Formulation and process engineering of freeze-dried orally disintegrating tablets

Orally disintegrating tablets (ODTs) which are also referred to as orodispersible and fast disintegrating tablets, are solid oral dosage forms which upon placing on the tongue, disperse/disintegrate rapidly before being swallowed as a suspension or solution. ODTs are therefore easier and more convenient to administer than conventional tablets and are particularly beneficial for paediatric and geriatric patients, who generally have difficulty swallowing their medication. The work presented in this thesis involved the formulation and process development of ODTs, prepared using freeze-drying. Gelatin is one of the principal excipients used in the formulation of freeze-dried ODTs. One of the studies presented in this thesis investigated the potential modification of the properties of this excipient, in order to improve the performance of the tablets. As gelatin is derived from animal sources, a number of ethical issues surround its use as an excipient in pharmaceutical preparations. This was one of the motivations, Methocel™ and Kollicoat® IR were evaluated as binders as alternative materials to gelatin. Polyox™ was also evaluated as a binder together with its potential uses as a viscosity increasing and mucoadhesive agent to increase the retention of tablets in the mouth to encourage pre-gastric absorption of active pharmaceutical ingredients (APIs). The in vitro oral retention of freeze-dried ODT formulations was one property which was assessed in a design of experiments – factorial design study, which was carried out to further understand the role that formulation excipients have on the properties of the tablets. Finally, the novel approach of incorporating polymeric nanoparticles in freeze-dried ODTs was investigated, to study if the release profile of APIs could be modified, which could improve their therapeutic effect. The results from these studies demonstrated that the properties of gelatin-based formulations can be modified by adjusting pH and ionic strength. Adjustment of formulation pH has shown to significantly reduce tablet disintegration time. Evaluating Methocel™, in particular low viscosity grades, and Kollicoat® IR as binders has shown that these polymers can form tablets of satisfactory hardness and disintegration time. Investigating Polyox™ as an excipient in freeze-dried ODT formulations revealed that low viscosity grades appear suitable as binders whilst higher viscosity grades could potentially be utilised as viscosity increasing and mucoadhesive agents. The design of experiments – factorial design study revealed the influence of individual excipients in a formulation mix on resultant tablet properties and in vitro oral retention of APIs. Novel methods have been developed, which allows the incorporation of polymeric nanoparticles in situ in freeze-dried ODT formulations, which allows the modification of the release profile of APIs.

Metaphor in translation:possibilities for process research

This paper explores potential benefits of closer interaction between metaphor studies and translation process research. It presents some developments within Translation Studies which make use of conceptual metaphor theory and illustrates some process research methods for investigating metaphors. The paper considers a number of methodological recommendations and argues that of greatest importance is the need to take full account of insights from metaphor studies and associated disciplines. Another important potential innovation is the use of a multilingual approach in respect of both product- and process-oriented studies in order to increase both the amount and generality of data available for analysis. Thirdly, it is important to extend and complement the current ST-oriented approach. The paper concludes by suggesting some options for triangulating data gathered through a combination of methods.

The neuroimaging research process from the participants' perspective

The aim of this study was to investigate participants' experiences of taking part in research conducted using fMRI or MEG procedures. Forty-four participants completed a questionnaire after taking part in either fMRI or MEG experiments; the questionnaire asked about experiences of and attitudes toward fMRI/MEG. Ten follow-up interviews were conducted to enable an in-depth analysis of these attitudes and experiences. The findings were generally positive: all participants thought fMRI and MEG were safe procedures, 93% would recommend participating in neuroimaging research to their friends and family, and participants were positive about participating in future neuroimaging research. However, some negative issues were identified. Some participants reported feeling nervous prior to scanning procedures, several participants reported side-effects after taking part, a number of participants were upset at being in a confined space and some participants did not feel confident about exiting the scanner in an emergency. Several recommendations for researchers are made, including a virtual tour of the scanning equipment during the consenting process in order to better prepare potential participants for the scanning experience and to minimize the potential psychological discomfort sometimes experienced in neuroimaging research. © 2006 Elsevier B.V. All rights reserved.

Investigating the delivery of antimicrobial proteins and aminoglycoside antibiotics to the airways

Biopharmaceuticals are finding wide applications in the management of diverse disease conditions. Pulmonary delivery of proteins may constitute an effective and efficient non-invasive alternative to parenteral delivery, which is currently the main route of administration of biopharmaceutical drugs. A particular area, in which pulmonary delivery of peptides and proteins may find ready application, is in the local delivery of antimicrobial peptides and proteins to the airway, a measure that could potentially bring about improvements to currently available antipseudomonal therapies. This thesis has therefore sought to develop inhalable antimicrobial proteins in combination with antibiotics that have particularly good antimicrobial activity against Pseudomonas aeruginosa infections in the respiratory tract of people with cystic fibrosis (CF). Through process optimisation, a suitable spray drying method was developed and used for the preparation of active, inhalable dry powder formulations of the antimicrobial protein, lactoferrin, and aminoglycosides (tobramycin and gentamicin). The physicochemical properties, aerosolisation performance and the antibacterial properties of the various spray-dried formulations were assessed. In addition, a relevant in vitro cellular model was employed to investigate the potential cytotoxic and pro-inflammatory effects of the various formulations on four bronchial human epithelial cells together with their effectiveness at reducing bacterial colonies when administered on to biofilm co-cultured on the epithelial cells. It was found that following spray drying the particles obtained were mostly spherical, amorphous and possessed suitable aerosolisation characteristics. The various spray-dried antimicrobial proteins (lactoferrin or apo lactoferrin) and co-spray dried combinations of the proteins and aminoglycosides were found to exhibit bactericidal activity against planktonic and biofilms of P. aeruginosa. In general, the spray drying process was found not to significantly affect the antimicrobial activities of the protein. Treatment of the different bronchial epithelial cell lines with the antimicrobial formulations showed that the various formulations were non-toxic and that the co-spray dried combinations significantly reduced established P. aeruginosa biofilms on the four bronchial epithelial cells. Overall, the results from this thesis demonstrates that spray drying could potentially be employed to prepare inhalable antimicrobial agents comprised of proteins and antibiotics. These new combinations of proteins and aminoglycosides has promising applications in the management of P. aeruginosa in the airway of cystic fibrosis patients.

Synthesis of hydrazine by the fixation process

A critical review of the literature concerning organic derivatives of hydrazine, the ammonia-chlorine reaction and the electrolytic formation of hydrazine has been carried out. Apparatus was constructed to study the electrolysis of liquid ammonia, the formation of chloramine and the fixation of chloramine with a ketone to form an isohydrazone. In the latter case the reaction was carried out in a 3" diameter stirred tank and also in a 1" diameter, 2' high column reactor where the liquid phase was continuously recirculated. Two methods of analysis of azines and isohydrazones in a ketone solution have been developed. One is a colorimetric technique using p-dimethylaminobenzaldehyde and the other involves the hydrolysis of the organic derivative to hydrazine sulphate. Hydrazine was detected in low concentration in some of the electrolytic experiments carried out but it was concluded that this method did not show sufficient promise to warrant further investigation. The gas phase formation of chloramine and acetone isohydrazone has also been studied but in this system difficulties were encountered with the chlorine jet blocking with ammonium chloride. The formation of isohydrazones in a stirred tank reactor has been investigated in some detail and the effect of several parameters was determined. The yield was found to be extremely sensitive to chlorine concentration and in order to obtain yields of more than 90 per cent, the molar concentration of chlorine in the gas phase had to be of the order of 5 per cent. An optimum temperature in the region of 0°C was also detected. These results disagree with those quoted in previous studies but extensive experimental work has confirmed the information presented in this thesis. It has also been shown that at high yields the chloramine formation reaction took place in the gas phase.

Servitization of manufacture:exploring the deployment and skills of people critical to the delivery of advanced services

Purpose - This "research note" sets out to fuel the debate around the practices and technologies within operations that are critical to success with servitization. It presents a study of four companies which are delivering advanced services and reports on the organisation and skill-sets of people within these. Design/methodology/approach - This has been case-based research at four manufacturers leading in their delivery of services. Findings - It describes the desirable behaviour of people in the front-line of service delivery, identifies the supporting skill-sets, how these people are organised, and explains why all these factors are so important. Originality/value - This paper contributes to the understanding of the servitization process and, in particular, the implications to broader operations of the firm. © 2013 Emerald Group Publishing Limited. All rights reserved.

Effects of fourth-order fiber dispersion on ultrashort parabolic optical pulses in the normal dispersion regime

We propose a new method for the generation of both triangular-shaped optical pulses and flat-top, coherent supercontinuum spectra using the effect of fourth-order dispersion on parabolic pulses in a passive, normally dispersive highly nonlinear fiber. The pulse reshaping process is described qualitatively and is compared to numerical simulations.

Investigating the process of translation:humour translation norms, strategies and approaches in children's literature

Research in the present thesis is focused on the norms, strategies,and approaches which translators employ when translating humour in Children's Literature from English into Greek. It is based on process-oriented descriptive translation studies, since the focus is on investigating the process of translation. Viewing translation as a cognitive process and a problem soling activity, this thesis Think-aloud protocols (TAPs) in order to investigate translator's minds. As it is not possible to directly observe the human mind at work, an attempt is made to ask the translators themselves to reveal their mental processes in real time by verbalising their thoughts while carrying out a translation task involving humour. In this study, thirty participants at three different levels of expertise in translation competence, i.e. tn beginner, ten competent, and ten experts translators, were requested to translate two humourous extracts from the fictional diary novel The Secret Diary of Adrian Mole, Aged 13 ¾ by Sue Townsend (1982) from English into Greek. As they translated, they were asked to verbalise their thoughts and reason them, whenever possible, so that their strategies and approaches could be detected, and that subsequently, the norms that govern these strategies and approaches could be revealed. The thesis consists of four parts: the introduction, the literature review, the study, and the conclusion, and is developed in eleven chapters. the introduction contextualises the study within translation studies (TS) and presents its rationale, research questions, aims, and significance. Chapters 1 to 7 present an extensive and inclusive literature review identifying the principles axioms that guide and inform the study. In these seven chapters the following areas are critically introduced: Children's literature (Chapter 1), Children's Literature Translation (Chapter 2), Norms in Children's Literature (Chapter 3), Strategies in Children's Literature (Chapter 4), Humour in Children's Literature Translation (Chapter 5), Development of Translation Competence (Chapter 6), and Translation Process Research (Chapter 7). In Chapters 8 - 11 the fieldwork is described in detail. the piolot and the man study are described with a reference to he environments and setting, the participants, the research -observer, the data and its analysis, and limitations of the study. The findings of the study are presented and analysed in Chapter 9. Three models are then suggested for systematising translators' norms, strategies, and approaches, thus, filling the existing gap in the field. Pedagogical norms (e.g. appropriateness/correctness, famililarity, simplicity, comprehensibility, and toning down), literary norms (e.g. sound of language and fluency). and source-text norms (e.g. equivalence) were revealed to b the most prominent general and specific norms governing the translators'  strategies and approaches in the process of translating humour in ChL. The data also revealed that monitoring and communication strategies (e.g. additions, omissions, and exoticism) were the prevalent strategies employed by translators. In Chapter 10 the main findings and outcomes of a potential secondary benefit (beneficial outcomes) are discussed on the basis of the research questions and aims of the study, and implications of the study are tackled in Chapter 11. In the conclusion, suggestions for future directions are given and final remarks noted.

Managing project risk using combined analytic hierarchy process and risk map

The main purpose of the study is to develop an integrated framework for managing project risks by analyzing risk across project, work package and activity levels, and developing responses. Design/methodology/approach: The study first reviews the literature of various contemporary risk management frameworks in order to identify gaps in project risk management knowledge. Then it develops a conceptual risk management framework using combined analytic hierarchy process (AHP) and risk map for managing project risks. The proposed framework has then been applied to a 1500 km oil pipeline construction project in India in order to demonstrate its effectiveness. The concerned project stakeholders were involved through focus group discussions for applying the proposed risk management framework in the project under study. Findings: The combined AHP and risk map approach is very effective to manage project risks across project, work package and activity levels. The risk factors in project level are caused because of external forces such as business environment (e.g. customers, competitors, technological development, politics, socioeconomic environment). The risk factors in work package and activity levels are operational in nature and created due to internal causes such as lack of material and labor productivity, implementation issues, team ineffectiveness, etc. Practical implications: The suggested model can be applied to any complex project and helps manage risk throughout the project life cycle. Originality/value: Both business and operational risks constitute project risks. In one hand, the conventional project risk management frameworks emphasize on managing business risks and often ignore operational risks. On the other hand, the studies that deal with operational risk often do not link them with business risks. However, they need to be addressed in an integrated way as there are a few risks that affect only the specific level. Hence, this study bridges the gaps. © 2010 Elsevier B.V. All rights reserved.

Servitization capabilities for advanced services:a multi-actor perspective

Servitization is the process by which manufacturers add services to their product offerings and even replace products with services. The capabilities necessary to develop and deliver advanced services as part of servitization are often discussed in the literature from the manufacturer’s perspective, e.g., having a service-focused culture or the ability to sell solutions. Recent research has acknowledged the important role of customers and, to a lesser extent, other actors (e.g., intermediaries) in bringing about successful servitization, particularly for use-oriented and results-oriented advanced services. The objective of this study is to identify the capabilities required to successful develop advanced services as part of servitization by considering the perspective of manufacturers, intermediaries and customers. This study involved interviews with 33 managers in 28 large UK-based companies from these three groups, about servitization capabilities. The findings suggest that there are eight broad capabilities that are important for advanced services; 1) personnel with expertise and deep technical product knowledge, 2) methodologies for improving operational processes, helping to manage risk and reduce costs, 3) the evolution from being a product- focused manufacturer to embracing a services culture, 4) developing trusting relationships with other actors in the network to support the delivery of advanced services, 5) new innovation activities focused on financing contracts (e.g., ‘gain share’) and technology implementation (e.g., Web-based applications), 6) customer intimacy through understanding their business challenges in order to develop suitable solutions, 7) extensive infrastructure (e.g., personnel, service centres) to deliver a local service, and 8) the ability to tailor service offerings to each customer’s requirements and deliver these responsively to changing needs. The capabilities required to develop and deliver advanced services align to a need to enhance the operational performance of supplied products throughout their lifecycles and as such require greater investment than the capabilities for base and intermediate services.

Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines

The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro-intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. © 2013 Controlled Release Society.

Constructive updating/downdating of oblique projectors:a generalization of the Gram-Schmidt process

A generalization of the Gram-Schmidt procedure is achieved by providing equations for updating and downdating oblique projectors. The work is motivated by the problem of adaptive signal representation outside the orthogonal basis setting. The proposed techniques are shown to be relevant to the problem of discriminating signals produced by different phenomena when the order of the signal model needs to be adjusted. © 2007 IOP Publishing Ltd.

Polymeric microspheres as protein transduction reagents

Discovering the function of an unknown protein, particularly one with neither structural nor functional correlates, is a daunting task. Interaction analyses determine binding partners, whereas DNA transfection, either transient or stable, leads to intracellular expression, though not necessarily at physiologically relevant levels. In theory, direct intracellular protein delivery (protein transduction) provides a conceptually simpler alternative, but in practice the approach is problematic. Domains such as HIV TAT protein are valuable, but their effectiveness is protein specific. Similarly, the delivery of intact proteins via endocytic pathways (e.g. using liposomes) is problematic for functional analysis because of the potential for protein degradation in the endosomes/lysosomes. Consequently, recent reports that microspheres can deliver bio-cargoes into cells via a non-endocytic, energy-independent pathway offer an exciting and promising alternative for in vitro delivery of functional protein. In order for such promise to be fully exploited, microspheres are required that (i) are stably linked to proteins, (ii) can deliver those proteins with good efficiency, (iii) release functional protein once inside the cells, and (iv) permit concomitant tracking. Herein, we report the application of microspheres to successfully address all of these criteria simultaneously, for the first time. After cellular uptake, protein release was autocatalyzed by the reducing cytoplasmic environment. Outside of cells, the covalent microsphere-protein linkage was stable for ≥90 h at 37°C. Using conservative methods of estimation, 74.3% ± 5.6% of cells were shown to take up these microspheres after 24 h of incubation, with the whole process of delivery and intracellular protein release occurring within 36 h. Intended for in vitro functional protein research, this approach will enable study of the consequences of protein delivery at physiologically relevant levels, without recourse to nucleic acids, and offers a useful alternative to commercial protein transfection reagents such as Chariot™. We also provide clear immunostaining evidence to resolve residual controversy surrounding FACS-based assessment of microsphere uptake. © 2014 by The American Society for Biochemistry and Molecular Biology Inc.

Chitosan-modified dry powder formulations for pulmonary gene delivery

Spray-drying is an effective process for preparing micron-dimensioned particles for pulmonary delivery. Previously, we have demonstrated enhanced dispersibility and fine particle fraction of spray-dried nonviral gene delivery formulations using amino acids or absorption enhancers as dispersibility-enhancing excipients. In this study, we investigate the use of the cationic polymer chitosan as a readily available and biocompatible dispersibility enhancer. Lactose-lipid:polycation:pDNA (LPD) powders were prepared by spray-drying and post-mixed with chitosan or spray-dried chitosan. In addition, the water-soluble chitosan derivative, trimethyl chitosan, was added to the lactose-LPD formulation before spray-drying. Spray-dried chitosan particles, displaying an irregular surface morphology and diameter of less than 2 mu m, readily adsorbed to lactose-LPD particles following mixing. In contrast with the smooth spherical surface of lactose-LPD particles, spray-dried trimethyl chitosan-lactose-LPD particles demonstrated increased surface roughness and a unimodal particle size distribution (mean diameter 3.4 mu m), compared with the multimodal distribution for unmodified lactose-LPD powders (mean diameter 23.7 mu m). The emitted dose and in vitro deposition of chitosan-modified powders was significantly greater than that of unmodified powders. Moreover, the inclusion of chitosan mediated an enhanced level of reporter gene expression. In summary, chitosan enhances the dispersibility and in vitro pulmonary deposition performance of spray-dried powders.

Knowledge-based system for casting process selection

Design of casting entails the knowledge of various interacting factors that are unique to casting process, and, quite often, product designers do not have the required foundry-specific knowledge. Casting designers normally have to liaise with casting experts in order to ensure the product designed is castable and the optimum casting method is selected. This two-way communication results in long design lead times, and lack of it can easily lead to incorrect casting design. A computer-based system at the discretion of a design engineer can, however, alleviate this problem and enhance the prospect of casting design for manufacture. This paper proposes a knowledge-based expert system approach to assist casting product designers in selecting the most suitable casting process for specified casting design requirements, during the design phase of product manufacture. A prototype expert system has been developed, based on production rules knowledge representation technique. The proposed system consists of a number of autonomous but interconnected levels, each dealing with a specific group of factors, namely, casting alloy, shape and complexity parameters, accuracy requirements and comparative costs, based on production quantity. The user interface has been so designed to allow the user to have a clear view of how casting design parameters affect the selection of various casting processes at each level; if necessary, the appropriate design changes can be made to facilitate the castability of the product being designed, or to suit the design to a preferred casting method.