ABSTRACT
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.
Subject(s)
Contraceptive Devices, Female , HIV Infections/prevention & control , HIV Reverse Transcriptase/pharmacokinetics , Pyrimidines/pharmacokinetics , Administration, Intravaginal , Delayed-Action Preparations , Diffusion , Dimethylpolysiloxanes/chemistry , Equipment Design , Equipment Safety , Excipients/chemistry , Female , HIV Reverse Transcriptase/administration & dosage , HIV Reverse Transcriptase/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Lactose/chemistry , Molecular Structure , Myristates/chemistry , Nylons/chemistry , Permeability , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Silicone Elastomers/chemistry , Solubility , Technology, Pharmaceutical/instrumentation , Technology, Pharmaceutical/standards , Temperature , Time FactorsABSTRACT
OBJECTIVES: The feasibility of providing prolonged and controlled release of the experimental non-nucleoside reverse transcriptase inhibitor TMC120 from a silicone vaginal ring in quantities sufficient to maintain a vaginal concentration offering protection against heterosexual HIV transmission was investigated. METHODS: Core-type, silicone elastomer vaginal rings containing TMC120 were manufactured, and in vitro release studies performed under sink conditions. The experimental release data, as determined by HPLC, were correlated with estimates of vaginal TMC120 concentrations required to inhibit HIV replication. RESULTS: Continuous, zero-order release of TMC120 from core-type vaginal rings was observed in vitro over a 71 day period, equivalent to 136 microg/day. The release rate is predicted to maintain vaginal concentrations of the antiretroviral in the range of several orders of magnitude in excess of reported HIV inhibitory concentration values. CONCLUSIONS: Continuous and prolonged zero-order release of TMC120 from a silicone vaginal ring device at quantities predicted to prevent HIV infection was observed.
