Triggered drug delivery from biomaterials

Importance of the field: Conventional dosing methods are frequently unable to deliver the clinical requirement of the patient. The ability to control the delivery of drugs from implanted materials is difficult to achieve, but offers promise in diverse areas such as infection-resistant medical devices and 10 responsive implants for diabetics. Areas covered in this review: This review gives a broad overview of recent progress in the use of triggers that can be used to achieve modulation of drug release rates from implantable biomaterials. In particular, these can be classified as being responsive to one or more of the following stimuli: a 15 chemical species, light, heat, magnetism, ultrasound and mechanical force. What the reader will gain: An overview of the potential for triggered drug delivery to give methods for tailoring the dose, location and time of release of a wide range of drugs where traditional dosing methods are not suitable. Particular emphasis is given to recently reported systems, and important 20 historical reports are included. Take home message: The use of externally or internally applied triggers of drug delivery to biomaterials has significant potential for improved delivery modalities and infection resistance.

Characterisation of the Thermal, Spectroscopic and Drug Dissolution Properties of Mefenamic Acid and Polyoxyethylene–Polyoxypropylene Solid Dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F681), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F681 as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/?uorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F681 up to a concentration of 35% (w/w). Conversely, the solubility in the solidstate matrix was limited to<15% (w/w); determined by Raman spectroscopy, PXRD and ?uorescence microscopy. As expected the dissolution properties of MA were signi?cantly in?uenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was signi?cantly slower. This study has clearly demonstrated the complexity of drug– polymer binary blends and in particular de?ning the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the signi?cant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends.

Moisture-Activated Rheological Structuring of Nonaqueous Poloxamine–Poly(Acrylic Acid) Systems Designed as Novel Biomedical Implants

This study reports the formulation/characterisation of novel polymeric platforms designed to behave as low-viscosity systems in the nonaqueous state, however, following uptake of aqueous ?uids, exhibit rheological structuring and mucoadhesion. The rheological/mechanical and mucoadhesive properties of platforms containing poly(acrylic acid) (PAA, 1%, 3%, 5%, w/w) and poloxamines (Tetronic 904, 901, 704, 701, 304), both in the absence and presence of phosphate buffered saline (PBS, pH 7.4) are described. With the exception of Tetronic 904, all formulations exhibited Newtonian ?ow in the nonaqueous state, whereas, all aqueous formulations displayed pseudoplastic ?ow. The consistency and viscoelastic properties were dependent on the concentrations of PAA and PBS and Tetronic grade. PBS signi?cantly increased the consistency, viscoelasticity and mucoadhesion, reaching a maximum at a de?ned concentration of PBS that was dependent on PAA concentration and Tetronic grade. Formulations containing Tetronic 904 exhibited greatest consistency and elasticity both prior to and after dilution with PBS. Increasing PAA concentration enhanced the mucoadhesive properties. Prolonged drug release of metronidazole was observed from formulations containing 10% (w/w) PBS, 3% and, particularly, 5% (w/w) PAA. It is suggested that the physicochemical properties of formulations containing 3% or 5% (w/w) PAA and Tetronic 904, would render them suitable platforms for administration to body cavities.

Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

Rheological Evaluation of the Isothermal Cure Characteristics of Medical Grade Silicone Elastomers

Silicone elastomer systems have been shown to offer potential for the fabrication of medical devices and sustained release drug delivery devices comprising low molecular weight drugs and protein therapeutics. For drug delivery systems in particular, there is often no clear rationale for selection of the silicone elastomer grade, particularly in respect of optimizing the manufacturing conditions to ensure thermal stability of the active agent and short cycle times. In this study, the cure characteristics of a range of addition-cure and condensation-cure, low-consistency, implant-grade silicone elastomers, either as supplied or loaded with the model protein bovine serum albumin (BSA) and the model hydrophilic excipient glycine, were investigated using oscillatory rheology with a view to better understanding the isothermal cure characteristics. The results demonstrate the influence of elastomer type, cure temperature, protein loading, and glycine loading on isothermal cure properties. By measuring the cure time required to achieve tan delta values representative of early and late-stage cure conditions, a ratio t(1)/t(2) was defined that allowed the cure characteristics of the various systems to be compared. Sustained in vitro release of BSA from glycine-loaded silicone elastomer covered rod devices was also demonstrated over 14 days. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 116: 2320-2327, 2010

Northern Ireland: The Politics of Constraint

The article surveys the interrupted experience of devolution in Northern Ireland since 1999 and draws a number of comparisons between the first devolved Assembly and Executive and their successors elected in 2007. It underlines the significance of the changed political, electoral and paramilitary context in the period leading up to the 2007 Assembly election which, together with a number of procedural changes effected by the 2006 St Andrews Agreement, enabled the restoration of power-sharing devolution to occur. Against the background of its legislative and policy record and the wider altered state of Northern Ireland, it concludes that the contrived consociational model of governance can work, up to a point, but perhaps as much because of the politics of constraint than consociationalism's much vaunted promise to reflect and engender the politics of accommodation.