Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study

Abstract

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

Pharmacokinetic Comparison between Methotrexate-Loaded Nanoparticles and Nanoemulsions as Hard- and Soft-Type Nanoformulations: A Population Pharmacokinetic Modeling Approach

“…Previous formulation studies have aimed to identify and compare differences in pharmacokinetics between free methotrexate solution and methotrexate-loaded nanoformulation administration groups [ 6 , 7 ]. These were pharmacokinetic studies on methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid)] and nanoemulsion formulations (olive oil and Labrasol), as well as free methotrexate solution as a control.…”

“…Research into changes in the pharmacokinetic properties of nano-sized formulations of various drugs is actively being conducted [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Most nanoformulation studies have reported that the bioavailability of nanoformulated drugs is largely improved and delayed-release patterns are observed in comparison to the standard drugs used as controls [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. These results clearly imply that changes of in vivo pharmacokinetics are associated with the nanoformulation of the drug.…”

“…These results clearly imply that changes of in vivo pharmacokinetics are associated with the nanoformulation of the drug. Most nanoformulation studies reported to date have made major comparisons between standard formulations (such as solutions) and nanoformulations [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Those studies reported major improvements in the pharmacokinetic properties of the nanoformulations.…”

“…Through a comparison between soft- and hard-type nanoformulations and exploration of effective covariates, we suggest which formulation would be more efficient in terms of pharmacokinetics, and attempt to aid in the development of new nanoformulations in the future. For this study, based on the results of administration of methotrexate-loaded nanoparticles [ 6 ] and nanoemulsions [ 7 ] in rats, the pharmacokinetic difference between these nanoformulations and methotrexate solution was first investigated through population pharmacokinetic analysis. Next, we identified the pharmacokinetic differences between nanoparticles (hard-type) and nanoemulsions (soft-type) containing methotrexate using a population pharmacokinetic modeling approach.…”

Design of Non-Haemolytic Nanoemulsions for Intravenous Administration of Hydrophobic APIs

“…Some of them are already approved for parenteral use, e.g., Labrafac ® WL 1349, Miglyol ® 812, Lipoid ® E PC, Lipoid ® S 100, Kollisolv ® PEG 400, Kolliphor ® HS15, Kolliphor ® EL, Kollisolv ® PG, and Tween ® 80 [34]. Among the excipients not approved for IV route, the three macrogolglycerides are recommended for oral, topical, or vaginal routes, but given their interesting properties, they are reported in several formulation assays for IV administration [35][36][37]. Transcutol ® HP is approved by the FDA for topical and transdermal routes, and besides, the manufacturer recommends its use for parenteral route.…”