The use of water soluble mucoadhesive gels for the intravesical delivery of epirubicin to the bladder for the treatment of non-muscle invasive bladder cancer

Objectives: To develop an epirubicin-loaded, water-soluble mucoadhesive gels that have the correct rheological properties to facilitate their delivery into the bladder via a catheter, while allowing for their spread across the bladder wall with limited expansion of the bladder and increasing the retention of epirubicin in the bladder and flushing with urine.

Methods: Epirubicin-loaded hydroxyl ethyl cellulose (HEC) and hydroxy propyl methyl cellulose (HPMC) gels were manufactured and tested for their rheological properties. Their ability to be pushed through a catheter was also assessed as was their in-vitro drug release, spreading in a bladder and retention of epirubicin after flushing with simulated urine.

Key findings: Epirubicin drug release was viscosity-dependent. The 1 and 1.5% HEC gels and the 1, 1.5 and 2% HPMC gels had the correct viscosity to be administered through a model catheter and spread evenly across the bladder wall under the pressure of the detrusor muscle. The epirubicin-loaded gels had an increased retention time in the bladder when compared with a standard intravesical solution of epirubicin, even after successive flushes with simulated urine.

Conclusion: The increased retention of epirubicin in the bladder by the HEC and HPMC gels warrant further investigation, using an in-vivo model, to assess their potential for use as treatment for non-muscle-invasive bladder cancer.

A metapopulation model of species boundaries

The majority, if not all, species have a limited geographic range bounded by a distribution edge. Violent ecotones such as sea coasts clearly produce edges for many species; however such ecotones, while sufficient for the formation of an edge, are not always necessary. We demonstrate this by simulation in discrete time of a spatially structured finite size metapopulation subjected to a spatial gradient in per-unit-time population extinction probability together with spatially structured dispersal and recolonisation. We find that relatively sharp edges separating a homeland or main geographical range from an outland or zone of relatively sparse and ephemeral colonisation can form in gradual environmental gradients. The form and placing of the edge is an emergent property of the metapopulation dynamics. The sharpness of the edge declines with increasing dispersal distance, and is dependent on the relative scales of dispersal distance and gradient length. The space over which the edge develops is short relative to the potential species range. The edge is robust against changes in both the shape of the environmental gradient and to a lesser extent to alterations in the kind of dispersal operating. Persistence times in the absence of environmental gradients are virtually independent of the shape of the dispersal function describing migration. The common finding of bell shaped population density distributions across geographic ranges may occur without the strict necessity of a niche mediated response to a spatially autocorrelated environment.

Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination

OBJECTIVES: We aimed to highlight the utility of novel dissolving microneedle (MN)-based delivery systems for enhanced transdermal protein delivery. Vaccination remains the most accepted and effective approach in offering protection from infectious diseases. In recent years, much interest has focused on the possibility of using minimally invasive MN technologies to replace conventional hypodermic vaccine injections.

METHODS: The focus of this study was exploitation of dissolving MN array devices fabricated from 20% w/w poly(methyl vinyl ether/maleic acid) using a micromoulding technique, for the facilitated delivery of a model antigen, ovalbumin (OVA).

KEY FINDINGS: A series of in-vitro and in-vivo experiments were designed to demonstrate that MN arrays loaded with OVA penetrated the stratum corneum and delivered their payload systemically. The latter was evidenced by the activation of both humoral and cellular inflammatory responses in mice, indicated by the production of immunoglobulins (IgG, IgG1, IgG2a) and inflammatory cytokines, specifically interferon-gamma and interleukin-4. Importantly, the structural integrity of the OVA following incorporation into the MN arrays was maintained.

CONCLUSION: While enhanced manufacturing strategies are required to improve delivery efficiency and reduce waste, dissolving MN are a promising candidate for 'reduced-risk' vaccination and protein delivery strategies.

Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33mg (90%) of the drug initially loaded into the arrays was delivered over 24h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263μgml(-1) at the 24h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10cm(2) could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs.

Tackling the problem of blood culture contamination in the intensive care unit using an educational intervention

Blood culture contamination (BCC) has been associated with unnecessary antibiotic use, additional laboratory tests and increased length of hospital stay thus incurring significant extra hospital costs. We set out to assess the impact of a staff educational intervention programme on decreasing intensive care unit (ICU) BCC rates to <3% (American Society for Microbiology standard). BCC rates during the pre-intervention period (January 2006-May 2011) were compared with the intervention period (June 2011-December 2012) using run chart and regression analysis. Monthly ICU BCC rates during the intervention period were reduced to a mean of 3·7%, compared to 9·5% during the baseline period (P < 0·001) with an estimated potential annual cost savings of about £250 100. The approach used was simple in design, flexible in delivery and efficient in outcomes, and may encourage its translation into clinical practice in different healthcare settings.

Towards an Improved Phasor Measurement Unit Data Communications Framework

This paper discusses a proposed new communications framework for phasor measurement units (PMU) optimized for use on wide area networks. Traditional PMU telecoms have been optimized for use in environments where bandwidth is restricted. The new method takes the reliability of the telecommunications medium into account and provides guaranteed delivery of data whilst optimizing for realtime delivery of the most current data. Other important aspects, such as security, are also considered.

Hydrogel-forming microneedle arrays made from light-responsive materials for on-demand transdermal drug delivery

We describe, for the first time, stimuli-responsive hydrogel-forming microneedle (MN) arrays that enable delivery of a clinically-relevant model drug (ibuprofen) upon application of light. MN arrays were prepared using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) by micromolding. The obtained MN arrays showed good mechanical properties. The system was loaded with up to 5% (w/w) ibuprofen included in a light-responsive 3,5-dimethoxybenzoin conjugate. Raman spectroscopy confirmed the presence of the conjugate inside the polymeric MN matrix. In vitro, this system was able to deliver up to three doses of 50 mg of ibuprofen upon application of an optical trigger over a prolonged period of time (up to 160 hours). This makes the system appealing as a controlled release device for prolonged periods of time. We believe that this technology has potential for use in ?on-demand? delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care.

Microneedle-mediated delivery of donepezil: Potential for improved treatment options in Alzheimer's disease

Transdermal drug delivery is an attractive route of drug administration, however there are relatively few marketed transdermal products. To increase delivery across the skin, strategies to enhance skin permeability are widely investigated, with microneedles demonstrating particular promise. Hydrogel-forming microneedles are inserted into the skin, and following dissolution of a drug loaded reservoir and movement of the drug through the created channels, the microneedle array is removed intact, and can then be readily and safely discarded. This study presents the formulation and evaluation of an integrated microneedle patch containing the Alzheimer's drug, donepezil hydrochloride. The integrated patch consisted of hydrogel-forming microneedles in combination with a donepezil hydrochloride containing film. Formulation and characterisation of plasticised films, prepared from poly(vinylpyrrolidone) or poly (methyl vinyl ether co-maleic anhydride/acid) (Gantrez(®)) polymers, is presented. Furthermore, in vitro permeation of donepezil hydrochloride across neonatal porcine skin from the patches was investigated, with 854.71 μg ± 122.71 μg donepezil hydrochloride delivered after 24 h, using the optimum patch formulation. Following administration of the patch to an animal model, plasma concentrations of 51.8 ± 17.6 ng/mL were obtained, demonstrating the success of this delivery platform for donepezil hydrochloride.

Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes

Aims/hypothesis: We aimed to determine whether plasma lipoproteins, after leakage into the retina and modification by glycation and oxidation, contribute to the development of diabetic retinopathy in a mouse model of type 1 diabetes.

Methods: To simulate permeation of plasma lipoproteins intoretinal tissues, streptozotocin-induced mouse models of diabetes and non-diabetic mice were challenged with intravitreal injection of human ‘highly-oxidised glycated’ low-density lipoprotein (HOG-LDL), native- (N-) LDL, or the vehicle PBS.Retinal histology, electroretinography (ERG) and biochemical markers were assessed over the subsequent 14 days.

Results: Intravitreal administration of N-LDL and PBS had noeffect on retinal structure or function in either diabetic or non-diabetic animals. In non-diabetic mice, HOG-LDL elicited a transient inflammatory response without altering retinal function,but in diabetic mice it caused severe, progressive retinal injury, with abnormal morphology, ERG changes, vascular leakage, vascular endothelial growth factor overexpression, gliosis, endoplasmic reticulum stress, and propensity to apoptosis.

Conclusions/interpretation: Diabetes confers susceptibility to retinal injury imposed by intravitreal injection of modified LDL. The data add to the existing evidence that extravasated, modified plasma lipoproteins contribute to the propagation of diabetic retinopathy. Intravitreal delivery of HOG-LDL simulates a stress known to be present, in addition to hyperglycaemia, in human diabetic retinopathy once blood retinal barriers are compromised.

Acute electronic cigarette use: nicotine delivery and subjective effects in regular users

Rationale Electronic cigarettes are becoming increasingly popular among smokers worldwide. Commonly reported reasons for use include the following: to quit smoking, to avoid relapse, to reduce urge to smoke, or as a perceived lower-risk alternative to smoking. Few studies, however, have explored whether electronic cigarettes (e-cigarettes) deliver measurable levels of nicotine to the blood. Objective This study aims to explore in experienced users the effect of using an 18-mg/ml nicotine first-generation e-cigarette on blood nicotine, tobacco withdrawal symptoms, and urge to smoke. Methods Fourteen regular e-cigarette users (three females), who are abstinent from smoking and e-cigarette use for 12 h, each completed a 2.5 h testing session. Blood was sampled, and questionnaires were completed (tobacco-related withdrawal symptoms, urge to smoke, positive and negative subjective effects) at four stages: baseline, 10 puffs, 60 min of ad lib use and a 60-min rest period. Results Complete sets of blood were obtained from seven participants. Plasma nicotine concentration rose significantly from a mean of 0.74 ng/ml at baseline to 6.77 ng/ml 10 min after 10 puffs, reaching a mean maximum of 13.91 ng/ml by the end of the ad lib puffing period. Tobacco-related withdrawal symptoms and urge to smoke were significantly reduced; direct positive effects were strongly endorsed, and there was very low reporting of adverse effects. Conclusions These findings demonstrate reliable blood nicotine delivery after the acute use of this brand/model of e-cigarette in a sample of regular users. Future studies might usefully quantify nicotine delivery in relation to inhalation technique and the relationship with successful smoking cessation/harm reduction.

Generate disaggregated soil allocation data using a Minimum Cross Entropy Model

Montado ecosystem in the Alentejo Region, south of Portugal, has enormous agro-ecological and economics heterogeneities. A definition of homogeneous sub-units among this heterogeneous ecosystem was made, but for them is disposal only partial statistical information about soil allocation agro-forestry activities. The paper proposal is to recover the unknown soil allocation at each homogeneous sub-unit, disaggregating a complete data set for the Montado ecosystem area using incomplete information at sub-units level. The methodological framework is based on a Generalized Maximum Entropy approach, which is developed in thee steps concerning the specification of a r order Markov process, the estimates of aggregate transition probabilities and the disaggregation data to recover the unknown soil allocation at each homogeneous sub-units. The results quality is evaluated using the predicted absolute deviation (PAD) and the "Disagegation Information Gain" (DIG) and shows very acceptable estimation errors.

Development and characterization of novel vehicles for topical drug delivery

Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2016

Nanofibers fabricated using triaxial electrospinning as zero order drug delivery systems

A new strategy for creating functional trilayer nanofibers through triaxial electrospinning is demonstrated. Ethyl cellulose (EC) was used as the filament-forming matrix in the outer, middle, and inner working solutions and was combined with varied contents of the model active ingredient ketoprofen (KET) in the three fluids. Triaxial electrospinning was successfully carried out to generate medicated nanofibers. The resultant nanofibers had diameters of 0.74 ± 0.06 μm, linear morphologies, smooth surfaces, and clear trilayer nanostructures. The KET concentration in each layer gradually increased from the outer to the inner layer. In vitro dissolution tests demonstrated that the nanofibers could provide linear release of KET over 20 h. The protocol reported in this study thus provides a facile approach to creating functional nanofibers with sophisticated structural features.

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults.

OBJECTIVE: The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. DESIGN: To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. RESULTS: Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. CONCLUSIONS: These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.

Production systems and supplier selection: a multi-phase process model

Purpose: This paper presents a combined multi-phase supplier selection model. The process repeatedly revisits the criteria and sourcing decision as the development process continues. This enables a structured adoption of product and production system innovation from strategic suppliers, where previously the literature purely focuses on product innovation or cost reduction. Design/methodology/approach: The authors adopted an embedded researcher style, inductive, qualitative case study of an industrial supply cluster comprising a focal automotive company and its interaction with three different strategic stamping suppliers. Findings: Our contribution is the multi-phased production and product innovation process. This is an advance from traditional supplier selection and also an extension of ideas of supplier-located product development as it includes production system development, and complements the literature on working with strategic suppliers. Specifically, we explicitly articulate the previously unreported issue of whether a supplier chosen for its innovation capabilities at the start of the new product development process will also be the most appropriate supplier during the production system development phase, when an ability to work collaboratively may be the most important attribute, or in the large-scale production phase when an ability to manufacture at low unit cost may be most important. Originality/value: The paper identifies a multi-phase approach to tendering within a fixed body of strategic suppliers which seeks to identify the optimum technological and process decisions as well as the traditional supplier sourcing choice. These areas have not been combined before and generate a valuable approach for firms to adopt as well as for researchers to extend our understanding of a highly complex process.