Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: preparation, characterization, and in vivo oral bioavailability and anticancer effect

Abstract

ObjectiveThe current study sought to design an oral delivery system of pemetrexed (PMX), a multitargeted antifolate antimetabolite, by enhancing its intestinal membrane permeability.Materials and methodsPMX was ionically complexed with a permeation enhancer such as Nα-deoxycholyl-l-lysyl-methylester (DCK) and prepared as an amorphous solid dispersion by mixing with dispersants such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and poloxamer 188 (P188), forming an HP-beta-CD/PMX/DCK/P188; the complex was incorporated into multiple water-in-oil-in-water nanoemulsions in a supersaturated state (HP-beta-CD/PMX/DCK/P188-NE).ResultsAfter complex formation, the partition coefficient and in vitro membrane permeability of PMX were markedly increased, but it showed similar cytotoxic and inhibitory effects on cancer cell proliferation/migration. Furthermore, the intestinal membrane permeability and epithelial cell uptake of PMX were synergistically improved after HP-beta-CD/PMX/DCK/P188 was incorporated into a nanoemulsion with a size of 14.5±0.45 nm. The in vitro permeability of HP-beta-CD/PMX/DCK/P188-NE across a Caco-2 cell monolayer was 9.82-fold greater than that of free PMX, which might be attributable to the partitioning of PMX to the epithelial cells being facilitated via specific interaction of DCK with bile acid transporters, as well as the enhanced lipophilicity accompanied by surfactant-induced changes in the intestinal membrane structure and fluidity. Therefore, the oral bioavailability of HP-beta-CD/PMX/DCK/P188-NE in rats was evaluated as 26.8%±2.98% which was 223% higher than that of oral PMX. Moreover, oral HP-beta-CD/PMX/DCK/P188-NE significantly suppressed tumor growth in Lewis lung carcinoma cell-bearing mice, and the tumor volume was maximally inhibited by 61% compared with that in the control group.ConclusionThese results imply that HP-beta-CD/PMX/DCK/P188-NE is an effective and promising delivery system for enhancing the oral absorption of PMX. Thus, there is the potential for new medical applications, including applications in metronomic cancer treatment.

Hydrophobic ion pairing: encapsulating small molecules, peptides, and proteins into nanocarriers

“…In the twenty years since Meyer and Manning's classic 1998 review, 1 hydrophobic ion pairing (HIP) has gained prominence as a useful strategy for making charged hydrophilic molecules into hydrophobic complexes. The technique has a number of applications and has been used, among others, to dissolve molecules in supercritical CO 2 , 2 dissolve enzymes in organic solvents without losing activity, 3 improve intestinal adsorption [4][5][6] or skin permeation, 7,8 or otherwise enhance bioavailability. 9 This review will focus on one of the most prevalent uses of hydrophobic ion pairing: the complexation and encapsulation of charged hydrophilic small molecule, peptide, or protein therapeutics into drug delivery vehicles.…”

Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

“…Labrasol exhibits a high tolerance and promotes absorption through tight junctions in the absence of intestinal membrane damage [41,42]. A previous study confirmed that a molecular dispersion of PMX and DCK exists as an amorphous inclusion complex, enhancing the intestinal membrane permeability of PMX [29]. Thus, incorporation of Labrasol and P188 into our formulation may enhance micellar stability, control particle size, and facilitate intestinal absorption of PMX/DCK by allowing the material to accumulate to high levels on the intestinal surface.…”

“…The plasma concentration of PMX was determined using liquid chromatography/mass spectrometry (LC/MS), as described previously [29]. In brief, the plasma samples were defrosted and centrifuged at 2500× g for 5 min at 4 °C and mixed with 300 µL of 2% NH 4 OH in water along with 100 µL of standard solution or plasma sample and 10 µL of 4-[ N -(2,4-diamino-6-pterinidinylmethyl)- N -methylamino]benzoic acid hemihydrochloride hydrate (DAMPA; 5 µg/mL, IS).…”

“…Then, we loaded the drug complex into the inner aqueous phase of multiple water-in-oil-in-water nanoemulsions, which resulted in a significant increase in oral bioavailability. However, the optimal formulation showed long-term instability during storage, which might be due to the incorporation of the drug complex in the inner aqueous phase of multiple nanoemulsions [29]. Hence, we designed an oral solid powder formulation of PMX with enhanced long-term stability.…”

<p>Phospholipid complex based nanoemulsion system for oral insulin delivery: preparation, in vitro, and in vivo evaluations</p>

“…Numerous studies indicate that nanoemulsion has a significant potential to increase the permeability of drugs. The proposed mechanisms were based on surfactant induced structural and fluidity changes in the membranes 24,25. IPC-NEs combined phospholipid complex technique with nanoemulsion system, exhibited synergic effect of nanoemulsion and IPC on the transport properties of insulin across the Caco-2 cell monolayers.…”