Nanomemulsion of megestrol acetate for improved oral bioavailability and reduced food effect

Abstract

Megestrol acetate (MGA) belongs to the BCS class II drugs with low solubility and high permeability, and its oral absorption in conventional dosage form MGA microcrystal suspension (MGA MS) is very limited and greatly affected by food. In this study, MGA nanoemulsion (MGA NE) was formulated based on solubility, phase-diagram and release studies. Then oral bioavailability of MGA NE and MGA MS was evaluated. A randomized two-way crossover trial was conducted on six male dogs under fed and fasting conditions. Blood concentrations of MGA were analyzed using LC-MS/MS. MGA NE yielded 5.00-fold higher oral bioavailability in fasting conditions and displayed more stable absorption profiles after food intake compared with MGA MS.

Quantitative Assessment of Food Effect on the Pharmacokinetics of Nano‐Crystallized Megestrol Acetate

“…In our analysis, the bioavailability of NCMA increased 2.2 times with food intake. This degree of increase was greater than that seen in previous studies that reported 1.1 times to 1.5 times increases with food intake [8,24]. The higher bioavailability increase in our study might be attributable to various factors, including ethnic differences and the composition of the high-fat meal.…”

“…In the simulation, the dosing scheme chosen was multiple dosing for 7 days assuming a steady-state, based on the drug elimination half-life of 20-50 hr reported in the literature [6][7][8]. The optimal daily dose, D*, to be administered under fasting conditions, was defined as the dose that minimizes the absolute relative error (ERR, %), which is defined as follows:…”

“…Subsequently, with advancements in pharmaceutical science, nano-crystallized megestrol acetate (NCMA) has been developed. Through animal and human studies, nano-crystallization has been found to enhance bioavailability in a fasting administration to some extent, thereby compensating for reduced systemic exposure compared with that in a fed administration [5][6][7][8].…”

Food for thought: formulating away the food effect – a PEARRL review

“…Various other lipid‐based formulations have also been investigated in preclinical species with varying levels of success, and with a general trend towards reducing rather than eliminating food effects . While the assertion that LBF are excellent candidates to eliminate food effect is widespread, the evidence from the literature, and from product literature in particular is underwhelming and a more systematic investigation is required to fully elucidate the potential for LBF to overcome food effects …”

Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects

“…It has also been difficult to optimize the dosage of megestrol acetate due to its pharmacokinetic characteristics, which are similar to those of other BCS Class II drugs. These characteristics include reduced bioavailability and susceptibility to food intake when taken orally [ 21 ]. Although megestrol acetate has increased bioavailability when administered after a high-fat meal [ 22 ], in clinical use, it is usually administered under fasting conditions because it is used in patients with cachexia.…”