Water in nigella oil microemulsion for enhanced oral bioavailability of linagliptin

Abstract

Linagliptin is hydrophilic antidiabetic with poor oral bioavailability due to poor permeability and pre-systemic metabolism. The objective was to assess w/o microemulsion for enhanced oral bioavailability of linagliptin. Nigella oil was used as oily phase based on its reported antidiabetic effect. Isopropyl myristate (IPM) or capryol were combined with nigella oil to impart intestinal membrane permeabilizing abilities. Pseudoternary phase diagrams were constructed utilizing nigella oil in presence and absence of isopropyl myristate or capryol as oily phase using Tween 60 as surfactant. W/O microemulsion formulations were selected from the constructed phase diagrams and linagliptin was loaded in the internal aqueous phase at a concentration of 0.5 mg/ml. The prepared formulations were physically evaluated and linagliptin in vitro release was monitored. Eventually, the in vivo hypoglycemic effect was assessed using diabetic rats. The developed microemulsions were of w/o type and exhibited Newtonian flow behavior with nigella/capryol microemulsion recording the lowest viscosity. The recorded droplet size values were 104.9, 121.2 and 86.4 nm for nigella, nigella/IPM and nigella/capryol microemulsions, respectively. All microemulsion formulations showed slower drug release rate compared with aqueous suspension with nigella/capryol microemulsion showing the highest release rate compared to other microemulsions. Release data from microemulsion best fitted to Higuchi model. In vivo oral hypoglycemic activity measurement reflected a more intensified hypoglycemic effect with rapid onset after oral ingestion of microemulsion compared to linagliptin dispersion. Nigella oil/IPM-based microemulsion was ranked as the most effective. The investigation highlighted the feasibility of w/o microemulsion for enhanced oral bioavailability of hydrophilic drugs like linagliptin.

Keywords: Class III drugs; Hypoglycemic effect; Linagliptin; Microemulsion; Nigella oil; Oral absorption.

Fig. 1

The pseudoternary phase diagrams of nigella oil (a), nigella oil/isopropyl myristate (b) and nigella oil/capryol (c) based systems with Tween 60 and water. W means water, O means oil or oil/penetration enhancer blends and S means surfactant. ME means microemulsion, LC means liquid crystal, EM means emulsion and PS means phase separation

Fig. 2

The transmission electron micrographs and zetasizer particle size distribution for different microemulsion formulations. Formulations details are presented in Table 1

Fig. 3

The Newtonian flow behavior of the tested microemulsion formulations. Formulations details are presented in Table 1

Fig. 4

The release profiles of linagliptin from different microemulsion formulations (a) and from linagliptin dispersion (b). Formulations details are presented in Table 1

Fig. 5

Cumulative amounts of blood glucose reduction as a function of time after oral administration of linagliptin aqueous dispersion or medicated w/o microemulsion formulations to diabetic rats (a) and after administration of saline or placebo (nonmedicated) w/o microemulsion formulations (b). Formulations details are in Table 1