An intravaginal ring for the sustained delivery of tenofovir disoproxil fumarate

Abstract

Recent clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) may prevent HIV infection in a significant number of HIV-1 negative individuals in venerable populations; however, trial efficacy has been highly variable, with notable successes and failures. Poor adherence to PrEP regimens has been implicated as a primary factor in determining efficacy of these trials. With the exception of CAPRISA 004 where use of a pericoital tenofovir gel led to a 39% reduction in HIV infection, all successful PrEP regimens to date have used the disoproxil fumarate ester prodrug of tenofovir (TDF) alone or in combination with emtricitabine (FTC). A sustained-release, intravaginal ring (IVR) formulation of TDF holds promise for improving adherence and, thus, increasing the effectiveness of PrEP. Here, a novel IVR delivering TDF with sustained zero-order release characteristics that may be controlled over nearly two orders of magnitude is described. Pod-IVRs containing 1-10 pods delivering TDF at 0.01 – 10 mg d−1 were fabricated and their release characteristics evaluated in vitro. The pod-IVRs stabilized TDF against hydrolytic degradation both in storage and during in vitro release experiments. Successful translation of the TDF pod-IVR from laboratory evaluation to large-scale clinical trials requires the ability to manufacture the devices at low cost and in high quantity. Methods for manufacturing and scale-up were developed and applied to pilot-scale production of TDF pod-IVRs that maintained the IVR’s release characteristics while significantly decreasing the variability in release rate observed between pod-IVRs. This pod-IVR enables for the first time the dose-ranging clinical studies that are required to optimize topical TDF PrEP in terms of efficacy and safety.

Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model

“…In vitro cumulative release profiles for the IVR formulation exhibited linear, sustained drug release (TDF, R 2 ϭ 0.93; MVC, R 2 ϭ 0.95), as is typical for pod-IVRs (21)(22)(23)(24)(25)27). The daily release rates obtained from the slopes of the 28-day cumulative release profiles are presented in Table 2.…”

“…4A) due to various degrees of hydrolysis to TFV (27). On average, TDF made up less than 2% of the molar sum of TDF and TFV in CVL fluid samples, where both analytes were quantifiable in Ͼ95% of the samples.…”

“…Samples were stored at Ϫ30°C prior to analysis. The concentrations of TDF and its hydrolysis products TFV isoproxil [mono(POC)TFV], TFV, and MVC were measured by high-performance liquid chromatography (HPLC) with UV detection as described previously (25,27).…”

Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model

“…The release rate from pod-IVRs is determined by the additive effect of the MAb solubility and three independently variable parameters: the composition and thickness of the pod's polymer membrane coating, the size and number of delivery channels through the ring exposing each individual pod to the vaginal fluid, and the number of pods in the ring. The pod-IVR design has been used for the delivery of relatively hydrophilic small-molecule antiretroviral drugs singly and in combination (43,44,48) and of ovine IgG as a model for human MAb (45). Formulation and in vitro release of VRC01-N.…”

“…Intravaginal ring (IVR) formulations of Nicotiana-manufactured VRC01 using a pod-based design (pod-IVR) (43)(44)(45) were fabricated and evaluated in vitro for release characteristics and MAb stability. Preliminary local safety and pharmacokinetics were investigated in a rhesus macaque primate model, in which it was found that steady-state vaginal fluid levels of VRC01-N were sustained over 21 days and the gp120 binding activity of the VRC01-N in the pod-IVR was retained in vivo.…”