Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day−1) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.

Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel "pod IVR" platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ؎ 109 g ml ؊1 (slow releasing) and 1.84 ؎ 1.97 mg ml ؊1 (fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ؎ 54.8 g g ؊1 and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ؎ 150 fmol/10 6 cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIV SF162p3 ) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.

No abstract