Abstract
The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems.
Highlights
The global HIV/AIDS pandemic continues to drive advances in biomedical technologies designed to quell the spread of the virus [1]
We recently demonstrated the three-month zero-order delivery of TFV from a hydrophilic polyether urethane (HPEU) reservoir intravaginal rings (IVR) [25]
We evaluated the feasibility of using end-caps made from the same polymers as the LNG-segment rate controlling membrane (RCM) (PEU-2 and 65D), but aimed to minimize the end-cap length due to their mechanical rigidity (EG-65D has a flexural modulus of 255 MPa) and the fact that a large cap would eliminate additional length from the TFV
Summary
The global HIV/AIDS pandemic continues to drive advances in biomedical technologies designed to quell the spread of the virus [1]. The recent USFDA approval of oral TruvadaH for HIV preexposure prophylaxis (PrEP) in discordant couples is a major biomedical advance [2]. In the CAPRISA 004 trial, topical vaginal application of the tenofovir (TFV) 1% gel used episodically before and after intercourse resulted in a 39% reduction in HIV infection in women [3]. It is conceptually clear that using oral and topical antiretroviral (ARV) drugs to interrupt the early events of sexual HIV transmission and dissemination is biologically and biomedically possible. Since the discovery of low rates of adherence in the Carraguard trial [13] and subsequently in the VOICE trial [4] it has been clear that infrequent use of gels by women likely has been a significant factor contributing to the low rates of effectiveness observed in most gel PrEP trials to date. If PrEP is to be a technological success, new PrEP modalities are desperately needed that are easier to use and more desirable to women, and are supported by high user demand
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