Development of a nanoparticle in-film-matrix for enhanced antiretroviral drug absorption in the female genital tract

Abstract

This study explored strategies for lipid–drug conjugation and delivery systems for enhancing antiretroviral (ARV) drug efficacy. Lipid–drug conjugates (LDCs) have the potential to enhance oral bioavailability, lipophilicity, toxicity, and drug adsorption. So, linking ARV drugs with lipids produces LDCs, which alters the pharmacokinetic properties of ARV drugs, resulting in improved effectiveness. Although LDCs may be administered without a delivery carrier, they are typically integrated into suitable delivery systems such as lipid nanoparticles, polymeric nanoparticles, micelles, liposomes, emulsions, and carbon nanotubes. Herein explored the possibility of Eudragit S100 (ES100), a methylmethacrylate-methacrylic acid copolymer, and sodium alginate as nanocarriers for a lipidic ARV prodrug [tenofovir disoproxil fumarate (TDF)] in the female genital tract (FGT). Vaginal CD4+ T cells constitute the primary significant target for successful establishment of HIV infection. Oral pre-exposure prophylaxis (PrEP) has been successful as a prevention tool for individuals at high risk of getting HIV-1. However, the challenges with this medication include strict user compliance, a decrease in condom use, bone and renal toxicity, and the development of antiviral resistance. To circumvent these drawbacks, topical delivery systems for PrEP have been proposed. Within these delivery systems, intra vaginal films possess a greater likelihood of enhancing drug delivery due to quick dissolving nature, small size for administration and lack of need for an applicator. Nanoparticle-based drug delivery systems, on the other hand, have the potential to deliver drugs that are poorly water-soluble, like most ARVs. Hence, in this research, TDF-loaded alginate-ES100 nanoparticles were developed, and subsequently incorporated into a hydroxypropyl methylcellulose (HPMC) film. Alginate, alginate-ES100 nanoparticles, and HPMC films were prepared using the ionic gelation, emulsion/gelation complexation method, and the casting method, respectively. Nanocarriers were tested using morphological, physicochemical, in vitro drug release, and cytotoxicity analyses. The presence of spherical and uniformly distributed nanoparticles was revealed in SEM and TEM nanoparticle images, whereas SEM images for films showed significant degrees of porosity and compactness. The FTIR spectrum showed that alginate and calcium chloride interacted due to ionic bonds linking divalent calcium ions and the -COO- of alginate groups. Alginate and ES100 interacted via the ester C=O amide stretching, resulting in the formation of a novel and potent anhydride bond. HPMC was also adhered to this anhydride bond. VI The results obtained from the XRD revealed sharp, clear peaks, which are associated with the high purity of the systems. The DSC results, on the other hand, suggest that there is a thermodynamic compatibility between sodium alginate, ES100, and the TDF drug, as evidenced by the endothermic and exothermic peaks observed. Moreover, the results of the DSC confirmed that the TDF-loaded nanoparticles were successfully incorporated into the HPMC polymer. Under experimental design and optimization, overall size distribution results ranged from 134.9 to 228.0 nm, while zeta potential results showed stable nanoparticles (−17.8 to −38.4 MV). The optimal nanoparticle formulation exhibited a maximum cumulative in vitro release of 72% (pH 4.2) for a duration of 96 hours, whereas the 2.5% film released the highest amount (54%) of the TDF drug for a duration of 96 hours. In vitro cytotoxicity tests revealed the safety of TDF-loaded nanoparticles on vaginal epithelial cells at concentrations of 0.025 mg/mL, 0.5 mg/mL, and 1 mg/mL for 72 h. Lastly, histopathology analysis showed mild to moderate changes when the film delivery system containing 60 mg of the TDF drug was inserted for four days in pigs. When taken together, the in vitro findings indicate that alginate-ES100 nanoparticles possess the capability to preserve and sustain the release of the TDF drug in the FGT. On the contrary, in vivo studies suggest the possibility of developing a low-dose, non-toxic microbicide that can be administered for a prolonged period in the vagina for HIV patients.