Formulation and characterization of liposomes containing drug absorption enhancers for optimized anti-HIV and antimalarial drug delivery.

Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. due to the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of drug absorption enhancers (DAEs) (also referred to as bioenhancers) into dosage forms, and exploration of nanocarriers such as liposomes as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Liposomes loaded with efavirenz or mefloquine in combination with drug absorption enhancers, as well as placebo dosage forms, were prepared using a thin-lipid film hydration technique and characterized for their particle size and zeta potentials, entrapment efficiency, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) using H-4-II-E liver cells in vitro. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1 mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26 mol/mol/mol) exhibited the best results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release, and permeability. DSPC:CHOL:DPPC liposomes released EFV-based formulations better than DPPC:CHOL liposomes for immediate release behaviour. DOPC:CHOL liposomes produced a controlled release and more drug was released in the presence of DAEs for both EFV (0.4-fold higher) and MQ-based (sevenfold higher) formulations in the first 2 h. However, these liposomes were less biocompatible (< 50% cell viability) with liver cells. DOPC:CHOL and DSPC:CHOL:DPPC liposomes could provide a useful nano-formulation platform, which could ensure drug loading, followed by sustained release of both anti-HIV and antimalaria drugs.

Determination of effective concentrations of drug absorption enhancers using in vitro and ex vivo models.

BACKGROUND: Achievement of an effective concentration of the pharmaceutically active ingredient in the blood and/or at the target site is an important aspect in the formulation of drugs and therefore needs to be quantified. Any concentration above therapeutic levels can cause toxic effects whereas low concentrations can be sub-therapeutic. This paper investigated different concentrations of selected commercially sourced analytical-grade pure chemicals as potential drug absorption enhancers in vitro and ex vivo to determine the lowest effective concentrations for optimizing drug absorption in oral dosage forms. METHODS: Recombinant cytochrome (CYP) 3A4 enzyme and recombinant p-glycoprotein membrane models were utilized for the investigation of in vitro inhibitory effects of drug absorption enhancers. Promega (2015) protocols were adopted for both assays. The everted porcine intestinal ex vivo model was employed for assessing effects of the drug absorption enhancers on the absorption of propranolol. RESULTS: The lowest effective CYP3A4 inhibitory concentrations were observed for curcumin (75µM and 100 µM), quercetin (75 and 100 µM) and glycyrrhizic acid (50 µM) while the most effective p-glycoprotein (P-gp) inhibition concentrations were curcumin (10, 15, 25, 50, 75 and 100 µM), sinomenine (50, 75, and 100 µM), quercetin (75 and 100 µM) and naringin (50 µM). Additive effects were observed between combinations of quercetin (75 µM) and curcumin (100 µM); quercetin (75 µM) and curcumin (75 µM); quercetin (75 µM) and curcumin (50 µM), and quercetin (75 µM) with curcumin (10 µM), which increased the basal ex vivo absorption of propranolol from 1.24 ± 0.03 µg/mL to 5.19 ± 0.12 µg/mL, 4.17 ± 0.05 µg/mL, 3.86 ± 0.10 µg/mL, and 4.07± 0.05 µg/mL respectively, after 2 hours. CONCLUSION: Incorporation of the drug absorption enhancers (e.g., curcumin and quercetin), at specific concentrations, in dosage forms could improve the bioavailability of the BCS Class III and IV drugs that are substrates of CYP3A4 and p-glycoprotein.