Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients incorporated into the IVRs.

On the abundance gradients of organic molecules along the TMC-1 ridge

Gradients in molecular abundances along the TMC-1 ridge have been observed by several authors, most recently in a comprehensive study by Pratap et al. These can be explained by there being a difference in density, C/O ratio, or chemical evolutionary state along the ridge. The presence at the carbon-rich

CH abundance gradient in TMC-1

Aims. The aim of this study is to examine if the well-known chemical gradient in TMC-1 is reflected in the amount of rudimentary forms of carbon available in the gas-phase. As a tracer we use the CH radical which is supposed to be well correlated with carbon atoms and simple hydrocarbon ions. Methods. We observed the 9-cm ?-doubling lines of CH along the dense filament of TMC-1. The CH column densities were compared with the total H2 column densities derived using the 2MASS NIR data and previously published SCUBA maps and with OH column densities derived using previous observations with Effelsberg. We also modelled the chemical evolution of TMC-1 adopting physical conditions typical of dark clouds using the UMIST Database for Astrochemistry gas-phase reaction network to aid the interpretation of the observed OH/CH abundance ratios. Results. The CH column density has a clear peak in the vicinity of the cyanopolyyne maximum of TMC-1. The fractional CH abundance relative to H2 increases steadily from the northwestern end of the filament where it lies around 1.0 × 10-8 , to the southeast where it reaches a value of 2.0 × 10-8. The OH and CH column densities are well correlated, and we obtained OH/CH abundance ratios of ~16–20. These values are clearly larger than what has been measured recently in diffuse interstellar gas and is likely to be related to C to CO conversion at higher densities. The good correlation between CH and OH can be explained by similar production and destruction pathways. We suggest that the observed CH and OH abundance gradients are mainly due to enhanced abundances in a low-density envelope which becomes more prominent in the southeastern part and seems to continue beyond the dense filament. Conclusions. An extensive envelope probably signifies an early stage of dynamical evolution, and conforms with the detection of a large CH abundance in the southeastern part of the cloud. The implied presence of other simple forms of carbon in the gas phase provides a natural explanation for the observation of “early-type” molecules in this region.