This doctoral thesis reports on a longitudinal, mixed methods investigation of staff and students’ views, expectations, and experiences of a collaborative pharmacy programme between Cardiff University School of Pharmacy and Pharmaceutical Sciences (CU) and Taylor’s University School of Pharmacy (TU). Despite a growing body of empirical research on transnational staff and students’ expectations and experiences, longitudinal mixed methods studies are rare. This study combined a qualitative interview-based and focus group approach with a quantitative questionnaire-based method. The overall aim is to gain a better understanding of the teaching and learning experiences of staff and students in a transnational education (TNE) programme. The qualitative element explored staff expectations and experiences in the early stage of the collaborative programme while student expectations and experiences were investigated at different points in time throughout their 4-year pharmacy study. The quantitative element investigated and compared the learning environment perceived by participating students in TU and CU. Data collection took place over a period of 36 months and comprised four phases. In Phase 1, staff and students’ initial expectations and experiences of a new collaborative pharmacy programme were explored using staff interviews and student focus groups. In Phase 2, a sample of students from CU and TU were recruited to participate in a questionnaire study to assess students’ perceived learning environment. In Phase 3, a number of studies were carried out using focus groups in order to find out students’ pre-arrival expectations and post-arrival experiences. Phase 4 involved a self-administered questionnaire with graduate students to assess students’ opinions about their overall experiences at the universities. The study revealed staff and students' expectations and their actual experiences in relation to the delivery of a transnational education. It was found that those students who participated were able to cope with sociocultural adjustment in a new learning environment. The study also provided indications of the need for training and professional development for staff to teach in a transnational environment. Finally, Malaysian students who come from a teachercentred pedagogy background should be informed and trained earlier before their transfer to lessen the impact brought about by intercultural differences in teaching and learning.

Central obesity is a complex cardiometabolic entity strongly linked to the constellation of risk factors such as insulin resistance, hypertension, dyslipidaemia and physical inactivity, which when combined lead to an increased risk of type 2 diabetes and cardiovascular disease. The available evidence suggests that these conditions are linked to microvascular dysfunction, which may appear much before the onset of overt cardiovascular and metabolic disease. However, in apparently healthy but viscerally obese subjects, little is known about the interactions between cardiometabolic risk factors, including microvasculature, which could be potential targets for early therapeutic intervention. Statins are attributed to have pleiotropic properties, but their effects on insulin resistance and microcirculation are still uncertain. The hypotheses for this study were that in centrally obese but non-diabetic subjects: • Skeletal muscle exchange capacity influences levels of HbA1c. • Diminished insulin sensitivity in skeletal muscle is associated with reduced microvascular exchange capacity. • Microvascular functional dilator capacity is independently associated with insulin sensitivity and age. • Six months of treatment with high dose statin improves insulin sensitivity and reverses microvascular dysfunction. • Cardiorespiratory fitness is independently associated with cardiac diastolic function and arterial stiffness. A double-blinded, randomised, placebo controlled trial was conducted in white Caucasians aged 29-69 with abdominal obesity and a cardio-metabolic phenotype. Insulin resistance was assessed by stepped hyperinsulinaemic euglycaemic clamp and fasting insulin sensitivity indices. Microvascular function was examined with venous congestion plethysmography and Laser Doppler Fluximetry. It was demonstrated that in centrally obese, non-diabetic subjects with modest insulin resistance, skeletal muscle exchange capacity was associated negatively and independently with HbA1c, positively and independently of visceral fatness with insulin sensitivity, and that functional dilator capacity was strongly and positively associated with insulin sensitivity and age, independently of each other. Six months of intensive treatment with Atorvastatin did not improve insulin sensitivity or microvascular function. A strong association was shown between cardiorespiratory fitness and measures of diastolic function and arterial stiffness. In conclusion, this thesis presented novel aspects of cardio-metabolic factors and microvascular relationships, which indicate the early onset of microvascular dysfunction in obesity and the importance of fitness in maintaining arterial flexibility and cardiac diastolic function. Atorvastatin has no role in improving insulin sensitivity and reversing microvascular dysfunction.

Staphylococcus epidermidis biofilm formation is a primary cause of medical device infections, which are persistent and difficult to eradicate because biofilms intrinsically exhibit a naturally high level of antibiotic resistance. Although biofilm antibiotic resistance or tolerance is a multifactorial process, some mechanisms such as limited diffusion, low metabolic activity and persister cells, contribute to the failure of antibiotics in the treatment of biofilm infections. Current, antibiotic treatment strategies may provide biofilm infections with intermittent exposure to sub-minimum inhibitory concentrations (sub-MIC) of antibiotics. Biofilms have been shown to display an increase in antibiotic tolerance when exposed to antibiotics at sub-MIC. Such mechanisms of adaptive antibiotic resistance are not well characterized but are of extreme clinical importance. This project showed that exposure to sub-MIC vancomycin increases the virulence of S. epidermidis biofilms because it induces vancomycin tolerance. BODIPY FL-vancomycin (fluorescent vancomycin conjugate) and confocal microscopy were used to show that the penetration of vancomycin through sub-MIC vancomycin pre-treated S. epidermidis biofilms was impeded, when compared to control, untreated biofilms. In addition, the results showed that a wide range of sub-MIC vancomycin concentrations induced an increased amount of extracellular DNA (eDNA) within the matrix of sub-MIC vancomycin treated biofilms. Finally, a set of ex vivo experiments using extracted exogenous S. epidermidis DNA revealed that exogenous S. epidermidis DNA binds vancomycin. Collectively these findings suggest that sub-MIC vancomycin exposure increase the abundance of eDNA in the matrix of S. epidermidis biofilms, which protects the biofilm community from subsequent vancomycin exposure by binding vancomycin as it travels through the matrix. Therefore the work in this project provides details of an eDNA-based mechanism of adaptive antibiotic tolerance in sub-MIC vancomycin treated S. epidermidis biofilms, which might be an important factor in the persistence of biofilms infections.

Hospital discharge is a complex process that can result in errors and delays for patients, particularly around the supply of medicines and communication of information. This programme of work (PoW) aimed to develop an innovative model of care for the supply of medication at hospital discharge to provide safe, quality and effective transfer for patients from hospital to community care. The PoW consisted of four phases which used both quantitative and qualitative approaches. Phase 1 involved semi-structured telephone interviews with 13 Chief Pharmacists. Analysis identified the current discharge process across the range of hospitals as well as key issues and examples of good practice at discharge. Discharge processes were similar across hospitals with issues common to all. Phase 2 used questionnaires to establish patient perceptions of the current discharge process in a large city-centre teaching hospital. The 104 inpatients recruited were 60% (n=62) male, average age was 55 (range 19-93), from both medical and surgical wards. Most patients, 89% (n=87) were satisfied with their hospital discharge but believed it took too long. The perceived main cause of delay was waiting for medicines. Other highlighted issues included limited counselling by pharmacists and a need for more patient involvement at discharge. Phase 3 utilised findings from phases 1 and 2 to inform the development of a new model of care for patient discharge. Phase 4 consisted of semi-structured interviews and focus groups with stakeholders in patient discharge (n=37), to evaluate the proposed new model of care. Stakeholders successfully evaluated the new model, highlighting areas of the new model of care that would work well and where problems may arise. The model of care was refined based on these findings, with the suggestions for overcoming logistical issues considered. The PoW successfully developed an innovative model of care for patient discharge.

Topical drugs are not developed by the same process as oral drugs. The process is more uncertain and contains gaps. This leads to a poor discharge of risks before going to the clinical phases. The topical drug development process is reviewed in the introduction of the thesis. In particular, past and current topical drug development practices are described and compared to the oral drug development process. The large risks taken during the topical drug development are pointed out. These risks are largely associated with a lack of pharmacokinetic's involvement prior to the drug candidate selection stage. Pharmacokinetics is considered after drug selection when it is often too late. Furthermore, the topical pharmacokinetic techniques available appear to be not suitable for three reasons: accessibility to the pharmacokinetic techniques, meaning of the data generated and reliability of these data. It concludes that the knowledge of target skin tissue concentration would be key for a more rational drug development process. To this end, the primary objective of this thesis is to define a way of measuring drug concentration in skin tissue after topical application that is reliable, effective and practical. A secondary objective is then from the knowledge of the skin tissue concentration, to develop a topical PharmacoKinetic/PharmacoDynamic model to predict likely efficacy for a topical drug candidate. First a direct skin tissue concentration approach is described that brings theoretical reliability into the pharmacokinetic data generated and improves throughput. However the pharmacokinetic data generated have limited use as total drug (bound + unbound) tissue concentration is measured while, pharmacodynamically, only the unbound fraction is of interest. An indirect skin tissue concentration determination is then proposed. It consists in predicting the in vivo unbound drug concentration in diseased skin tissues. Three steps are required: In the first step, the in vitro percutaneous flux is linked with the unbound drug concentration in the dermis. From there, the in vivo unbound drug concentration in all the skin tissues is defined using different physiological parameters. Finally, taking into account the effect of the skin disease on skin permeability and dermal capillary clearance, the in vivo unbound drug concentration in skin tissues in diseased skin is defined. The predicted concentration is therefore calculated from a constant (which is skin disease dependent) and from the in vitro percutaneous flux (which is an accessible and reliable experimental pharmacokinetic data). A PharmacoKinetic/PharmacoDynamic model is then built. This model delivers two types of information: -1- The "efficacy index" which is a prediction of efficacy for a drug candidate based on percutaneous flux and drug potency and -2- the "systemic safety index" which is an assessment of systemic exposure based on total systemic clearance and plasma protein binding. To check the validity of this new model, a validation exercise is run with the key eight topical drugs classes: NSAIDS, anaesthetics, retinoids, corticosteroids, vitamin D3 derivatives, antifungals, antibacterials for acne and immunomodulators. For seven out of the eight classes, the validation of the model is good. For the last class, the antibacterials for acne, the model underpredicts efficacy and it is suggested that the route of entry of antibacterial agents in acne occurs via the sebaceous duct as opposed to the more classic stratum corneum pathway. Finally, three pilot studies are conducted with the aim to improve the quality and relevance of the data generated with in vitro percutaneous flux studies as well as the access to this technique and throughput of this technique.

The existence of polymorphic forms of drug substances has implications for therapeutic performance, handling and storage. This study investigates the development of a novel approach to surface analysis of drug polymorphs, with the aim of extending the capabilities of this approach to perform real time analysis of polymorphic transformation during pharmaceutical product development. This was achieved here, using diffuse reflectance visible spectroscopy (DRVS) and the colour change which occurs when pH indicator dyes are deposited on the surface. The pH indicators used were phenol red (PR), thymol blue (TB) and methyl red (MR). Two polymorphs each of indomethacin (IMC), carbamazepine (CBZ), caffeine (CFN), sulfanilamide (SFN) and furosemide (FRS) were examined. The interaction of the adsorbed dye with each of the polymorphs showed different behaviour, manifested by different colours. An analysis of the crystal structures and the acid/base properties of the drug molecules provided a rationalisation for the different colours exhibited by the polymorphs‘ surfaces. The least stable form of each polymorphic pair studied showed more extensive interaction with the adsorbed dye molecules. Observed colour reveal underlying differences at a molecular level between the surfaces of pairs of polymorphs. The different colours exhibited by the indomethacin polymorphs were further examined using hygroscopicity studies, contact angle measurements and computer simulation. The contact angles of several liquids with the polymorph surface were measured in order to characterise the nature of the functional groups exposed on the surface of the polymorphs. The surface structure and external morphologies of polymorphs were predicted by molecular modelling using the attachment energy model. The predicted morphology was confirmed by scanning electron micrographs (SEM) and the miller index of the dominant face was confirmed by X-ray powder diffraction (XRD). Results revealed that although the surfaces of both polymorphs are largely hydrophobic, the metastable form- IMC-α has a greater number of polar functional groups on the surface. Further measurements were carried out using DRVS and adsorbed TB to study the kinetics of the solid-state transformation of SFN- to SFN-. The rate of transformation was followed at 128ºC by monitoring the ratio of the two DRVS bands at 454 nm and 604 nm. The kinetic data was analysed using sixteen solid-state kinetic models to obtain the best fit. The thermally induced polymorphic transformation of the SFN-β (particle size of ≥ 450μm) can be best described by the first order kinetic model (R2 = 0.992) with a rate constant, k of 2.43 x 102 s-1. The DRVS instrument used herein is not adapted for in situ studies; however, because of its non-destructive interaction with the sample and rapid data collection time of 5s per spectrum, it does offer considerable potential as a tool for real time monitoring of polymorphic transformation.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia de Produção. / Made available in DSpace on 2013-07-16T01:45:29Z (GMT). No. of bitstreams: 1 261825.pdf: 2471716 bytes, checksum: 7dd76bf16259254a2f73b2a143b57d9b (MD5)

Conventional adult dosage forms such as tablets and capsules are often not suitable for the paediatric and geriatric population due to either swallowing difficulties or a requirement for tailored dosing to meet individual needs. Alternative oral formulations such as orally disintegrating tablets (ODTs) are available; however these usually require the incorporation of taste masking techniques. One approach to taste masking is to reduce contact between the bitter active pharmaceutical ingredient (API) and taste buds. This may be achieved by hindering release in the oral cavity using reverse enteric polymeric coatings. In vitro dissolution testing can be employed to elucidate taste masking capability by quantifying release of the API in simulated oral cavity conditions. This provides a robust analytical approach circumventing the expense and ethical challenges associated with human taste testing panels or animal testing. To achieve taste masking, drug release should be below the bitterness threshold concentration of the API. A vast array of dissolution methodologies has been employed in the evaluation of taste masked formulation performance in literature, with little agreement between approaches, and a lack of biorelevance. For optimal predictability, the dissolution test should be biorelevant and the dissolution media should mimic human saliva as closely as possible. Human saliva is thus a biological fluid of great importance in the field of dissolution testing. However, until now, no consensus has been reached on its key characteristics relevant to dissolution testing. As a result, it is difficult to select or develop an in vitro dissolution medium to best represent human saliva. In this thesis, for the first time, the pH, buffer capacity, surface tension, viscosity and flow rate of both unstimulated (US) and stimulated (SS) human saliva were investigated with a sufficient number of participants to generate statistically meaningful results (Chapter 3). This provides a platform of reference for future dissolution studies using simulated salivary fluids (SSFs).

Pharmacists in Jordan are greatly positioned to play a key role in shaping the future direction of the country’s healthcare system, particularly in terms of improving patient and health outcomes. However, the available literature reports a number of problems affecting the Jordanian pharmacy sector across the professional practice, education and regulation spheres; issues which have been hindering the adequate provision of pharmaceutical care services, as well as the overall development of the profession. This study aims to examine the current status of the pharmacy profession in Jordan, notably in terms of the challenges and opportunities it faces, with a particular focus on the educational sector. To that end, a mixed methods approach was employed in which a series of studies were conducted. In the first study, semi-structured interviews and focus group sessions were carried out to identify and explore the main challenges facing the profession. Interview transcripts were thematically analysed, with eight principal ‘challenge areas’ being identified. These results were validated by focus group findings, and tailored recommendations were produced to address each challenge. In the second study, data from the Official National Register of pharmacists were obtained, collated and analysed, so as to establish workforce trends. Geographical, sectoral and gender distribution imbalances were identified; gaps in the current workforce intelligence were also highlighted and discussed. The third study employed a set of surveys to collect academic and institutional capacity information from pharmacy schools in Jordan. Surveys were completed using data triangulated from multiple sources (including official documents, schools websites and dean interviews). In the final study, a secondary qualitative content analysis of the interview transcripts was undertaken to identify gaps in pharmacy graduates’ skills and competencies. The Global Competency Framework for pharmacy was used as the starter coding framework. Sixty eight (68) behaviours from across the Framework’s four competency domains were identified by participants as lacking in graduates. As such, this thesis represents the first holistic investigation of the status of the pharmacy profession, workforce and education in Jordan, including the opportunities and challenges faced by the sector. This work’s original contribution to knowledge lies not only in the new baseline information produced, but also in the evidence-based guidance and recommendations presented to local stakeholders and researchers.

The popularity of dry powder inhalers (DPIs) to deliver drugs to the lungs is constantly increasing thanks to their advantages over nebulisers and pressurised metered dose inhalers (pMDIs), including the high stability of dry powders, avoidance of propellant gases and ease of use. DPIs generate dry powder aerosols that deposit on the lung mucosa upon inhalation. In order to achieve the desired therapeutic outcome, drug particles must first dissolve in the lung lining fluids, then diffuse across these fluids to reach the epithelium and be absorbed. The fate of inhaled particles once deposited on the lung surfaces has not been yet fully understood. However, the particle physicochemical properties are believed to play a role on their dissolution, interaction with lung lining fluids and permeability across the lung epithelium. The main aim of this doctoral thesis was a better understanding of the relationships between drug particle physicochemical properties and their fate in the lung tissue in terms of dissolution and drug absorption. Increased knowledge in this area would indeed assist the development of novel and more effective inhaled medications. The first objective was the development and validation of a simple and low cost deposition system to apply aerosolised dry powder particles in a narrow size range and a controlled dose to both epithelial and non-epithelial lung models (Calu-3 cells grown at the air-liquid interface (ALI) and airway mucus) for in-vitro studies. The deposition system consisted of a vacuum desiccator fitted with a PennCentury Dry Powder Insufflator™ – Model DP-4 without the needle but equipped with a PennCentury Air Pump™ – Model AP-1 (Penn-Century. Inc. Wyndmoor, PA). We demonstrated that it was able to homogeneously disperse different types of dry powders (micronised and spray dried), and consistently deliver controlled doses of drug in a narrow particle size range (3-5 µm). However, the system presented a major limitation as no real separation between respirable (< 10 μm) and non-respirable (>10 μm) particles could be achieved. The system was then exploited to investigate the effect of the formulation on drug absorption across Calu-3 cell layers. Salbutamol sulfate and indomethacin, respectively in class III (high solubility, low permeability) and II (low solubility and high permeability) of the Biopharmaceutical Classification System (BCS), were chosen as model dry powders. It was demonstrated that for both drugs, a dry powder formulation led to a faster absorption across Calu-3 layers than their solution counterpart. Indomethacin was more permeable than salbutamol in either case, proving that our system was capable of discriminating between drugs with different permeability profiles according to the BCS. Indomethacin low water solubility did not limit its absorption. Accordingly, the potential of novel indomethacin formulations produced by colleagues at University College London (UCL) as platforms to improve the absorption of poorly soluble drugs could not be appreciated. In the case of salbutamol, we attempted to gain a better understanding of its mechanism of absorption through the lung epithelium, particularly when delivered as a dry powder. The data showed that Organic Cation Transporters (OCT) are likely to contribute to salbutamol absorption when applied in solution, but no valid conclusions could be drawn when the drug was delivered as dry powder due to Calu-3 cell layers being disrupted during the course of the experiment. Finally, the role of mucus on salbutamol and indomethacin particle dissolution and drug absorption was investigated. A system consisting of a thin mucus layer coating Transwell® insert membranes was developed. Drug permeation across the mucus layer was monitored and compared with that across the Calu-3 cell layers. The rate of permeation of salbutamol sulfate and indomethacin across the three barriers investigated (clean Transwell® inserts, mucus layer and Calu-3 cell layers) followed an opposite order (clean insert > mucus layer > Calu-3 cell layer for salbutamol sulfate, Calu-3 cell layer > mucus layer > clean insert for indomethacin), demonstrating that the mucus was acting as a barrier in the case of salbutamol, but conversely promoted dissolution of indomethacin particles. A contribution to the clarification of the role of the mucus was made with the identification of some of the parameters that affect drug-mucus interaction: ionisation and lipophilicity. Solubility in water did not seem to have the same impact as for oral delivery. In this respect, we showed that the BCS, which only takes into account drug solubility and permeability, was a non-adequate description for the prediction of the behaviour of indomethacin in the lungs.