Purpose Nanoparticles formulated from the biodegradable co-polymer poly(lactic-co-glycolic acid) (PLGA), were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting for PSC-RANTES anti-HIV-1 activity. Materials and Methods PSC-RANTES nanoparticles formulated via a double emulsion process and characterized in both in vitro and ex vivo systems to determine PSC-RANTES release rate, nanoparticle tissue permeation, and anti-HIV bioactivity. Results Spherical, monodisperse (PDI = 0.098 ± 0.054) PSC-RANTES nanoparticles (d = 256.58 ± 19.57 nm) with an encapsulation efficiency of 82.23 ± 8.35% were manufactured. In vitro release studies demonstrated a controlled release profile of PSC-RANTES (71.48 ± 5.25% release). PSC-RANTES nanoparticle maintained comparable anti-HIV activity with unformulated PSC-RANTES in a HeLa cell-based system with an IC50 of approximately 1pM. In an ex vivo cervical tissue model, PSC-RANTES nanoparticles displayed a fivefold increase in tissue uptake, enhanced tissue permeation, and significant localization at the basal layers of the epithelium over unformulated PSC-RANTES. Conclusions These results indicate that PSC-RANTES can readily be encapsulated into a PLGA nanoparticle drug delivery system, retain its anti-HIV-1 activity, and deliver PSC-RANTES to the target tissue. This is crucial for the success of this drug candidate as a topical microbicide product.

Women comprise almost 50% of the population of people living with HIV and the majority of these women contracted the virus through sexual transmission in monogamous relationships in the developing world. In these environments, where women are not empowered to protect themselves through the negotiation of condom use, effective means of preventing HIV transmission are urgently needed. In the absence of an approved and effective vaccine, microbicides have become the strategy of choice to provide women with the ability to prevent HIV transmission from their infected partners. Topical microbicides are agents specifically developed and formulated for use in either the vaginal or rectal environment that prevent infection by sexually transmitted infectious organisms, including pathogenic viruses, bacteria and fungi. Although a microbicidal product will have many of the same properties as other anti-infective agents and would be similarly developed through human clinical trials, microbicide development bears its own challenges related to formulation and delivery and the unique environment in which the product must act, as well as the requirement to develop a product that is acceptable to the user. Herein, perspectives based on preclinical and clinical microbicide development experience, which have led to an evolving microbicide development algorithm, will be discussed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010”.

Purpose Polymeric quick dissolving films were developed as a solid dosage topical microbicide formulation for the vaginal delivery of the highly potent and non-toxic, dual-acting HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) pyrimidinedione, IQP-0528. Methods Formulated from approved excipients, a polyvinyl alcohol (PVA) based film was manufactured via solvent casting methods. The film formulations were evaluated based upon quantitative physicochemical evaluations defined by a Target Product Profile (TPP) Results Films dosed with 0.1 % (w/w) of IQP-0528 disintegrated within 10 minutes with over 50% of drug released and near 100% total drug released after 30 minutes. The IQP-0528 films were found to be non-toxic in in vitro CEM-SS and PBMC cell-based assays and biologically active with sub-nanomolar efficacy against HIV-1 infection. In a 12 month stability protocol, the IQP-0528 films demonstrated no significant degradation at International Conference on Harmonization (ICH) recommended standard (25°C / 65% relative humidity (R.H.)) and accelerated (40°C / 75% R.H.) environmental conditions. Conclusions Based on the above evaluations, a vaginal film formulation has been identified as a potential solid dosage form for the vaginal delivery of the topical microbicide candidate IQP-0528.

Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection (“percent protected”). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.Electronic supplementary materialThe online version of this article (doi:10.1007/s13346-015-0227-1) contains supplementary material, which is available to authorized users.