Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels

Abstract

The primary objective of this study was to evaluate sodium caprate as an oral penetration enhancer for low molecular weight heparin (LMWH), ardeparin. In vitro studies using Caco-2 cell monolayer indicated that 0.0625% of sodium caprate gave approximately 2-fold enhancement of ardeparin compared to negative control with almost 100% cell survival as evaluated by MTT cytotoxicity assay. In vivo studies in rats with ardeparin (1,200 IU/kg) and sodium caprate (100 mg/kg) led to a relative bioavailability of 27% with plasma anti-factor Xa levels within the therapeutic range (>0.2 IU/ml). Moreover, under these conditions, histological examination provided evidence that there was no damage to the gastrointestinal wall. Regional permeability studies using rat intestine indicated the colon as the region of maximum permeation. These results suggest that, at the dose administered, sodium caprate acts as a relatively safe and efficient absorption enhancer in the quest for alternatives for the oral delivery of LMWH.

Figure 1

Caco-2 cell viability after exposure to various concentrations of sodium caprate for 6 and 12 h. The values are means of three independent experiments. ^*Significantly different compared with control (p < 0.05).

Figure 2

Regional permeability of ardeparin across rat GI tissues. ^*Significantly different as compared to control. Data are shown as the mean concentration and error bars represent the SEM (n = 3).

Figure 3

Anti-factor Xa activity-time profiles of ardeparin in rats after oral administration of various formulations. Data are shown as the mean concentration, and error bars represent the SEM (n = 4–6).

Figure 4

H&E photomicrographs of gastric and intestinal tissue sections after oral administration of sodium caprate (100 mg/kg and LMWH 1200 IU/kg). All panels represent cross-sections of gastric and intestinal tissues. The original magnification was 100 × for all panels. A, stomach (control); B, stomach (test); C, duodenum (control); D, duodenum (test); E, jejunum (control); F, jejunum (test); G, ileum (control); H, ileum (test); I, colon (control); J, colon (test).