Composite films for vaginal delivery of tenofovir disoproxil fumarate and emtricitabine

Abstract

Prevention of male-to-female HIV transmission remains a huge challenge and topical pre-exposure prophylaxis (PrEP) using microbicides may help overcoming the problem. In this work, different types of films containing the antiretroviral drugs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) were developed. Formulations based in poly(vinyl alcohol) and pectin were produced as single- or double-layered films. Films containing TDF/FTC or TDF/FTC-loaded Eudragit® L 100 nanoparticles (NPs) obtained by nano spray-drying were tested for physicochemical, technological and biological properties relevant to microbicide development. All systems featured organoleptic and mechanical properties considered suitable for vaginal use and potentially favoring users’ acceptability. Film design (single- or double-layered, and the incorporation or not of NPs) had a greater impact on disintegration time and drug release in a simulated vaginal fluid. Upon film disintegration, pH and osmolality of the fluid remained within values considered compatible with the vaginal environment. Double-layered films significantly reduced burst effect and the overall release of both drugs as compared to fast releasing, single-layered films. The effect on delaying drug release was most noticeable when TDF/FTC-loaded NPs were incorporated into double-layered films. This last design seems particularly advantageous for the development of a coitus-independent, on-demand microbicide product. Moreover, all film types were shown potentially safe when evaluated by the MTT metabolic activity and lactate dehydrogenase release assays using HeLa and CaSki cervical cell lines. Overall, results support that proposed films may be suitable for the vaginal delivery of TDF/FTC in the context of topical PrEP.

Introduction

Oral pre-exposure prophylaxis (PrEP) based on tenofovir is currently recommended by the World Health Organization as an effective strategy for preventing sexual HIV transmission [1]. Once daily Truvada® (Gilead Sciences), a combination product containing 300 mg of tenofovir disoproxil fumarate (TDF) and 200 mg of emtricitabine (FTC), is the most usual regimen, being currently approved by the US Food and Drug Administration and the European Medicines Agency for the protection of individuals at high risk of infection. Oral PrEP is already available in various countries worldwide, including the United States, France, South Africa, Canada or Australia. Others are expected to follow [2]. Various clinical studies support that the use of TDF/FTC is highly effective when used consistently [3], [4], [5]. However, conflicting results from two trials suggest that protection provided by oral PrEP to women may be diminished as compared to men who have sex with men [6], [7]. Poor adherence to daily regimens seems to be the main reason for these observations [8], although acceptability issues, onset of systemic effects, and differential risk perception may also play key roles [9]. One additional but highly relevant question concerns actual biological differences between the cervicovaginal and colorectal compartments that limit the drug concentration that is reached in each mucosae following oral administration of TDF/FTC. For instance, a recent pharmacokinetics/pharmacodynamics (PK/PD) modeling study found that only nearly perfect adherence to oral PrEP with TDF/FTC may be able to provide considerable protection in the female genital tract, while discontinuous use could still prevent rectal HIV transmission [10]. Data from clinical trials also seem to backup this hypothesis [11], [12]. Thus, further insights are needed regarding the most appropriate way to pursuit PrEP strategies for women, namely by enabling higher and prolonged TDF/FTC levels at the cervicovaginal tract.

An interesting alternative to oral TDF/FTC regimens in women could be topical PrEP with vaginal microbicides [13]. These investigational products have been designed to be present in the vagina during and following intercourse and prevent male-to-female HIV transmission. The ability to generate high local drug levels while minimizing systemic exposure may be beneficial, not only for enhancing protection in the mucosa but also for avoiding side effects [14]. For example, moderate protection from infection was observed in previous clinical trials for women using a tenofovir gel [15] or a dapivirine ring [16], [17], without differences being observed in terms of adverse events as compared to matching placebos. One important issue of the development of a microbicide product has to deal with the choice of dosage form. The use of vaginal rings has been previously proposed for the delivery of the TDF/FTC combination [18], [19]. Despite allowing maintaining potentially protective drug levels in the vagina for several weeks to months, rings require continuous use and may not be acceptable, particularly by women engaging in erratic sexual activity. Vaginal tablets containing tenofovir (base) and FTC have also been developed as microbicides for discontinuous use [20], but this dosage form is regarded by women as less preferable [21]. Conversely, vaginal films are typically well accepted, easy and discrete to use, and suitable for the design of on-demand microbicides [22]. The technology involved in film manufacturing is well established, allowing to obtain highly reproducible, stable, inexpensive and versatile drug delivery platforms that can be scaled up utilizing conventional industrial setups. Polymers used as matrix-forming materials usually confer mucoadhesive properties to films, which are regarded as beneficial in prolonging vaginal drug retention [23]. Furthermore, the modification of the basic film design by incorporating drug-loaded nanocarriers that allow to better control release kinetics represents an appealing strategy [24]. In this study, we report on the development of different composite films, including one produced by the incorporation of drug-loaded nanoparticles (NPs), to obtain novel platforms for the vaginal delivery of TDF and FTC in the context of topical PrEP.