Leadership in high-value services for manufacturers:people and the delivery of advanced services

This short paper sets out to further develop the debate around the practices and technologies within operations that are critical to success with servitization. This paper draws findings from four companies that are leading in their delivery of advanced services, and reports on the organisation and skill-sets of people within these organisations. In particular it examines the roles and activities of people within the front-office, identifies the skill-sets that are espoused as being critical, and then seeks to present the rational that explains this importance. It concludes by proposing a working hypothesis for future studies in this field.

Leadership in high-value services for manufacturers:information and communication technologies and the delivery of advanced services

Services-led competitive strategies are critically important to western manufacturers. This paper contributes to our foundational knowledge of such strategies by examining the enabling information and communication technologies that successfully servitized manufacturers appear to be adopting. Although these are preliminary findings from a longer-term research programme, through this article we seek to offer immediate assistance to manufacturers who wish to understand how they might exploit the servitization movement.

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.

Functional carbon nanotubes for photonic applications

Carbon nanomaterials are an active frontier of research in current nanotechnology. Single wall Carbon Nanotube (SWNT) is a unique material which has already found several applications in photonics, electronics, sensors and drug delivery. This thesis presents a summary of the author’s research on functionalisation of SWNTs, a study of their optical properties, and potential for an application in laser physics. The first significant result is a breakthrough in controlling the size of SWNT bundles by varying the salt concentrations in N-methyl 2-pyrrolidone (NMP) through a salting out effect. The addition of Sodium iodide leads to self-assembly of CNTs into recognizable bundles. Furthermore, a stable dispersion can be made via addition polyvinylpyrrolidone (PVP) polymer to SWNTs-NMP dispersion, which indicates a promising direction for SWNT bundle engineering in organic solvents. The second set of experiments are concerned with enhancement of photoluminescence (PL), through the formation of novel macromolecular complexes of SWNTs with polymethine dyes with emission from enhanced nanotubes in the range of dye excitation. The effect appears to originate from exciton energy transfer within the solution. Thirdly, SWNT base-saturable absorbers (SA) were developed and applied to mode locking of fibre lasers. SWNT-based SAs were applied in both composite and liquid dispersion forms and achieved stable ultrashort generation at 1000nm, 1550nm, and 1800 nm for Ytterbium, Erbium and Thulium-doped fibre laser respectively. The work presented here demonstrates several innovative approaches for development of rapid functionalised SWNT-based dispersions and composites with potential for application in various photonic devices at low cost.

Strategies and therapeutic opportunities for the delivery of drugs to the esophagus

Targeting of drugs and therapies locally to the esophagus is an important objective in the development of new and more effective dosage forms. Therapies that are retained within the oral cavity for both local and systemic action have been utilized for many years, although delivery to the esophagus has been far less reported. Esophageal disease states, including infections, motility disorders, gastric reflux, and cancers, would all benefit from localized drug delivery. Therefore, research in this area provides significant opportunities. The key limitation to effective drug delivery within the esophagus is sufficient retention at this site coupled with activity profiles to correspond with these retention times; therefore, a suitable formulation needs to provide the drug in a ready-to-work form at the site of action during the rapid transit through this organ. A successfully designed esophageal-targeted system can overcome these obstacles. This review presents a range of dosage form approaches for targeting the esophagus, including bioadhesive liquids and orally retained lozenges, chewing gums, gels, and films, as well as endoscopically delivered therapeutics. The techniques used to measure efficacy both in vitro and in vivo are also discussed. Drug delivery is a growing driver within the pharmaceutical industry and offers benefits both in terms of clinical efficacy, as well as in market positioning, as a means of extending a drug's exclusivity and profitability. Emerging systems that can be used to target the esophagus are reported within this review, as well as the potential of alternative formulations that offer benefits in this exciting area.

Lipoplexes formulation and optimisation:in vitro transfection studies reveal no correlation with in vivo vaccination studies

The aim of these studies was to compare the effect of liposome composition on physico-chemical characteristics and transfection efficacy of cationic liposomes both in vitro and in vivo. Comparison between 4 popularly used cationic lipids, showed 3b-N-(dimethylaminoethyl)carbamate (DC-Chol) to promote the highest transfect levels in cells in vitro with levels being at least 6 times higher than those of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA). 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and dimethyldioctadecylammonium (DDA) and approximately twice as efficient as dipalmitoyl-trimethylammonium-propane (DPTAP). To establish the role of the helper lipid, DC-Chol liposomes were formulated in combination with either 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol (Chol) (1:1 molar ratio) with and without the addition of phosphatidyl choline. The choice of helper lipid incorporated within the bilayer was found to influence the formation of complexes, their resultant structure and their transfection efficiency in vitro, with SUV-DNA complexes containing optimum levels of DOPE giving higher transfection than those containing cholesterol. The inclusion of PC within the formulation also reduced transfection efficiency in vitro. However, when administered in vivo, SUV-DNA complexes composed of PC:Chol:DC-Chol at a molar ratio of 16:8:4 micromole/ml were the most effective at inducing splenocyte proliferation upon exposure to antigen in comparison to control spleens. These results demonstrate that there is no in vitro/in vivo correlation between the transfection efficacy of these liposome formulations and in vitro transfection in the above cell model cannot be taken as a reliable indicator for in vivo efficacy of DNA vaccines.

Liposome-mediated DNA immunisation via the subcutaneous route

Compared to naked DNA immunisation, entrapment of plasmid-based DNA vaccines into liposomes by the dehydration-rehydration method has shown to enhance both humoural and cell-mediated immune responses to encoded antigens administered by a variety of routes. In this paper, we have investigated the application of liposome-entrapped DNA and their cationic lipid composition on such potency after subcutaneous immunisation. Plasmid pI.18Sfi/NP containing the nucleoprotein (NP) gene of A/Sichuan/2/87 (H3N2) influenza virus in the pI.18 expression vector was incorporated by the dehydration-rehydration method into liposomes composed of 16 μmol egg phosphatidylcholine (PC), 8 μmoles dioleoyl phosphatidylethanolamine (DOPE) or cholesterol (Chol) and either the cationic lipid 1,2-diodeoyl-3-(trimethylammonium) propane (DOTAP) or cholesteryl 3-N-(dimethyl amino ethyl) carbamate (DC-Chol). This method, entailing mixing of small unilamellar vesicles (SUV) with DNA, followed by dehydration and rehydration, yielded incorporation values of 90-94% of the DNA used. Mixing or rehydration of preformed cationic liposomes with 100 μg plasmid DNA also led to similarly high complexation values (92-94%). In an attempt to establish differences in the nature of DNA association with these various liposome preparations their physico-chemical characteristics were investigated. Studies on vesicle size, zeta potential and gel electrophoresis in the presence of the anion sodium dodecyl sulphate (SDS) indicate that, under the conditions employed, formulation of liposomal DNA by the dehydration-rehydration generated submicron size liposomes incorporating most of the DNA in a manner that prevents DNA displacement through anion competition. The bilayer composition of these dehydration-rehydration vesicles (DRV(DNA)) can also further influence these physicochemical characteristics with the presence of DOPE within the liposome bilayer resulting in a reduced vesicle zeta potential. Subcutaneous liposome-mediated DNA immunisation employing two DRV(DNA) formulations as well as naked DNA revealed that humoural responses (immunoglobulin total IgG, and subclasses IgG1 and 1gG2a) engendered by the plasmid encoded NP were substantially higher after dosing twice, 28 days apart with 10 μg liposome-entrapped DNA compared to naked DNA. At all time points measured, mice immunised with naked DNA showed no greater immune response compared to the control, non-immunised group. In contrast, as early as day 49, responses were significantly higher in mice injected with DNA entrapped in DRV liposomes containing DOTAP compared to the control group and mice immunised with naked DNA. By day 56, all total IgG responses from mice immunised with both DRV formulations were significantly higher. Comparison between the DRV formulations revealed no significant difference in immune responses elicited except at day 114, where the humoural responses of the group injected with liposomal formulation containing DC-Chol dropped to significantly lower levels that those measured in mice which received the DOTAP formulation. Similar results were found when the IgG1 and IgG2a subclass responses were determined. These results suggest that, not only can DNA be effectively entrapped within liposomes using the DRV method but that such DRV liposomes containing DNA may be a useful system for subcutaneous delivery of DNA vaccines. © 2003 Taylor & Francis Ltd.

Polymer-phospholipid complexes for the solubilisation and delivery of drugs to the eye

Aim: Topical application of ophthalmic drugs is very inefficient; contact lenses used as drug delivery devices could minimize the drug loss and side effects. Styrene-maleic acid copolymers (PSMA) can form polymer-phospholipid complexes with dipalmitoyl phosphatidylcholine (DMPC) in the form of nanometric vesicles, which can easily solubilise hydrophobic drugs. They can be dispersed on very thin contact lens coatings to immobilize the drug on their surface. Methods: Two types of complexes stable at different pH values (5 and 7 respectively) where synthesized and loaded with drugs of different hydrophilicities during their formation process. The drug release was studied in vitro and compared to the free drug. Results: The mean sizes of the complexes obtained by light scattering were 50 nm and 450 nm respectively with low polydispersities. However, they were affected by the drugs load and release. An increase was observed in the duration of the release in the case of hydrophobic drugs, from days to weeks, avoiding initial “burst” and with a lesser amount of total drug released due to the interaction of the drug with the phospholipid core. The size and charge of the different drugs and the complexes nature also affected the release profile. Conclusions: Polymer-phospholipid complexes in the form of nanoparticles can be used to solubilise and release hydrophobic drugs in a controlled way. The drug load and release can be optimised to reach therapeutic values in the eye.

Studies on DNA methylation and mechanisms of hypomethylation

The methylation of cytosinc residues in DNA is thought to play an important role in the regulation of gene expression, with active genes generally being hypomethylated. With this in mind peptides were synthcsised to mimic the cytosine-5 methylation activity carried out by DNA mcthylase, which however, showed no ability to carry out this function. The imidazotetrazinoncs are a novel group of antitumour agents which have demonstrated good activity against a range of murinc tumours and human tumour xenografts, and hypomethylation of DNA has been implicated in the mechanism of action. Studies have been conducted on the mechanism by which such agents cause hypomethylation, using DNA methylase partially purified from murine L1210 leukaemia cells. Unmodified calf thymus DNA does not inhibit the transfer of methyl groups from SAM to M.lysodeikticus DNA by partially purified DNA methylase. However, if the calf thymus DNA is modified by alkylating agents such as imida-zotetrazinones or nitrosoureas, the treated DNA becomes an inhibitor of the methylation reaction. This has been correlated with the induction of DNA damage, such as single strand breaks, since X-ray treated DNA and deoxyribonuclease treatment produces a similar effect. The mechanism of inhibition by the drug treated or damaged DNA is thought to occur by binding of the enzyme to an increased concentration of non-substrate DNA, presumably by the occurrence of single strand breaks, since neither sonication nor treatment with the restriction enzyme Mspl caused an inhibition. Attempts were made to elucidate the strict structure activity relationship for antitumour activity observed amongst the imidazotctrazinones. The transfection of a murine colon adcnocarcinoma cell line (MAC 13) with DNA extracted from GM892 or Raji cells previously treated with either the methyl (temozolomide) or ethyl (ethazolastone) imidazotetrazinone was performed. X-irradiated DNA did not cause any suppression of cell growth, suggesting that it was not due to physical damage. Transfection of MAC 13 cells with DNA extracted from GM892 cells, was more effective at inhibiting growth than DNA from Raji cells. Temozolomide treated cellular DNA was a more potent growth inhibitor than that from ethazolastone treated cells. For both agents the growth inhibitory effect was most marked with DNA extracted 6h after drug addition, and after 24h no growth suppression was observed. This suggested that the growth inhibitory effect is due to a repairable lesion. .The methylation of M.lysodeikticus DNA by DNA methylase is inhibited potently and specifically by both hereto and homoribo and dcoxyri-bopolynucleotides containing guanine residues. The inhibitory effect is unaffected by chain length or sugar residue, but is abolished when the O-6 residue of guanine is substituted as in poly d(OGG)2o. Potent inhibition is also shown by polyinosinic and polyxanthylic acids but not by polyadenylic acid or by heteropolymers containing adcnine and thymine. These results suggest that the 6 position of the purine nucleus is important in binding of the DNA methylase to particular regions of the DNA and that the hydrogen bonding properties of this group are important in enzyme recognition. This was confirmed using synthetic oligonucleotides as substrates for DNA methylase. Enzymatic methylation of cytosine is completely suppressed, when O6 methylguanine replaces guanine in CG sites.

Trigger release liposome systems:local and remote controlled delivery?

Target-specific delivery has become an integral area of research in order to increase bioavailability and reduce the toxic effects of drugs. As a drug-delivery option, trigger-release liposomes offer sophisticated targeting and greater control-release capabilities. These are broadly divided into two categories; those that utilise the local environment of the target site where there may be an upregulation in certain enzymes or a change in pH and those liposomes that are triggered by an external physical stimulus such as heat, ultrasound or light. These release mechanisms offer a greater degree of control over when and where the drug is released; furthermore, targeting of diseased tissue is enhanced by incorporation of target-specific components such as antibodies. This review aims to show the development of such trigger release liposome systems and the current research in this field.

Fabrication of magnetic drug-loaded polymeric composite nanofibres and their drug release characteristics

Magnetic polymer nanofibres intended for drug delivery have been designed and fabricated by electrospinning. Magnetite (Fe3O4) nanoparticles were successfully incorporated into electrospun nanofibre composites of two cellulose derivatives, dehydroxypropyl methyl cellulose phthalate (HPMCP) and cellulose acetate (CA), while indomethacin (IDN) and aspirin have been used as model drugs. The morphology of the neat and magnetic drug-loaded electrospun fibres and the release characteristics of the drugs in artificial intestinal juice were investigated. It was found that both types of electrospun composite nanofibres containing magnetite nanoparticles showed superparamagnetism at room temperature, and their saturation magnetisation and morphology depend on the Fe3O4 nanoparticle content. Furthermore, the presence of the magnetite nanoparticles did not affect the drug release profiles of the nanofibrous devices. The feasibility of controlled drug release to a target area of treatment under the guidance of an external magnetic field has also been demonstrated, showing the viability of the concept of magnetic drug-loaded polymeric composite nanofibres for magneto-chemotherapy.

Particulate delivery systems for vaccines

This review focuses on the use of particulate delivery systems for the purposes of immunization. This includes poly(lactide-co-glycolide) (PLGA), ISCOMs, liposomes, niosomes, virosomes, chitosan, and other biodegradable polymers. These systems are evaluated in terms of their use as carriers for protein subunit and DNA vaccines. There is an extensive focus on recent literature, the understanding of biological interactions, and relation of this to our present understanding of immunological mechanisms of action. In addition, there is consideration of formulation techniques including emulsification, solvent diffusion, DNA complexation, and entrapment. The diversity of formulation strategies presented is a testament to the exponential growth and interest in the area of vaccine delivery systems. A case study for the application of particulate vaccine carriers is assessed in terms of vaccine development and recent insights into the possible design and application of vaccines against two of the most important pathogens that threaten mankind and for which there is a significant need: Mycobacterium tuberculosis and human immunodeficiency virus. This review addresses the rationale for the use of particulate delivery systems in vaccine design in the context of the diversity of carriers for DNA- and protein-based vaccines and their potential for application in terms of the critical need for effective vaccines. © 2005 by Begell House, Inc.

New oil modified acrylic polymer for pH sensitive drug release:experimental results and statistical analysis

We report results of an experimental study, complemented by detailed statistical analysis of the experimental data, on the development of a more effective control method of drug delivery using a pH sensitive acrylic polymer. New copolymers based on acrylic acid and fatty acid are constructed from dodecyl castor oil and a tercopolymer based on methyl methacrylate, acrylic acid and acryl amide were prepared using this new approach. Water swelling characteristics of fatty acid, acrylic acid copolymer and tercopolymer respectively in acid and alkali solutions have been studied by a step-change method. The antibiotic drug cephalosporin and paracetamol have also been incorporated into the polymer blend through dissolution with the release of the antibiotic drug being evaluated in bacterial stain media and buffer solution. Our results show that the rate of release of paracetamol getss affected by the pH factor and also by the nature of polymer blend. Our experimental data have later been statistically analyzed to quantify the precise nature of polymer decay rates on the pH density of the relevant polymer solvents. The time evolution of the polymer decay rates indicate a marked transition from a linear to a strictly non-linear regime depending on the whether the chosen sample is a general copolymer (linear) or a tercopolymer (non-linear). Non-linear data extrapolation techniques have been used to make probabilistic predictions about the variation in weight percentages of retained polymers at all future times, thereby quantifying the degree of efficacy of the new method of drug delivery.

Improving brain drug targeting through exploitation of the nose-to-brain route:a physiological and pharmacokinetic perspective

With an ageing population and increasing prevalence of central-nervous system (CNS) disorders new approaches are required to sustain the development and successful delivery of therapeutics into the brain and CNS. CNS drug delivery is challenging due to the impermeable nature of the brain microvascular endothelial cells that form the blood-brain barrier (BBB) and which prevent the entry of a wide range of therapeutics into the brain. This review examines the role intranasal delivery may play in achieving direct brain delivery, for small molecular weight drugs, macromolecular therapeutics and cell-based therapeutics, by exploitation of the olfactory and trigeminal nerve pathways. This approach is thought to deliver drugs into the brain and CNS through bypassing the BBB. Details of the mechanism of transfer of administrated therapeutics, the pathways that lead to brain deposition, with a specific focus on therapeutic pharmacokinetics, and examples of successful CNS delivery will be explored. © 2014 Bentham Science Publishers.

Sustained delivery of salbutamol and beclometasone from spray-dried double emulsions

The sustained delivery of multiple agents to the lung offers potential benefits to patients. This study explores the preparation of highly respirable dual-loaded spray-dried double emulsions. Spray-dried powders were produced from water-in-oil-in-water (w/o/w) double emulsions, containing salbutamol sulphate and/or beclometasone dipropionate in varying phases. The double emulsions contained the drug release modifier polylactide co-glycolide (PLGA 50 : 50) in the intermediate organic phase of the original micro-emulsion and low molecular weight chitosan (Mw<190 kDa: emulsion stabilizer) and leucine (aerosolization enhancer) in the tertiary aqueous phase. Following spray-drying resultant powders were physically characterized: with in vitro aerosolization performance and drug release investigated using a Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. Powders generated were of a respirable size exhibiting emitted doses of over 95% and fine particle fractions of up to 60% of the total loaded dose. Sustained drug release profiles were observed during dissolution for powders containing agents in the primary aqueous and secondary organic phases of the original micro-emulsion; the burst release of agents was witnessed from the tertiary aqueous phase. The novel spray-dried emulsions from this study would be expected to deposit and display sustained release character in the lung.