Electrospun fibers for vaginal administration of tenofovir disoproxil fumarate and emtricitabine in the context of topical pre-exposure prophylaxis

Abstract

Women are particularly vulnerable to sexual HIV-1 transmission. Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is highly effective in avoiding new infections in men, but protection has only been shown to be moderate in women. Such differences have been associated, at least partially, to poor drug penetration of the lower female genital tract and the need for strict adherence to continuous daily oral intake of TDF/FTC. On-demand topical microbicide products could help circumvent these limitations. We developed electrospun fibers based on polycaprolactone (PCL fibers) or liposomes associated to poly(vinyl alcohol) (liposomes-in-PVA fibers) for the vaginal co-delivery of TDF and FTC, and assessed their pharmacokinetics in mice. PCL fibers and liposomes-in-PVA fibers were tested for morphological and physicochemical properties using scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. Fibers featured organoleptic and mechanical properties compatible with their suitable handling and vaginal administration. Fluorescent quenching of mucin in vitroused as a proxy for mucoadhesionwas intense for PCL fibers, but mild for liposomes-in-PVA fibers. Both fibers were shown safe in vitro and able to rapidly release drug content (15-30 min) under sink conditions. Liposomes-in-PVA fibers allowed increasing genital drug concentrations after a single intravaginal administration when compared to continuous daily treatment for five days with 25-times higher oral doses. For instance, the levels of tenofovir and FTC in vaginal lavage were around 4-and 29-fold higher, respectively. PCL fibers were also superior to oral treatment, although to a minor extent (approximately 2-fold higher drug concentrations in lavage). Vaginal tissue drug levels were generally low for all treatments, while systemic drug exposure was negligible in the case of fibers. These data suggest that proposed fibers may provide an interesting alternative or an ancillary option to oral PrEP in women.

Lipid Nanocarriers for Anti-HIV Therapeutics: a Focus on Physicochemical Properties and Biotechnological Advances

“…In another study, a hybrid system composed of polymeric nanofibers containing liposomes loaded with FTC and TDF provided rapid onset of local ARV levels in mice after a single vaginal administration compared to five days of continuous daily use of oral TDF/FTC [123]. These results may be also translatable into a fairly wide protection time window in humans [123].…”

“…Moreover, SLN possessed an adequate size and high density of negative surface charge that creates a hydrophilic surface that facilitates diffusion and minimizes entrapment into mucus [126]. In another study, a hybrid system composed of polymeric nanofibers containing liposomes loaded with FTC and TDF provided rapid onset of local ARV levels in mice after a single vaginal administration compared to five days of continuous daily use of oral TDF/FTC [123]. These results may be also translatable into a fairly wide protection time window in humans [123].…”

Nanofiber Carriers of Therapeutic Load: Current Trends

“…Although, in this case, it was not clear whether electrospinning preserved spherical structures of liposomes or gave rise to phospholipid bilayers, good EGCG release and activity against UV- and H 2 O 2 -caused oxidative stress were achieved. Similarly, HIV-1 prophylactic formulations were prepared in electrospun PVA/liposome NFs loaded with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) [ 132 ]. Good dispersibility of liposomes in hydrophilic PVA polymer led to better polymer alignment and decrease of NF diameter.…”

Recent advances in electrospun nanofiber vaginal formulations for women's sexual and reproductive health

“…However, certain vaginal formulations also suffer drawbacks, including low retention times due to leakage or messiness (for gels and creams), discomfort after administration, or repetitive dosing regimens. Fibers have emerged as a new option for vaginal drug administration, with particular focus on HIV microbicides targeted at HIV acquisition (Nunes et al, 2021).…”

“…Electrospun fibers containing tenofovir disoproxil fumarate and emtricitabine have also been reported for vaginal PrEP (Nunes et al, 2021). Liposomes containing both drug substances were first prepared using the thin film hydration method.…”