Formulation and optimisation of novel transfersomes for sustained release of local anaesthetic

Objective: To investigate the effect of formulation parameters on the preparation of transfersomes as sustained‐release delivery systems for lidocaine and to develop and validate a new high‐performance liquid chromatography (HPLC) method for analysis. Method: Taguchi design of experiment (DOE) was used to optimise lidocaine‐loaded transfersomes in terms of phospholipid, edge activator (EA) and phospholipid : EA ratio. Transfersomes were characterised for size, polydispersity index (PDI), charge and entrapment efficiency (%EE). A HPLC method for lidocaine quantification was optimised and validated using a mobile phase of 30%v/v PBS (0.01 m) : 70%v/v Acetonitrile at a flow rate of 1 ml/min, detected at 255 nm with retention time of 2.84 min. The release of lidocaine from selected samples was assessed in vitro. Key findings: Transfersomes were 200 nm in size, with PDI ~ 0.3. HPLC method was valid for linearity (0.1–2 mg/ml, R2 0.9999), accuracy, intermediate precision and repeatability according to ICH guidelines. The %EE was between 44% and 56% and dependent on the formulation parameters. Taguchi DOE showed the effect of factors was in the rank order : lipid : EA ratio ˃ EA type ˃ lipid type. Optimised transfersomes sustained the release of lidocaine over 24 h. Conclusion: Sustained‐release, lidocaine‐loaded transfersomes were successfully formulated and optimised using a DOE approach, and a new HPLC method for lidocaine analysis was developed and validated

Pre-formulation and systematic evaluation of amino acid assisted permeability of insulin across in vitro buccal cell layers

The aim of this work was to investigate alternative safe and effective permeation enhancers for buccal peptide delivery. Basic amino acids improved insulin solubility in water while 200 and 400 µg/mL lysine significantly increased insulin solubility in HBSS. Permeability data showed a significant improvement in insulin permeation especially for 10 µg/mL of lysine (p < 0.05) and 10 µg/mL histidine (p < 0.001), 100 µg/mL of glutamic acid (p < 0.05) and 200 µg/mL of glutamic acid and aspartic acid (p < 0.001) without affecting cell integrity; in contrast to sodium deoxycholate which enhanced insulin permeability but was toxic to the cells. It was hypothesized that both amino acids and insulin were ionised at buccal cavity pH and able to form stable ion pairs which penetrated the cells as one entity; while possibly triggering amino acid nutrient transporters on cell surfaces. Evidence of these transport mechanisms was seen with reduction of insulin transport at suboptimal temperatures as well as with basal-to-apical vectoral transport, and confocal imaging of transcellular insulin transport. These results obtained for insulin is the first indication of a possible amino acid mediated transport of insulin via formation of insulin-amino acid neutral complexes by the ion pairing mechanism

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs

The Tumor Microenvironment: The Making of a Paradigm

What has been will be again, what has been done will be done again; there is nothing new under the su