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.

The importance of localised delivery of chemotherapeutic drugs for cancer treatment and specifically solid tumours has been widely reported. In this study, the anticancer drug N4-myristoyl gemcitabine (a lipophilic form of gemcitabine) was formulated as organogel to achieve a localised depot delivery. Thus, the first goal of this study was to evaluate the suitability of the oragnogel for intartumoural injection and this attained by investigating the thermostability and elasticity of the organogel. Further to this, the second goal was to slow the release of N4-myristoyl gemcitabine from the organogel. Accomplishment of these two goals will guarantee a better efficacy of cancer treatment by obtaining direct contact of the organogel containing the N4-myristoyl gemcitabine with the cancerous cells. The studies herein selected the 12-hydroxystearic acid (12-HSA) as the gelator and using 2 types of solvents the liquid part of the organogel. The first type of solvent was a series of oils which were soybean oil (SO), medium chain triglyceride (MCT), glyceryl tributyrate (TGB) and glyceryl triacetate (GTA) whilst, the second type of solvent was propylene glycol (PG). Initially thermal stability was screened using table top rheology and DSC from 0.5% to 5% w/w 12-HSA in different oils. Also to test the mechanical strength of the organogels, amplitude sweep, frequency sweep, time dependant recovery and creep and recovery tests were executed to differentiate between the organogels. The best organogels were the 5% w/w 12-HSA in SO and MCT due to their highest thermal stability, denser scaffolds, thixotropic behaviour and were the least compliant. The same experiments were utilised to evaluate the selected range of 0.5% to 14% w/w 12-HSA in PG. 14% w/w 12-HSA in PG was selected again due to its higher thermal stability, thixotropic behaviour and was less compliant compared to other concentrations of 12-HSA in PG. Drug release from the selected organogels was then carried out. The cumulative percentage released from 0.5% and 0.3% w/w N4-myristoyl gemcitabine in 5% w/w 12-HSA/MCT organogels as a solid organogel was 18.95% and 26.62% after 30 days whilst for the organogel liquefied with N-methyl pyrrolidone (NMP), the cumulative percentage released was 35.02% and 34.37% within the same frame time. Further to this, a sample and separate release method was used to study the liquefied form of the 5% w/w 12-HSA/MCT. Also, this method revealed that the 5% w/w 12-HSA/MCT organogels gave a slow release of N4-myristoyl gemcitabine and 56.18% and 70.07% was released from the 0.5% and 0.3% w/w selected organogels respectively within 30 days. For the 14% w/w 12-HSA in PG organogel, the cumulative percentage released for 0.5% and 0.3% w/w N4-myristoyl gemcitabine in 14% w/w 12-HSA/PG organogels was 26% and 40% respectively after 30 days. To conclude, our selected organogels (5% w/w 12-HSA/MCT and 14% w/w 12-HSA/PG) met the goal of our work firstly, by showing the strength and the elasticity to be injected. Secondly, they were able to slow down the release of N4-myristoyl gemcitabine.

Extrusion based three dimensional (3D) printing is defined as a process used to make a 3D object layer by layer directly from a computer aided device (CAD). The application of extrusion based 3D printing process to manufacture functional oral solid tablets with relatively complex geometries is demonstrated in this thesis. In Chapter 3 the viability of using a basic desktop 3D printer (Fab@Home) to print functional guaifenesin bilayer tablets (GBTs) is demonstrated. Guaifenesin is an over the counter (OTC) water soluble medicine used as expectorant for reduction of chest congestion caused by common cold and infections in respiratory system. The bilayer tablets were printed using the standard pharmaceutical excipients; hydroxypropyl methyl cellulose (HPMC) 2208, 2910, sodium starch glycolate (SSG), microcrystalline cellulose (MCC) and polyacrylic acid (PAA) in order mimic the commercial model formulation (Mucinex®) guaifenesin extended-release bilayer tablets. The 3D printed guaifenesin bilayer tablets (GBTs) were evaluated for mechanical properties as a comparison to the commercial GBTs and were found to be within acceptable range as defined by the international standards stated in the USP. Drug releases from the 3D printed GBTs were decreased as the amount of HPMC 2208 increased due to the increased wettability, swelling properties and gel barrier formation of the HPMC. The 3D printed GBTs also showed, as required, two release profiles: immediate release (IR) from the top layer containing disintegrants; SSG and MCC and sustained release (SR) profile from the lower layer containing HPMC 2208. The kinetic drug release data from the 3D printed and commercial GBTs were best modelled using the Korsmeyer–Peppas model with n values between 0.27 and 0.44. This suggests Fickian diffusion drug release through a hydrated HPMC gel layer. Other physical characterisations: X-Ray Powder Diffraction (XRPD), Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR), and Differential Scanning Calorimetry (DSC) showed that there was no detectable interaction between guaifenesin and the used excipients in both 3D printed and commercial GBTs. A more complex printer (RegenHu 3D bioprinter) was subsequently used to print complex multi-active tablets containing captopril, nifedipine, and glipizide as a model therapeutic combination. These drugs are frequently used to treat hypertension and diabetes mellitus. The 3D printed tablets were evaluated for drug release and showed that captopril was released by osmosis through permeable cellulose acetate (CA) film and both glipizide and nifedipine were released by diffusion through the hydrophilic HPMC 2208 matrix. According to XRPD and ATR-FTIR results, there was no detectable interaction between the actives and the used excipients. In the final experimental chapter, a combined treatment regimen: atenolol, ramipril, hydrochlorothiazide (anti-hypertensive medications), pravastatin (cholesterol lowering agent), and aspirin (anti-platelets) were printed into more complex geometry (polypill) using the RegenHu 3D bioprinter. This combined drug regimen is manufactured by Cadila Pharmaceuticals Limited as a capsule formulation under the trade name of Polycap™ and is currently the only polypill formulation commercially available and is used to treat and prevent cardiovascular diseases. The printed polypills were characterized for drug release using USP dissolution testing and showed the intended immediate and sustained release profiles based upon the active/excipient ratio used. Aspirin and hydrochlorothiazide were immediately released after the polypill contacted the dissolution medium, and atenolol, ramipril, and pravastatin were released over a period of 12 hrs. XRPD and ATR-FTIR showed that there was no detectable interaction between the actives and the used excipients. In this work, extrusion based 3D printing technique was used to print oral solid dosage forms with complex and well-defined geometries and function. The technology of 3D printing could offer the opportunity to print oral tablets with high and precise drug dosing and controlled drug release profiles tailored for sub-populations or individuals. If the manufacturing and regulatory issues associated with 3DP can be resolved such personalised medicine delivered by 3D printing could improve patient compliance and provide more effective treatment regimes.

Successful tissue repair requires orchestrating a range of biochemical and biophysical factors to direct cell differentiation towards tissue specific lineages. Biodegradable poly DL lactic acid-co-glycolic acid (PDLLGA) microspheres have been reported as a promising injectable cell delivery system with controllable growth factor release potential for different tissue engineering applications. Injectable PDLLGA microspheres have been shown to form highly porous scaffolds at body temperature with a mechanical strength comparable to bone tissues. However, as the elastic properties of the injury microenvironment were shown to have a pivotal role on directing stem cell lineage specification, this work has proposed photo-crosslinkable gelatine methacrylate (gel-MA) hydrogels as promising surface coatings with tunable elastic properties. Moreover, as PDLLGA microspheres have limited functional groups on their surface, this work has evaluated different surface modification and grafting approaches to enable proper grafting of thick gel-MA hydrogel layer to the surface. Surface adsorption, surface entrapment, and oxygen plasma treatment approaches have been proposed and evaluated to modify the surface of PDLLGA microspheres with high density of gel-MA molecules. Surface analytical techniques such as ToF SIMs and XPS have been used to evaluate and quantify the density of gel-MA molecules on the surface, while fluorescent and scanning electron microscopies have been used to visualise the fluorescent deposition of fit-C gel-MA to the surface. Later, grafting-to and encapsulation approaches have been investigated to graft a thick layer (10-20 μm thick) of gel-MA hydrogel to the surface of PDLLGA microspheres following modification with gel-MA. Fluorescein isothiocyanate labelled human serum albumin Fit-C HSA has been loaded into PDLLGA microspheres as a model protein to study its release behaviour from the proposed system. Release data have shown a comparable release profile between PDLLGA microspheres before and after coating with the hydrogel layer suggesting no adverse effect of the proposed coating approach on the release behaviour. Gel-MA hydrogels with tunable elastic properties have been prepared and analysed using texture analyser and atomic force microscopy (AFM). Hydrogels have been later imaged with focused ion beam scanning electron microscope (FIB-SEM) using a novel approach to capture the hydrated structure of the hydrogel. Data obtained from the texture analyser using the compression and indentation mode tests have shown that the elastic modulus values were significantly higher than the values obtained from tension mode tests. In comparison, the values obtained from the texture analyser with the tension mode test were comparable with the values obtained using the AFM nano-indentation tests. This has been explained with the poroelastic behaviour of the hydrated hydrogel structure where a micron size pores have been observed. To verify findings, human mesenchymal stem cells have been cultured on the surface of gel-MA hydrogels to study their phenotypic behaviour and stained with anti-osteogenic or anti-neurogenic immunofluorescent markers to define their fate accordingly. Images have shown that cells cultured on hydrogels with AFM analysed elastic values of (~26, ~9.3, and ~0.1 KPa) have committed to a phenotypic behaviour related to the elastic modulus values of bone, muscle, and neuronal tissues respectively. In comparison, the elastic modulus values obtained from gel-MA hydrogel microbeads with AFM have been notably higher and appeared to be dependent on the cross-linking temperatures. Finally, the proposed cell delivery system can be used to control the chemical and the mechanical properties of the stem cell microenvironment which may pave the way towards directing stem cell differentiation into tissue specific cell lineages for different tissue repair applications.

No description available.

The National Health Service (NHS) focuses on quality of care as a priority. With the NHS planning to go paperless by 2018, more hospitals in England are making the transition from paper to electronic prescribing (ePrescribing) systems. The aim of this programme of work was to understand and explore the influence different in-patient prescribing systems can have on key NHS healthcare professionals (doctors, nurses and pharmacists) working practices in England and quality healthcare. The programme of work, a three phase sequential design, used both qualitative and quantitative approaches. The first phase involved structured telephone interviews with chief pharmacists. Chief pharmacist interviews (n=65) focused upon the type of in-patient prescribing systems in use within each Trust and gained a management perspective of the different prescribing systems. Phases two and three were carried out at three acute NHS hospitals in England, at various stages of developing and implementing their prescribing systems. Phase two data were collected through multidisciplinary team (MDT) focus group discussions. The MDT discussions explored a number of areas associated with the prescribing systems in use: these included clinical workflow, communication, collaboration, patient safety and the use of a clinical indication on the prescription chart. Phase three data were collected using documentation analysis of the prescribing system and medical records, taken from patients cared for by the MDTs involved in phase two. Information extracted included any documentation made of a newly initiated medication, as well as the design of the prescribing system. The clarity and accuracy of documentation in the prescribing system and medical notes were compared to the GMC standards Good Practice in Prescribing Guidelines. Triangulation of data indicated how a change in prescribing system can impact upon individuals working practices by changing the design and clarity of the prescription chart, enforcing of regulations, accessibility and reliability, communication between key HCPs and the patient. These influences can be considered latent conditions in the systems that need addressing to prevent quality of patient care being compromised. The use of Socio-technical systems (STS) theory considered the interaction between humans and technology when using the prescribing systems. Understanding the issues where social and technical aspects interact in the prescribing system, emphasised where healthcare quality is impacted and therefore facilitated recommendations to improve working practices. The findings will help healthcare organisations to consider the impact a change in prescribing system can have on working practices and the latent failures that need consideration within the prescribing systems. The Electronic Prescribing and Medicines Administration (EPMA) system design must take into account the visual and physical needs of the user and consider how they can be improved to facilitate clinical workflow.

S. pneumoniae is one of the most significant human pathogens, causing high morbidity and mortality rates globally. Although there are vaccine available such as PPV 23, PCV7, PCV10, and PCV13, they are ineffective in some situations due to the differing epidemiology of various serotypes depending on the site of infection and the geographical location. Furthermore, they are expensive to produce and distribute. Universal research is presently concentrated on establishing other pneumococcalvaccine approaches such as using pneumococcal surface protein A (PspA) which relate to pathogenesis and are common to all serotypes. In this study polymeric nanoparticles (NPs) encapsulating PspA4Pro were incorporated into microcarriers using L-leucine and spray dried to produce nanocomposite micro#particles (NCMPs) dry powder for inhalation. Parameters for the preparation of protein-loaded polyester poly (Glycerol Adipate-co-ω-Pentadecalactone), (PGA-co-PDL) NCMPs were optimised using Taguchi design and BSA as a model protein, by the double emulsion solvent evaporation method followed by spray drying. Particle size was mainly affected by the polymer mass and small particle size ≤ 500nm was achieved. The most important factor for obtaining a high BSA loading was BSA concentration. The spray drying process was optimised to produce NCMPs with a porous corrugated surface, 50% yield, MMAD of 1.71±0.10 μm and FPF% of 78.57±0.1%. Adsorption of chitosan hydrochloride (CHL) onto PGA-co-PDL NPs can be used assuccessful strategies to produce cationic NPs. Cationic NPs were prepared with similarparticle size to anionic NPs ≤ 500nm. The In vitro aerosolisation performance ofcationic NPs/NCMPs showed FPF% of 46.79±11.21% and MMAD of 1.49±0.29 μm. Further cell viability studies on A549 cell line showed a good profile with a cell viability of 79±4.7% for anionic NPs/NCMPs and 78.85±9.96% for cationic xviii NPs/NCMPs at 2.5 mg/ml concentration after 24 h exposure. The previous results introduced a successful method for preparing anionic and cationic NPs/NCMPs for delivering PspA4Pro as dry powder via inhalation. The particle size of PspAPro4 loaded anionic NPs and cationic NPs were 310±25.3 nm and 409.7±49.5 nm, respectively, to be effectively taken up by dendritic cells (DCs). The PspA4Pro loading in anionic NPs was 65.73±5.6 μg/mg and in cationic NPs was 9.84±1.4 μg/mg. The PspA4Pro released from anionic and cationic NPs/NCMPs preserved its primary and secondary structure as evaluated by SDS-PAGE and circular dichroism. In vitro release studies showed that the anionic NPs/NCMPs formulations achieved a cumulative release of 21.01±1.5% while the cationic NPs/NCMPs formulation released 83.13 ±0.84% after 48 h. DCs uptake studies provide evidence of particles uptake by DCs upon incubation for 1 h as visualized by confocal microscopy. These results indicate the use of optimised methods for developing polymeric based NCMPs for vaccine delivery via inhalation against pneumococcal diseases.

Nasopharyngeal cancer lies in the upper part of throat behind the nose and near the base of the skull called the nasopharynx. It is more commonly diagnosed in parts of Asia, particularly in the southern China. Five local edible plants from different families; namely curry leaf (Murraya koenigii), temu kunci (Boesenbergia rotunda), spring onion leaf (Allium cepa), mushroom bean (Phaseolus vulgaris) and bunga kantan (Phaeomeria imperialis) were macerated to obtain methanol, ethyl acetate and hexane crude extracts. Each crude extract was tested against nasopharyngeal carcinoma (HK-1) and normal nasopharyngeal epithelial (NP-69) cell lines. All crude extracts from temu kunci (Boesenbergia rotunda) were found to contain flavonoids, alkaloids and polyphenols. Both methanolic and hexane crude extracts were found to exhibit cytotoxic effects against HK-1 cells but non-toxic against NP-69 cell line. Of all the bioactive compounds previously extracted from B. Rotunda, we have selected four commercially available flavonoids and polyphenols to narrow down our search to one potential anticancer agent. These compounds were tested against HK-1 and NP-69 cell lines for cytotoxicity and it was found that cardamonin exhibits highest cytotoxic effect against HK-1 cells with IC50 of 22 μg/mL. Cardamonin, a naturally occurring chalcone from the rhizome of Boesenbergia rotunda (locally known as temu kunci) was found to induce apoptosis in human nasopharyngeal carcinoma (HK-1) cell line in vitro. It exhibits a significant cytotoxic effect against human nasopharyngeal carcinoma cell line without affecting normal immortalized nasopharyngeal epithelial cell line (NP-69) in MTT assay. Based on these results, HK-1 cell line was treated with IC50 22 μg/mL in time-dependent manner 24, 48 and 72 hrs to further investigate the mechanisms of apoptosis. Apoptotic cells induced by cardamonin were illustrated by change in cellular morphology, increase in G2/M phase population and DNA fragmentation. Furthermore, up-regulation of caspase-3 and caspase-8 activities substantiated the induction of apoptosis through caspase-dependent pathway. Cardamonin leads to a decrease in overproduction of reactive oxygen species (ROS), disruption in mitochondrial membrane potential and drop in intracellular ATP level in HK-1 cells. Present study also revealed up-regulation of pro-apoptotic protein, Bax and apoptotic signalling factor, cytochrome c resulting in down-regulation of anti-apoptotic protein, Bcl-2. There was no fold change in caspase-9 gene expression level suggesting that HK-1 cellular apoptosis occurred independent of caspase-9. Activation of caspase-3 was directly regulated by caspase-8 and does not require caspase-9. Current findings on the mode of actions of cardamonin suggested its potential application as an anticancer agent against nasopharyngeal carcinoma.