid in contact angle and solid in AFM method), scale of measurements (contact area 200 nm2 in AFM, several mm2 in contact angle) and possible polar interactions. However, the surface free energy values derived from direct solid-solid interactions in AFM adhesion force measurements may have more relevances in applications that relate to solid-solid interactions, such as in pharmaceuticals. The influence of polar interaction in AFM adhesion force measurements at low relative humidity was further investigated in Chapter 4. The techniques of colloid probe and plasma polymerized coating were employed: Plasma polymerized hexane and allylamine were coated on the surfaces of glass beads mounted on AFM cantilevers. Plasma Polymerized Hexane had only a dispersion surface free energy while plasma polymerized allylamine had both dispersion and polar surface free energy components. The differences in normalized adhesion forces between these two kinds of colloid probes can reveal the influence of polar interactions at low relative humidity in AFM adhesion force measurements. For most samples, the experimental adhesion forces with plasma polymerized allylamine colloid probes were smaller than the theoretical values calculated from dispersion interactions. The polar interactions in such conditions were repulsive so they had decreased the experimental adhesion forces. So in AFM adhesion force measurements, the polar interactions existed even at very low humidity. However the relative magnitude of polar interactions were smaller than the dispersion interactions and for silicon sample the polar interactions were negligible. In Chapter 5, properties including Young’s modulus, melting points and phase transition temperature were measured at the nanoscale with AFM, SThM and the nano-TA system. The variation of Young’s modulus with temperature, for the excipients hydroxypropylmethylcellulose (HPMC), dibasic calcium phosphate dihydrate (DCPD) was studied. The differences in Young’s modulus between DCPD and its anhydrous form were revealed with AFM measurements. The melting point and phase transition temperature were measured by nano-TA system with sub-100 nm spatial resolution. The thermal properties obtained from nano-TA system were consistent with those from bulk measurements using DSC: e.g. the dehydration of lactose monohydrate (150 ºC) was confirmed by nano-TA system and DSC measurements. In Chapter 6, the methods to derive surface free energy and thermal properties described in previous chapters were employed to spatially locate and characterize an API (AZD 3409 malate salt) and excipient (lactose monohydrate) on the surface of a model tablet at the nanoscale using AFM and the nano-TA system. The API and excipient were mixed with the ratio of 20:80. 50:50 and 80:20 w/w and compressed into discs to create the model tablets. The surfaces of model tablets were first characterized by ATR-IR, NIR and ToF-SIMS. Then AFM adhesion force measurements were carried out to map the location of each component in the mixed discs. In addition, in situ topography AFM images of the discs were recorded. At the position of force mapping, the nano-TA system was employed to correlate the thermal properties including the melting points of both materials and the dehydration of the lactose monohydrate with surface free energy information from force mapping. The surface free energy and thermal properties data were consistent with bulk measurements in previous chapters. In situ correlation between AFM force mapping (surface energy) and nano-TA system (thermal properties) at 5 differences positions on a model disc surface showed consistent identification of the two materials. This proof of principal work can be extended to more complex formulations and has the potential to be employed in early stage solid state stability testing to identify the appearance of new species at surfaces or solid-solid interfaces.

This thesis explores what UK community pharmacists experience as ethical problems in their work, how they try to resolve such problems and how the community pharmacy setting may be of influence. Utilising existing normative ethical theories, but acknowledging the status of empirical ethics research and also the social context of ethical problems, semi-structured interviews were conducted with a purposive sample of twenty three community pharmacists from the north of England, UK. It was found that pharmacists encountered ethical problems in the routine minutiae of dispensing prescriptions and medicines sales. Ethical problems often involved legal and procedural concerns and could be distinguished from philosophical dilemmas and many pharmacists understood law and ethics synonymously. Ethical passivity emerged as a description of pharmacists who were ethically inattentive, displayed legalistic self-interest and failed to act ethically. Ethical reasoning was often incomplete and involved appeals to consequences, the golden rule, common sense and religious faith. Some pharmacists were ethically active and sensitive to ethical issues and experienced ethical doubt and uncertainty. The code of ethics and the advice of professional bodies were not considered helpful. The community pharmacy setting precipitated ethical problems and was inimical to ethical practice since pharmacists' relative isolation from others precluded ethical discussion and relationships; pharmacists' subordination to doctors precipitated problems and vitiated ethical responsibility; routinization of pharmacists' work meant difficult ethical situations could be avoided. The findings of this thesis raise questions as to how pharmacists can be effectively educated in ethical issues at an under- and post-graduate level; how values can be adequately transmitted within the profession given the ineffectiveness of the code of ethics; whether pharmacists are ethically prepared for new primary care roles; and whether isolation and subordination may be ethically problematic in healthcare more generally.

The potential application of inkjet printing technology to produce precisely dosage care is demonstrated in this thesis. Inkjet printing technology as it offers the opportunity to deliver quantities with high accuracy can produce medicines tailored for each patient. The viability of this method was first demonstrated by using Felodipine as an active pharmaceutical ingredient polyvinyl pirrolidone (PVP) as an excipient. Felodipine is an antihypertensive drug which is poorly soluble in water and PVP is a highly soluble polymer commonly used to improve drugs' bioavailability. These were dissolved at various ratios in a mixture of ethanol and DMSO (95/5). Using a piezoelectric driven dispenser, picolitre size droplets of the solutions were dispensed onto suitable hydrophobic substrates. The dried products were characterized using AFM, localized nano-thermal analysis and high resolution vibrational spectroscopy (ATR-IR and Raman). Results indicate intimate mixing of the micro-dot API and excipient mixtures. Specifically, ATR-IR confirmed the interaction of felodipine and PVP by means of hydrogen bonding. Nanothermal analysis indicates a single glass transition point which is lowered as the API concentration increases. Finally, confocal Raman microscopy mapping on single droplets allows the visualization of the homogeneous distribution of the drug. Also, capozide has been used as a model therapeutic system which could be produced rapidly as a viable formulation using the inkjet printing technology. Capozide consists of captopril, an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic drug, in varying ratios. These active pharmaceutical ingredients (APIs) and poly(lactic-co-glycolic acid) (PLGA) were dissolved in appropriate solvents and using a piezoelectric driven dispenser and pipetting, picolitre and microlitre size droplets respectively were deposited onto hydrophobic coated glass slides. Captopril and PLGA were dissolved in chloroform, ethanol and DMSO (75/18/7). Hydrochlorothiazide (HCT) and PLGA were dissolved in acetone and DMSO (93/7). The dried products where characterised using AFM and high resolution Raman microscopy. The results showed that both capropril and HCT are phase separated with the PLGA. Also, the dissolution profiles of the final products were measured using HPLC where it has been shown that PLGA can control the release of the drug from the formulation. These results are a promising first step to produce pharmaceutical by means of inkjet printing.

Osteoarthritis (OA) is a chronic degenerative disease of the joint. Current treatments for this disease (such as glucocorticoid steroids) aim to reduce pain and increase mobility. Intra-articular injection is used in OA as treatment can be targeted to affected joints only. There is currently a lack of sustained release formulations for intra-articular injection. The aim of this thesis was to produce and characterise an injectable intra-articular drug delivery system capable of providing delivery of the steroid dexamethasone phosphate (DXMP) over 3 months. This would be an injectable hydrogel that contains drug loaded nanoparticles. Initially two systems Pluronic F127 gels and polyelectrolyte complexes between hyaluronic acid (HA) and chitosan, were investigated. The complexes between HA and chitosan were selected for the hydrogel portion of this system as they showed the greatest stability and promise in initial studies. To improve the polyelectrolyte complex properties a modified HA was synthesised. This modified polymer caused faster complex formation and produced stronger, more resilient complexes. DXMP was incorporated into poly(glycerol-adipate) (PGA) nanoparticles. A low but sufficient drug loading was achieved and particles were found to give a sustained drug release over 28 days. Nanoparticles were found to be efficiently incorporated and well retained within complexes. Nanoparticles slightly improved complex formation and properties. Composites were able to be formulated into an injectable form. Drug release from directly loaded complexes was rapid. A full release profile was not determined from composites of nanoparticle loaded complexes, however, over 60% of the loaded drug was recovered after 56 days of release study. Dexamethasone crystals were also incorporated directly into complexes to investigate the necessity of the use of nanoparticles. This gave a sustained drug release over 90 days making this system worthy of further investigation. These results highlight the different responses of these systems using drugs with different hydrophobicities.

In many low-income countries, the disease burden is high but health workers are scarce. To increase the number of health workers, one of the most urgent tasks is to produce more health workers. Grounded in the disciplinary focus of pharmacy, this research looks for alternative, innovative strategies to build the capacity of an education institution in a resource-poor setting. Malawi was chosen as a case study country because of its newly established pharmacy degree programme. A broadly ethnographic approach is employed in order to enhance cultural sensitivity and to understand capacity problems from an insider perspective. The fieldwork took place in 2010 and explored a wide range of pharmaceutical activities in the country. An interpretivist epistemology has also facilitated this research to cross beyond its science-based roots in the ‘human resource for health’ (HRH) research paradigm into other disciplinary areas, notably education and African Studies. The first objective of this study was to explore the roles of pharmacists in Malawi. It was agreed by all stakeholders that pharmacists should become managers of medicines, particularly at the district hospitals. Pharmacists were expected to solve the chronic problems of rampant drug pilferage and shortages in essential drugs. Although pharmacy technicians had traditionally assumed the managerial roles at district hospitals, they were deemed unfit for these roles at present day. Some were even accused of stealing drugs. This phenomenon was caused by multiple contextual factors, including a new perception about professionalism. Because of their professional titles, pharmacists were perceived to be superior to the pharmacy technicians in terms of knowledge, power and ethics. This perception was not supported by concrete evidence of pharmacists’ more superior behaviour. A deeper investigation revealed this perception was most probably shaped by colonial legacies and Western views. Home grown definition of professionalism was suppressed because it was not an agenda deemed important by the community of global health governance. The primary agenda by the global health governance to scale up service delivery, but ignoring the growth of domestic agendas for professionalism, may need reconsidering in post-Millennium Development Goal era. The second objective of the study was to explore capacity problems in pharmacy education in Malawi. Capacity problems faced by the education institution were found to be similar to problems reported in the wider literature of African higher education, which include underfunding, understaffing, lack of university autonomy from the state, small student intake and hence high unit costs. There were also serious problems concerning leadership and accountability. Rather than simply filling up these capacity gaps, this study argues that it is more important to see how the problems are closely linked with local contexts. Several cultural contexts, for instance regionalism and traditional practice of witchcraft, were found to be strong divisive factors threatening cohesiveness in an institution. The euphoria for personal freedom, after a 30-year dictatorship, still had its impact on governance and accountability. Colonial legacies and donor policies, which were often interventionist, left little space to inspire creativity and leadership. To link contexts to capacity building, this research argues for the importance of using an interdisciplinary approach. In fact, the journey of how this study evolved from single to an interdisciplinary was recorded in this thesis. The third objective of the study was to explore stakeholders’ opinions and interests toward supporting capacity building in pharmacy education. Although the study did identify several groups of domestic stakeholders who were able to mobilise resources for the benefits of the education institution, a more serious capacity problem was the absence of initiative from the education institution to engage these stakeholders. However, institution was more eager to engage with foreign stakeholders. Closely linked to the culture of aid dependency, foreign aid was found to have the greatest influence on institutional capacity building. Hence, the question about whether aid is good or bad, as well as how to make aid work, becomes one of the emphases of this research. This study argues that aid does not need to be big, but to be genuinely helpful.

The oral route for drug administration offers an efficient and convenient method for drug delivery. However, there is an assortment of drugs which exhibit narrow absorption windows in the upper small intestine and as a result demonstrate limited bioavailabilities. One approach in the improvement of bioavailability in these cases is to retain the delivery system proximal to the absorption window for a prolonged period of time. Although controlled release products are widely available on the market, marketed gastroretentive systems remain elusive. This work explores the manufacture and characterisation of a multi-unit gastroretentive system utilising the biocompatible polymer poly (lactic-coglycolic acid). The novel PGSS technique enables the production of PLGA particles whilst omitting the use of volatile organic solvents. Morphological and microCT analyses of the particles revealed a highly porous matrix with porosity values in the order of 30-40%. The relationship between porosity, density and in vitro floating ability for particles with sizes between 100-2000 J.1m revealed that particle size plays an important role; larger microparticles possess decreased density, higher porosity and increased buoyancy. Encapsulation of two model drugs, riboflavin and furosemide, was carried out during the processing step with high encapsulation efficiencies (80-100%) being revealed. Release of the drugs in PBS (pH7.4) was found to be sustained over a period of 24 hours with a decrease in cumulative release in simulated gastric fluid (pHl.2). The introduction of the hydrophilic polymer poly(ethylene glycol) was found to modulate release rate; PEG with a molecular weight equal of more than 3 KDa increased the rate of release in PBS media up to 20% over hrs, however this was not observed for release in SGF. A comparison of morphology prior to and following exposure to the release media confirms that the emergence of intricate porous channels on exposure to the release medium is related to an increase in release rate. In order to augment the gastroretentive potential of the system the mucoadhesive polymer, chitosan was incorporated both as a post processing surface modification and as part of the initial formulation. ToF-SIMS surface analysis confirmed the presence of chitosan at the surface of the particles in both cases. Initially the potential for the particles to interact with mucus was evaluated utilising in vitro tests. The presence of chitosan significantly improved adsorption of mucin to particles, as well as enhancing adhesion of particles to a mucus producing epithelial cell layer. The thiolated chitosan derivative chitosan-N-acetyl-cysteine demonstrated an increase in adhesion of mucin solution; however the modified chitosan resulted in a decrease in adhesion to mucus producing cell line which was considered to be a result of the mucolytic actions it may exert on the mucus layer. Oral administration of buoyant particles to a rat model improved the pharmacokinetics of the anti-hypoglycaemia drug metformin, with addition of mucoadhesive properties providing further improvement. This study demonstrates that introduction of buoyancy and mucoadhesion functionalities to particles prepared by the PGSS method could improve delivery of drugs demonstrating narrow absorption windows in the upper small intestine.

The blood-borne virus, hepatitis C (HCV), is causing an increasing burden of chronic and terminal liver disease, world-wide. The development of successful drug treatments for this infection has been hampered by the lack of an efficient and physiologically relevant in vitro model of viral pathogenesis. The recent characterisation of the JFH1 clone of HCV, which is capable of both infection and replication in some types of cell lines, has revolutionised the potential of in vitro HCV research. Yet very few studies have been able to investigate the pathogenesis of HCV in normal, healthy hepatocytes, and none has examined the effects of such infection on other human liver cells. This thesis presents the techniques and results of work to optimise human primary liver cell cultures, in order to permit investigation of the JFH1 clone of HCV. A protocol was developed for the isolation of healthy human hepatocytes from surgically resected liver tissue. Methods for the non-viral transfection of primary hepatocytes were then optimised and compared. Finally, the expression of a JFH1 replicon (incorporating the luciferase marker gene) was assessed in human primary hepatocytes, both in monoculture and in three-dimensional co-culture with hepatic stellate cells (HSCs). The level of expression of the JFH1 replicon in human primary hepatocytes was considerably lower than that found in the human hepatoma Huh7 cell line, as expected, and highly dependent upon the batch of primary cells used. Hepatocytes which were grown in co-culture with HSCs showed some evidence of a greater capacity to support the translation and replication of JFH1. Luciferase was largely undetectable by 48 hours, particularly in hepatocyte-HSC co-cultures, suggesting that innate anti-viral mechanisms are preserved in these cultures. Further studies, to examine the intriguing dialogue between these models and JFH1, now have the potential to provide unique insights into the pathogenesis of HCV in the human liver.