Nanoparticle-in-microparticle drug delivery systems of β-casein micelles for the local oral co-administration of antiretroviral combinations

Abstract The antiretroviral (ARV) cocktail revolved the treatment of the human immunodeficiency virus (HIV) infection. Drug combinations have been also tested to treat other infectious diseases, including the recent coronavirus disease 2019 (COVID-19) outbreak. To simplify administration fixed-dose combinations have been introduced, however, oral anti-HIV therapy still struggles with low oral bioavailability of many ARVs. This work investigated the co-encapsulation of two clinically relevant ARV combinations, tipranavir (TPV):efavirenz (EFV) and darunavir (DRV):efavirenz (EFV):ritonavir (RTV), within the core of β-casein (bCN) micelles. Encapsulation efficiency in both systems was ∼100%. Cryo-transmission electron microscopy and dynamic light scattering of the ARV-loaded colloidal dispersions indicate full preservation of the spherical morphology, and x-ray diffraction confirm that the encapsulated drugs are amorphous. To prolong the physicochemical stability the formulations were freeze-dried without cryo/lyoprotectant, and successfully re-dispersed, with minor changes in morphology. Then, the ARV-loaded micelles were encapsulated within microparticles of Eudragit® L100, which prevented enzymatic degradation and minimized drug release under gastric-like pH conditions in vitro. At intestinal pH, the coat dissolved and released the nanocarriers and content. Overall, our results confirm the promise of this flexible and modular technology platform for oral delivery of fixed dose combinations.