Rationale and Safety Assessment of a Novel Intravaginal Drug-Delivery System with Sustained DL-Lactic Acid Release, Intended for Long-Term Protection of the Vaginal Microbiome

Hans Verstraelen, Chris Vervaet, Jean-Paul Remon, Hans Verstraelen, Chris Vervaet, Jean-Paul Remon

Abstract

Bacterial vaginosis is a prevalent state of dysbiosis of the vaginal microbiota with wide-ranging impact on human reproductive health. Based on recent insights in community ecology of the vaginal microbiome, we hypothesize that sustained vaginal DL-lactic acid enrichment will enhance the recruitment of lactobacilli, while counteracting bacterial vaginosis-associated bacteria. We therefore aimed to develop an intravaginal device that would be easy to insert and remove, while providing sustained DL-lactic acid release into the vaginal lumen. The final prototype selected is a vaginal ring matrix system consisting of a mixture of ethylene vinyl acetate and methacrylic acid-methyl methacrylate copolymer loaded with 150 mg DL-lactic acid with an L/D-lactic acid ratio of 1:1. Preclinical safety assessment was performed by use of the Slug Mucosal Irritation test, a non-vertebrate assay to evaluate vaginal mucosal irritation, which revealed no irritation. Clinical safety was evaluated in a phase I trial with six healthy nulliparous premenopausal volunteering women, with the investigational drug left in place for 7 days. Colposcopic monitoring according to the WHO/CONRAD guidelines for the evaluation of vaginal products, revealed no visible cervicovaginal mucosal changes. No adverse events related to the investigational product occurred. Total release from the intravaginal ring over 7 days was estimated through high performance liquid chromatography at 37.1 (standard deviation 0.9) mg DL-lactic acid. Semisolid lactic acid formulations have been studied to a limited extent in the past and typically consist of a large volume of excipients and very high doses of lactic acid, which is of major concern to mucosal safety. We have documented the feasability of enriching the vaginal environment with pure DL-lactic acid with a prototype intravaginal ring. Though the efficacy of this platform remains to be established possibly requiring further development, this approach may offer a novel avenue to modulate and protect the vaginal microbiota.

Trial registration: ClinicalTrials.gov NCT02314429.

Conflict of interest statement

Competing Interests: The invention described in the manuscript is filed as a patent under references WO2013010915A1, European Patent EP2731587 A1, and US Patent 9,168,303 with assignee Ghent University. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. TREND study flowchart of the…
Fig 1. TREND study flowchart of the phase I trial.
Legend: *patients were selected based on chronological order of enrolment. To ascertain that the study could take place as planned, an excess number of eligible study participants were recruited. Similarly, at each stage two back-up study subjects were standby to allow for rapid replacement of subjects, as proved necessary in one case, who violated the prohibitions explained in the informed consent form.

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