Characterisation of protein stability in rod-insert vaginal rings

A major goal in vaccine development is elimination of the 'cold chain', the transport and storage system for maintenance and distribution of the vaccine product. This is particularly pertinent to liquid formulation of vaccines. We have previously described the rod-insert vaginal ring (RiR) device, comprising an elastomeric body into which are inserted lyophilised, rod-shaped, solid drug dosage forms, and having potential for sustained mucosal delivery of biomacromolecules, such as HIV envelope protein-based vaccine candidates. Given the solid, lyophilised nature of these insert dosage forms, we hypothesised that antigen stability may be significantly increased compared with more conventional solubilised vaginal gel format. In this study, we prepared and tested vaginal ring devices fitted with lyophilised rod inserts containing the model antigen bovine serum albumin (BSA). Both the RiRs and the gels that were freeze-dried to prepare the inserts were evaluated for BSA stability using PAGE, turbidimetry, microbial load, MALDI-TOF and qualitative precipitate solubility measurements. When stored at 4°C, but not when stored at 40°C/75% RH, the RiR formulation offered protection against structural and conformational changes to BSA. The insert also retained matrix integrity and release characteristics. The results demonstrate that lypophilised gels can provide relative protection against degradation at lower temperatures compared to semi-solid gels. The major mechanism of degradation at 40°C/75% RH was shown to be protein aggregation. Finally, in a preliminary study, we found that addition of trehalose to the formulation significantly reduces the rate of BSA degradation compared to the original formulation when stored at 40°C/75% RH. Establishing the mechanism of degradation, and finding that degradation is decelerated in the presence of trehalose, will help inform further development of RiRs specifically and polymer based freeze-dried systems in general.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Continuous phase synchronised drives (for a rod-making machine)

Traditional high speed machinery actuators are powered and coordinated by mechanical linkages driven from a central drive, but these linkages may be replaced by independently synchronised electric drives. Problems associated with utilising such electric drives for this form of machinery were investigated. The research concentrated on a high speed rod-making machine, which required control of high inertias (0.01-0.5kgm2), at continuous high speed (2500 r/min), with low relative phase errors between two drives (0.0025 radians). Traditional minimum energy drive selection techniques for incremental motions were not applicable to continuous applications which require negligible energy dissipation. New selection techniques were developed. A brushless configuration constant enabled the comparison between seven different servo systems; the rate earth brushless drives had the best power rates which is a performance measure. Simulation was used to review control strategies, such that a microprocessor controller with a proportional velocity loop within a proportional position loop with velocity feedforward was designed. Local control schemes were investigated as means of reducing relative errors between drives: the slave of a master/slave scheme compensates for the master's errors: the matched scheme has drives with similar absolute errors so the relative error is minimised, and the feedforward scheme minimises error by adding compensation from previous knowledge. Simulation gave an approximate velocity loop bandwidth and position loop gain required to meet the specification. Theoretical limits for these parameters were defined in terms of digital sampling delays, quantisation, and system phase shifts. Performance degradation due to mechanical backlash was evaluated. Thus any drive could be checked to ensure that the performance specification could be realised. A two drive demonstrator was commissioned with 0.01kgm2 loads. By use of simulation the performance of one drive was improved by increasing the velocity loop bandwidth fourfold. With the master/slave scheme relative errors were within 0.0024 radians at a constant 2500 r/min for two 0.01 kgm^2 loads.

The Rod photoreceptor ABCR gene and its significance in ocular disease

This article describes the advances in molecular genetics which have led to the discovery of the ABCR gene, the structure and possible function of the ABCR protein and the importance of this protein in ocular disease.

Hierarchical ZnO “rod like” architecture synthesized via reverse micellar route for improved photocatalytic activity

Hierarchical ZnO “rod like” architecture was successfully synthesized via reverse micellar route and characterized by various techniques. The FESEM studies show controlled decomposition of zinc oxalate into ZnO “rod like” architecture at 500 °C with slow heat rate at 1°/min. Interestingly, improved photocatalytic activity was observed for the degradation of Rhodamine B, due to the self assembly of hexagonal nanoparticles of zinc oxide forming hierarchical ZnO “rod like” architecture which can greatly enhance the light utilization rate due to its special architecture and enlarge the specific surface area, providing more reaction sites and promoting mass transfer. More importantly, the reusability studies of this architecture were most economical.