Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption

Abstract

Lopinavir is an antiretroviral, antiparasitic agent and recently utilized in treatment of COVID-19. Unfortunately, lopinavir exhibited poor oral bioavailability due to poor dissolution, extensive pre-systemic metabolism, and significant P-glycoprotein intestinal efflux. Accordingly, the aim was to enhance dissolution rate and intestinal absorption of lopinavir. This employed co-processing with menthol which is believed to modify crystalline structures and inhibit intestinal efflux. Lopinavir was mixed with menthol at different molar ratios before ethanol assisted kneading. Formulations were evaluated using FTIR spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and dissolution studies. Optimum ratio was utilized to assess lopinavir intestinal permeability. This employed in situ rabbit intestinal perfusion technique. FTIR, DSC and XRD indicated formation of lopinavir-menthol co-crystals at optimum molar ratio of 1:2. Additional menthol underwent phase separation due to possible self-association. Co-crystallization significantly enhanced lopinavir dissolution rate compared with pure drug to increase the dissolution efficiency from 24.96% in case of unprocessed lopinavir to 91.43% in optimum formulation. Lopinavir showed incomplete absorption from duodenum and jejuno-iliac segments with lower absorptive clearance from jejuno-ileum reflecting P-gp efflux. Co-perfusion with menthol increased lopinavir intestinal permeability. The study introduced menthol as co-crystal co-former for enhanced dissolution and augmented intestinal absorption of lopinavir.

Keywords: Co-crystal; Dissolution rate; In situ; Intestinal permeability; Lopinavir; Menthol.

Graphical abstract

Fig. 1

FTIR spectra of menthol, pure lopinavir, and formulations containing lopinavir and menthol at molar ratios of 1:1,1:1.5, 1:2, and 1:3.

Fig. 2

Representative DSC thermograms of menthol, pure lopinavir, and formulations containing lopinavir and menthol at molar ratios of 1:1,1:1.5, 1:2, and 1:3.

Fig. 3

X-ray diffraction patterns of menthol, pure lopinavir, and formulations containing lopinavir and menthol at molar ratios of 1:1,1:1.5, 1:2, and 1:3.

Fig. 4

Dissolution profiles of pure lopinavir, and formulations containing lopinavir and menthol at molar ratios of 1:1,1:1.5, 1:2, and 1:3.

Fig. 5

Absorptive clearance of lopinavir from deudenum (left) and jejuno-ileum (right) as a function of the net water flux. The data obtained after perfusion of aqueous drug solution (a,b), and after co-perfusion with menthol (c,d).