Characterisations of the weak expectation property

We use representations of operator systems as quotients to deduce various characterisations of the weak expectation property (WEP) for C∗ -algebras. By Kirchberg’s work on WEP, these results give new formulations of Connes’ embedding problem.

A proposed model membrane and test method for microneedle insertion studies

A commercial polymeric film (Parafilm M (R), a blend of a hydrocarbon wax and a polyolefin) was evaluated as a model membrane for microneedle (MN) insertion studies. Polymeric MN arrays were inserted into Parafilm M (R) (PF) and also into excised neonatal porcine skin. Parafilm M (R) was folded before the insertions to closely approximate thickness of the excised skin. Insertion depths were evaluated using optical coherence tomography (OCT) using either a force applied by a Texture Analyser or by a group of human volunteers. The obtained insertion depths were, in general, slightly lower, especially for higher forces, for PF than for skin. However, this difference was not a large, being less than the 10% of the needle length. Therefore, all these data indicate that this model membrane could be a good alternative to biological tissue for MN insertion studies. As an alternative method to OCT, light microscopy was used to evaluate the insertion depths of MN in the model membrane. This provided a rapid, simple method to compare different MN formulations. The use of Parafilm M (R), in conjunction with a standardised force/time profile applied by a Texture Analyser, could provide the basis for a rapid MN quality control test suitable for in-process use. It could also be used as a comparative test of insertion efficiency between candidate MN formulations. 

Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer

Objectives: To develop and manufacture both immediate and sustained release vaginal tablets containing the anticancer drug disulfiram, which has the potential to be used as a non-invasive treatment for cervical cancer. 
Methods: Disulfiram-loaded vaginal tablets were manufactured at pilot scale using the direct compression method. These tablets were tested in accordance with the European Pharmacopeia testing of solid dosage form guidelines. They were also tested using a biorelevant dissolution method as well as a dual-chambered release model designed to better mimic the dynamic nature of the vaginal vault.
Key findings: We have developed both immediate and sustained release vaginal tablets, which when manufactured at pilot scale are within the limits set by the European Pharmacopeia for the testing of solid dosage forms. Furthermore, these tablets are capable of releasing disulfiram in vitro using the dual-chambered release model at levels 25 000 times and 35 000 times greater than its IC50 concentration for the HeLa cervical cancer cell line. 
Conclusions: The successful pilot manufacture and testing of both the immediate and sustained release disulfiram-loaded vaginal tablets warrant further investigation, using an in-vivo model, to assess their potential for use as a non-invasive treatment option for cervical cancer.

Identification of systemic immune response markers through metabolomic profiling of plasma from calves given an intra-nasally delivered respiratory vaccine

Vaccination procedures within the cattle industry are important disease control tools to minimize economic and welfare burdens associated with respiratory pathogens. However, new vaccine, antigen and carrier technologies are required to combat emerging viral strains and enhance the efficacy of respiratory vaccines, particularly at the point of pathogen entry. New technologies, specifically metabolomic profiling, could be applied to identify metabolite immune-correlates representative of immune protection following vaccination aiding in the design and screening of vaccine candidates. This study for the first time demonstrates the ability of untargeted UPLC-MS metabolomic profiling to identify metabolite immune correlates characteristic of immune responses following mucosal vaccination in calves. Male Holstein Friesian calves were vaccinated with Pfizer Rispoval® PI3 + RSV intranasal vaccine and metabolomic profiling of post-vaccination plasma revealed 12 metabolites whose peak intensities differed significantly from controls. Plasma levels of glycocholic acid, N-[(3α,5β,12α)-3,12-Dihydroxy-7,24-dioxocholan-24-yl]glycine, uric acid and biliverdin were found to be significantly elevated in vaccinated animals following secondary vaccine administration, whereas hippuric acid significantly decreased. In contrast, significant upregulation of taurodeoxycholic acid and propionylcarnitine levels were confined to primary vaccine administration. Assessment of such metabolite markers may provide greater information on the immune pathways stimulated from vaccine formulations and benchmarking early metabolomic responses to highly immunogenic vaccine formulations could provide a means for rapidly assessing new vaccine formulations. Furthermore, the identification of metabolic systemic immune response markers which relate to specific cell signaling pathways of the immune system could allow for targeted vaccine design to stimulate key pathways which can be assessed at the metabolic level.

Immunogenetic responses in calves to intranasal delivery of bovine respiratory syncytial virus (BRSV) epitopes encapsulated in poly (DL-lactide-co-glycolide) microparticles

Bovine respiratory syncytial virus (BRSV) is the principal aetiological agent of the bovine respiratory disease complex. A BRSV subunit vaccine candidate consisting of two synthetic peptides representing putative protective epitopes on BRSV surface glycoproteins in soluble form or encapsulated in poly(lactide-co-glycolide) (PLG) microparticles were prepared. Calves (10 weeks old) with diminishing levels of BRSV-specific maternal antibody were intranasally administered a single dose of the different peptide formulations. Peptide-specific local immune responses (nasal secretion IgA), but not systemic humoral (serum IgG) or cellular responses (serum IFN-γ), were generated by all forms of peptide. There was a significant reduction in occurrence of respiratory disease in the animals inoculated with all peptide formulations compared to animals given PBS alone. Furthermore no adverse effects were observed in any of the animals post vaccination. These results suggest that intranasal immunisation with the peptide subunit vaccine does induce an as yet unidentified protective immune response.

Advances in Learning Bayesian Networks of Bounded Treewidth

This work presents novel algorithms for learning Bayesian networks of bounded treewidth. Both exact and approximate methods are developed. The exact method combines mixed integer linear programming formulations for structure learning and treewidth computation. The approximate method consists in sampling k-trees (maximal graphs of treewidth k), and subsequently selecting, exactly or approximately, the best structure whose moral graph is a subgraph of that k-tree. The approaches are empirically compared to each other and to state-of-the-art methods on a collection of public data sets with up to 100 variables.

Re-Visiting Sylvia Townsend Warner

Sylvia Townsend Warner was born in 1893 in Harrow and died in Dorset in 1978. Her writing career was both productive and diverse, spanning poems, short stories, novels, music reviews, a biography, translations of Proust, and a guide to Somerset. But this list, impressive as it is, does not do justice to the idiosyncrasy and heterogeneity of her work. While she is well known mostly for the seven novels she published, those works are all radically different in style and content. Indeed, Townsend Warner's singularity has, it could be argued, made it difficult to place her in the various fields and sub-fields of 20th-century literary studies. She shares as many similarities as differences with the high modernists who dominated the literary landscape of the interwar period. Likewise she fits, yet also resists, the more recent formulations of intermodernist and middlebrow scholarship that have attempted to interrogate and expand the horizons of mid-20th century literature.

Printability of calcium phosphate: Calcium sulphate powders for the application of tissue engineered bone scaffolds using the 3D printing technique

In this study, calcium phosphate (CaP) powders were blended with a three-dimensional printing (3DP) calcium sulfate (CaSO4)-based powder and the resulting composite powders were printed with a water-based binder using the 3DP technology. Application of a water-based binder ensured the manufacture of CaP:CaSO4 constructs on a reliable and repeatable basis, without long term damage of the printhead. Printability of CaP:CaSO4 powders was quantitatively assessed by investigating the key 3DP process parameters, i.e. in-process powder bed packing, drop penetration behavior and the quality of printed solid constructs. Effects of particle size, CaP:CaSO4 ratio and CaP powder type on the 3DP process were considered. The drop penetration technique was used to reliably identify powder formulations that could be potentially used for the application of tissue engineered bone scaffolds using the 3DP technique. Significant improvements (p < 0.05) in the 3DP process parameters were found for CaP (30-110 μm):CaSO4 powders compared to CaP (< 20 μm):CaSO4 powders. Higher compressive strength was obtained for the powders with the higher CaP:CaSO4 ratio. Hydroxyapatite (HA):CaSO4 powders showed better results than beta-tricalcium phosphate (β-TCP):CaSO4 powders. Solid and porous constructs were manufactured using the 3DP technique from the optimized CaP:CaSO4 powder formulations. High-quality printed constructs were manufactured, which exhibited appropriate green compressive strength and a high level of printing accuracy.

Static and dynamic degradation of sintered calcium phosphate ceramics

The chemical compositions of calcium phosphate materials are similar to that of bone making them very attractive for use in the repair of critical size bone defects. The bioresorption of calcium phosphate occurs principally by dissolution. To determine the impact of composition and flow conditions on dissolution rates, calcium phosphate tablets were prepared by slip casting of ceramic slips with different ratios of hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP). Dissolution was evaluated at pH4 using both a static and dynamic flow regime. Both the composition of the HA:ß-TCP tablet and flow regime noticeably influenced the rate of dissolution; the 50:50 HA:ß-TCP composition demonstrating the greatest level of dissolution, and, exposure of the ceramic specimens to dynamic conditions producing the highest rate of dissolution. Understanding the impact of phase composition and flow condition with respect to the dissolution of calcium phosphate will aid in the development and improvement of materials for bone substitution.

Development of an app to support learning in A-level maths

This project involved producing an app for smart devices to enable modernised learning for A-level maths students. Research in a stakeholder school showed that 94% of pupils surveyed within the upper-secondary level owned a smartphone and most owned a tablet also, emphasising the opportunity for using apps to support learning. The app was developed using iBuildApp, an online app-creation programme which requires no programming. Past exam questions and solutions, notes and video tutorials were included and the topic was vectors, identified by teachers as problematic. Pupils generally found the app easy to use and wanted further development. The videos were popular despite this not ranking highly as a preferred method of revision previously. Teachers were happy for pupils to use the app to supplement their learning, both in the classroom and outside.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87μg/mL in rats at 24h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.

Novel Supercritical Carbon Dioxide Impregnation Technique for the Production of Amorphous Solid Drug Dispersions: A Comparison to Hot Melt Extrusion

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

Solubility parameter based screening methods for early stage formulation development of itraconazole amorphous solid dispersions

Objectives: This article uses conventional and newly extended solubility parameter (δ) methods to identify polymeric materials capable of forming amorphous dispersions with itraconazole (itz). Methods: Combinations of itz and Soluplus, Eudragit E PO (EPO), Kollidon 17PF (17PF) or Kollidon VA64 (VA64) were prepared as amorphous solid dispersions using quench cooling and hot melt extrusion. Storage stability was evaluated under a range of conditions using differential scanning calorimetry and powder X-ray diffraction. Key findings: The rank order of itz miscibility with polymers using both conventional and novel δ-based approaches was 17PF > VA64 > Soluplus > EPO, and the application of the Flory–Huggins lattice model to itz–excipient binary systems corroborated the findings. The solid-state characterisation analyses of the formulations manufactured by melt extrusion correlated well with pre-formulation screening. Long-term storage studies showed that the physical stability of 17PF/vitamin E TPGS–itz was poor compared with Soluplus and VA64 formulations, and for EPO/itz systems variation in stability may be observed depending on the preparation method. Conclusion: Results have demonstrated that although δ-based screening may be useful in predicting the initial state of amorphous solid dispersions, assessment of the physical behaviour of the formulations at relevant temperatures may be more appropriate for the successful development of commercially acceptable amorphous drug products.

Improving antimicrobial release kinetics from hydrophobic polymer implants via ion pairing to combat biomedical-device related infection

Purpose The aim of this study is to improve the drug release properties of antimicrobial agents from hydrophobic biomaterials using using an ion pairing strategy. In so doing antimicrobial agents may be eluted and maintained over a sufficient time period thereby preventing bacterial colonisation and subsequent biofilm formation on medical devices. Methods The model antimicrobial agent was chlorhexidine and the selected fatty acid counter ions were capric acid, myristic acid and stearic acid. The polymethyl methacrylate films were loaded with 2% of fatty acid:antimicrobial agent at the following molar ratios; 0.5:1M, 1:1M and 2:1M and thermally polymerized using azobisisobutyronitrile initiator. Drug release experiments were subsequently performed over a 3-month period and the mass of drug released under sink conditions (pH 7.0, 37oC) quantified using a validated HPLC-UV method. Results In all platforms, a burst of chlorhexidine release was observed over the initial 24-hour period. Similar release kinetics were observed between the formulations during the initial 28 days. However, as time progressed, the chlorhexidine baseline plateaued after 56 days whereas formulations containing the counterions appeared to continuously elute linearly with time. As can be observed in figure 1, the rank order of total chlorhexidine release in the presence of 0.5M fatty acid was myristic acid (40%) > capric acid (35%) > stearic acid (30%)> chlorhexidine baseline (15%). Conclusion The incorporation of fatty acids within the formulation significantly improved chlorhexidine solubility within both the monomer and the polymer and enhanced the drug release kinetics over the period of study. This is attributed to the greater diffusivity of chlorhexidine through PMMA in the presence of fatty acids. In th absence of fatty acids, chlorhexidine release was facilitated by dissolution of surface associated drug particles. This study has illustrated the ability of fatty acids to modulate chlorhexidine release from a model biomaterial through enhanced diffusivity. This strategy may prove advantageous for improved medical devices with enhanced resistance to infection.