Production of pH-responsive microparticles by spray drying: investigation of experimental parameter effects on morphological and release properties

During spray drying, emphasis is placed on process optimisation to generate favourable particle morphological and flow properties. The effect of the initial feed solution composition on the drug release from the prepared microparticles is rarely considered. We investigated the effects of solvent composition, feed solution concentration and drug-loading on sodium salicylate, hydrocortisone and triamcinolone release from spray dried Eudragit L100 microparticles. Eudragit L100 is a pH-responsive polymer whose dissolution threshold is pH 6 so dissolution testing of the prepared microparticles at pH 5 and 1.2 illustrated non-polymer controlled burst release. Increasing the water content of the initial ethanolic feed solution significantly reduced hydrocortisone burst release at pH 5, as did reducing the feed solution concentration. These findings caution that changes in feed solution concentration or solvent composition not only affect particles’ morphological characteristics but can also negatively alter their drug release properties. This work also illustrate that drug-free microparticles can have different morphological properties to drug-loaded microparticles. Therefore, process optimisation needs to be carried out using drug-loaded systems. Depending on the physicochemical properties of the encapsulated API, drug-loading can affect the polymer solubility in the initial feed solution with consequent impact on microparticles morphological and release properties.

Asymptotic expansions for Taylor coefficients of the composition of two functions

We give an asymptotic expansion for the Taylor coe±cients of L(P(z)) where L(z) is analytic in the open unit disc whose Taylor coe±cients vary `smoothly' and P(z) is a probability generating function. We show how this result applies to a variety of problems, amongst them obtaining the asymptotics of Bernoulli transforms and weighted renewal sequences.

Evaluation of drug physical form during granulation, tabletting and storage

An active pharmaceutical ingredient (API) was found to dissociate from the highly crystalline hydrochloride form to the amorphous free base form, with consequent alterations to tablet properties. Here, a wet granulation manufacturing process has been investigated using in situ Fourier transform (FT)-Raman spectroscopic analyses of granules and tablets prepared with different granulating fluids and under different manufacturing conditions. Dosage form stability under a range of storage stresses was also investigated. Despite the spectral similarities between the two drug forms, low levels of API dissociation could be quantified in the tablets; the technique allowed discrimination of around 4% of the API content as the amorphous free base (i.e. less than 1% of the tablet compression weight). API dissociation was shown to be promoted by extended exposure to moisture. Aqueous granulating fluids and manufacturing delays between granulation and drying stages and storage of the tablets in open conditions at 40◦C/75% relative humidity (RH) led to dissociation. In contrast, non-aqueous granulating fluids, with no delay in processing and storage of the tablets in either sealed containers or at lower temperature/humidity prevented detectable dissociation. It is concluded that appropriate manufacturing process and storage conditions for the finished product involved minimising exposure to moisture of the API. Analysis of the drug using FT-Raman spectroscopy allowed rapid optimisation of the process whilst offering quantitative molecular information concerning the dissociation of the drug salt to the amorphous free base form.

Using HIT to deliver integrated care for the frail elderly in the UK: current barriers and future challenges

In this paper we briefly describe the results of a 3 year project examining the use of Health Information Technologies (e.g., electronic patient record systems) to deliver integrated care. In particular, we focus on one group of patient (the frail elderly) and efforts to design an e-health supported healthcare pathway (the frail elderly pathway – FEP). The aim of FEP is to bring together clinicians and staff from health and social care and allow them to share patient information. Our findings show that progress in delivering a fully-supported and working FEP has been slow, not least because of the difficulties experienced by healthcare staff in using current IT systems. In addition, there are many strategic and technical issues which remain unresolved (e.g., systems interoperability).

A nipple shield delivery system for oral drug delivery to breastfeeding infants : Microbicide delivery to inactivate HIV

A new drug delivery method for infants is presented which incorporates an active pharmaceutical ingredient (API)-loaded insert into a nipple shield delivery system (NSDS). The API is released directly into milk during breastfeeding. This study investigates the feasibility of using the NSDS to deliver the microbicide sodium dodecyl sulfate (SDS), with the goal of preventing mother-to-child transmission (MTCT) of HIV during breastfeeding in low-resource settings, when there is no safer alternative for the infant but to breastfeed. SDS has been previously shown to effectively inactivate HIV in human milk. An apparatus was developed to simulate milk flow through and drug release from a NSDS. Using this apparatus milk was pulsed through a prototype device containing a non-woven fiber insert impregnated with SDS and the microbicide was rapidly released. The total SDS release from inserts ranged from 70 to 100% of the average 0.07 g load within 50 ml (the volume of a typical breastfeed). Human milk spiked with H9/HIVIIIB cells was also passed through the same set-up. Greater than 99% reduction of cell-associated HIV infectivity was achieved in the first 10 ml of milk. This proof of concept study demonstrates efficient drug delivery to breastfeeding infants is achievable using the NSDS.

Olive leaf phenolics and cardiovascular risk reduction: Physiological effects and mechanisms of action

Olive oil, an important component of the Mediterranean diet, is rich in polyphenols and is known to possess positive health effects relative to other dietary fats. In addition, the leaves of the olive plant (Olea europaea) contain similar phenolics (oleuropein, luteolin-7-glucoside, apigenin-7-glucoside, verbascoside and hydroxytyrosol) to those of olives and olive oil, although at higher concentrations. For example, the most abundant is the secoiridoid, oleuropein, representing 1–14% of olive leaf weight vs. 0.005–0.12% in olive oil. Although currently considered a waste product of the olive oil industry, recent research has suggested beneficial effects of phenolic-rich olive leaf extracts (OLE) in modifying cardiovascular risk biomarkers such as blood pressure, hyperglycaemia, oxidative stress and inflammation, as well as improving vascular function and lipid profiles. Despite this, data regarding the biological actions of OLE has mostly derived from animal, in vitro and ex vivo studies, with limited evidence deriving from human trials. Although the absorption and metabolism of olive oil phenolics has been investigated, less is known about the bioavailability of phenolics from OLE, limiting the interpretation of existing in vitro and ex vivo data. The current review will begin by describing the phenolic composition of olive leaves in comparison with that of the better studied olive oil. It will then review the effects of OLE on cardiovascular risk factors, covering both animal and human studies and will end by considering potential mechanisms of action

Immunosenescence and the gut microbiota: the role of probiotics and prebiotics

The global population is becoming increasingly older presenting medical and economic challenges to society. One factor associated with the aging process is immunosenescence, which may be defined as the decline in immunity with age, and represents a potential causative factor for many age related illnesses. The profile of the gut microbiota is also known to alter with aging and these changes have been linked the declines in the immunity observed in immunosenescence. For example, above the age of 60 years populations of bifidobacteria have been observed to decrease markedly, leading to a reduction in the inhibition of the growth of some pathogens and potentially an increase in the susceptibility to infections. As such, an interest exists in attempting to reverse their decline in elderly individuals, through the use of both probiotics and prebiotics. Both approaches have shown to be encouraging in altering microbiota profiles beneficially and in reducing immunosenescence by reducing the colonisation potential of pathogens and counteracting chronic inflammation. The current review will give an overview of the process of immunosenescence and its role in disease, detail how the microbiota are involved in its progression and highlight data suggesting that pre- and probiotics may counteract these age-related events.

Impact of probiotics, prebiotics and synbiotics on lipid metabolism in humans

Public health strategies for reducing the risk of coronary heart disease have focused on lowering plasma lipids, particularly cholesterol levels, with recent studies also highlighting triacylglycerol (TAG) as an important modifiable risk factor. One approach is to supplement the diet with probiotics, prebiotics or synbiotics. Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Putative health benefits include improved resistance to gastrointestinal infections, reduction in lipid levels and stimulation of the immune system. Prebiotics are selectively fermented dietary components that are aimed at improving host health through selective fermentation by the gut microbiota, such as bifidobacteria and lactobacilli. Animal studies have shown prebiotics to markedly reduce circulating TAG and to a lesser extent cholesterol concentrations, with favourable but inconsistent findings with respect to changes in lipid levels in human studies. Here we provide an overview of the effects, and possible mechanisms, of probiotics, prebiotics and synbiotics (combination of a probiotic and prebiotic) on circulating lipeamia in humans.

Pairwise assembly of organopalladium(II) units with cyanurato(3-) and trithiocyanurato(3-) ligands: formation of chiral Pd12, Pd10 and Pd9 cage-molecules

The o-palladated, chloro-bridged dimers [Pd{2-phenylpyridine(-H)}-μ-Cl]2 and [Pd{N,N-dimethylbenzylamine(-H)}-μ-Cl]2 react with cyanuric acid in the presence of base to afford closed, chiral cage-molecules in which twelve organo-Pd(II) centers, located in pairs at the vertices of an octahedron, are linked by four tetrahedrally-arranged cyanurato(3-) ligands. Incomplete (Pd10) cages, having structures derived from the corresponding Pd12 cages by replacing one pair of organopalladium centers with two protons, have also been isolated. Reaction of [Pd{2-phenylpyridine(-H)}-μ-Cl]2 with trithiocyanuric acid gives an entirely different and more open type of cage-complex, comprising only nine organopalladium centers and three thiocyanurato(3-) ligands: cage-closure in this latter system appears to be inhibited by steric crowding of the thiocarbonyl groups.

Proactive R&D management and firm growth: a punctuated equilibrium model

The external environment is characterized by periods of relative stability interspersed with periods of extreme change, implying that high performing firms must practice exploration and exploitation in order to survive and thrive. In this paper, we posit that R&D expenditure volatility indicates the presence of proactive R&D management, and is evidence of a firm moving from exploitation to exploration over time. This is consistent with a punctuated equilibrium model of R&D investment where shocks are induced by reactions to external turbulence. Using an unbalanced panel of almost 11,000 firm-years from 1997 to 2006, we show that greater fluctuations in the firm's R&D expenditure over time are associated with higher firm growth. Developing a contextual view of the relationship between R&D expenditure volatility and firm growth, we find that this relationship is weaker among firms with higher levels of corporate diversification and negative among smaller firms and those in slow clockspeed industries.

Preference and consumption of a taste enhanced meat meal by older hospital patients: a pilot study

BACKGROUND: Older hospital patients are considered to be at risk of malnutrition due to insufficient dietary intake. OBJECTIVE: To determine whether taste enhancement, using ingredients naturally high in umami compounds, increases preference and consumption of a meal by older hospital patients. METHODS: 31 patients (65–92 years) on elderly carewards in aUKNHS Trust hospital took part in a single-blinded preference and consumption study. They tasted two meats (control and enhanced, presented in balanced order) and stated their preference. At lunch, control and enhanced cottage pie and gravy were served concurrently; patients were asked to consume ad libitum and intake was measured. RESULTS: Taste enhanced meat was significantly preferred (P = 0.001). Although mean consumption was higher for the enhanced compared to control meal (137 g versus 119 g), with higher levels of energy (103 kcal versus 82 kcal) and protein (4.6 g versus 3.4 g) consumed; differences were not significant. CONCLUSIONS: Natural ingredients rich in umami taste compounds can successfully be used to increase preference of meat based meals by older hospital patients. Larger trials are needed to determine whether such increases in preference can significantly increase consumption.

The effects of flavonoid and other polyphenol consumption on cognitive performance: A systematic research review of human experimental and epidemiological studies

Literature reviews suggest flavonoids, a sub-class of polyphenols, are beneficial for cognition. This is the first review examining the effect of consumption of all polyphenol groups on cognitive function. Inclusion criteria were polyphenol vs. control interventions and epidemiological studies with an objective measure of cognitive function. Participants were healthy or mildly cognitively impaired adults. Studies were excluded if clinical assessment or diagnosis of Alzheimer’s disease, dementia, or cognitive impairment was the sole measure of cognitive function, or if the polyphenol was present with potentially confounding compounds such as caffeine (e.g. tea studies) or Ginkgo Biloba. 28 studies were identified; 4 berry juice studies, 4 cocoa studies, 13 isoflavone supplement studies, 3 other supplement studies, and 4 epidemiological surveys. Overall, 16 studies reported cognitive benefits following polyphenol consumption. Evidence suggests that consuming additional polyphenols in the diet can lead to cognitive benefits, however, the observed effects were small. Declarative memory and particularly spatial memory appear most sensitive to polyphenol consumption and effects may differ depending on polyphenol source. Polyphenol berry fruit juice consumption was most beneficial for immediate verbal memory, whereas isoflavone based interventions were associated with significant improvements for delayed spatial memory and executive function. Comparison between studies was hampered by methodological inconsistencies. Hence, there was no clear evidence for an association between cognitive outcomes and polyphenol dose response, duration of intervention, or population studied. In conclusion, however, the findings do imply that polyphenol consumption has potential to benefit cognition both acutely and chronically.

Assumption of knowledge and the Chinese Room in Turing test interrogation

Whilst common sense knowledge has been well researched in terms of intelligence and (in particular) artificial intelligence, specific, factual knowledge also plays a critical part in practice. When it comes to testing for intelligence, testing for factual knowledge is, in every-day life, frequently used as a front line tool. This paper presents new results which were the outcome of a series of practical Turing tests held on 23rd June 2012 at Bletchley Park, England. The focus of this paper is on the employment of specific knowledge testing by interrogators. Of interest are prejudiced assumptions made by interrogators as to what they believe should be widely known and subsequently the conclusions drawn if an entity does or does not appear to know a particular fact known to the interrogator. The paper is not at all about the performance of machines or hidden humans but rather the strategies based on assumptions of Turing test interrogators. Full, unedited transcripts from the tests are shown for the reader as working examples. As a result, it might be possible to draw critical conclusions with regard to the nature of human concepts of intelligence, in terms of the role played by specific, factual knowledge in our understanding of intelligence, whether this is exhibited by a human or a machine. This is specifically intended as a position paper, firstly by claiming that practicalising Turing's test is a useful exercise throwing light on how we humans think, and secondly, by taking a potentially controversial stance, because some interrogators adopt a solipsist questioning style of hidden entities with a view that it is a thinking intelligent human if it thinks like them and knows what they know. The paper is aimed at opening discussion with regard to the different aspects considered.

Ovid, Remedia amoris 95: uerba dat omnis amor

Anagrams and syllabic wordplay of the kind championed by Frederick Ahl in his Metaformations have not always been favourably received by scholars of Latin poetry; I would hesitate to propose the following instance, were it not for the fact that its occurrence seems peculiarly apposite to the context in which it appears. That Roman poets were prepared to use such techniques to enhance the presentation of an argument by exemplifying its operation at a verbal level is demonstrated by the famous passage of Lucretius (DRN 1.907–14; also 1.891–2) in which the poet seeks to illustrate the tendency of semina … ardoris to create fire in wood by the literal presence of elements from the word for ‘fires’ (IGNes) in that denoting wood (lIGNum). A similar conception may underlie the association insinuated by the love elegists between amor and mors, suggesting that death is somehow ‘written into’ love: so Propertius declares laus in amore mori (2.1.47), while Tibullus appears to point to the lurking presence of death in the pursuit of love in the lines interea, dum fata sinunt, iungamus amores: | iam ueniet tenebris Mors adoperta caput (1.1.69–70) – so swift and unexpected is death's approach that it is already present in aMOReS in the preceding line. Ovid's awareness of the poetic potential of this kind of play (if that is the right word for it) is fully exhibited in his celebrated account of Echo and Narcissus in Metamorphoses 3, where the subject matter gives the poet ample scope to exploit the humorous and pathetic possibilities afforded by Echo's fragmented repetitions of the frustrated entreaties of her beloved.