INTRODUCTION

Patient compliant and women-controlled methods for prevention of male-to-female sexual transmission of HIV-1 are urgently needed. Providing inhibitory concentrations of HIV-1 reverse transcriptase inhibitors to impede the replication of virus in the female genital tissue offers a mechanism for prophylaxis of HIV-1. To this end, an intravaginal ring (IVR) for long duration delivery of dapivirine, a non-nucleoside reverse transcriptase inhibitor of HIV-1, was developed using a medical grade polyether urethane TecoflexTM (PU). Our goal was to develop an IVR for delivery of antivirals that is inexpensive and simple to fabricate in large quantities using a commonly available extrusion technology.

MATERIALS AND METHODS

Thermal stability of dapivirine was evaluated with and without PU matrix using NMR, LC/MS and DSC. High thermal stability of dapivirine enabled simple melt-extrusion as the fabrication technique. Monolithic IVRs with dapivirine loadings ranging from 2.5 – 20 mg/g were fabricated. Release profile of dapivirine was measured for 30 days in 25:75 v/v isopropanol-water as sink condition. Release was also evaluated under physiologically relevant conditions simulated using dispersions of egg phosphotidylcholine liposomes.

RESULTS AND DISCUSSION

DSC revealed high solubility of dapivirine in the PU matrix (> 200 mg/g). A sustained release of dapivirine with zero-order kinetics was demonstrated for a period of 30 days. The release rate was directly proportional to the amount of drug loaded. Under physiologically relevant conditions that employed liposome dispersions, zero order release of dapivirine was demonstrated over one week. The high solubility of dapivirine in PU matrix and/or the potential formation of micro-reservoirs of dapivirine in the crystalline hard segment microdomains present in the PU matrix might have caused the observed zero-order release rate.

CONCLUSION

Monolithic IVRs delivering dapivirine at a constant rate were developed using a medical grade polyether urethane. The zero-order release profile and a potentially cost-effective design of this IVR qualify it for further development and clinical research.