Efficacy, safety and mechanism of HP-β-CD-PEI polymers as absorption enhancers on the intestinal absorption of poorly absorbable drugs in rats.

CONTEXT: Oral bioavailability of some hydrophilic therapeutic macromolecules was very poor, thus leading to their limited application in clinic.

OBJECTIVE: To investigate the efficacy, safety and mechanism of HP-β-CD-PEI polymers on the intestinal absorption of some poorly absorbable drugs in rats.

METHODS: Effects of HP-β-CD-PEI polymers on the intestinal absorptions of drugs were investigated by an in situ closed loop method in rats. The safety of HP-β-CD-PEI polymer was evaluated by measurement of lactate dehydrogenase (LDH) activity and amount of protein released from rat intestinal perfusate. The absorption enhancing mechanisms were explored by the measurement of zeta potential, transepithelial electrical resistance (TEER) and in vitro transport of FD4 (a paracellular marker) across rat intestinal membranes, respectively.

RESULTS: HP-β-CD-PEI polymers, especially HP-β-CD-PEI1800, demonstrated excellent absorption enhancing effects on drug absorption in a concentration-dependent manner and the enhancing effect was more efficient in the small intestine than that in the large intestine. Five percent (w/v) HP-β-CD-PEI1800 obviously decreased the TEER, accompanied with increase in the intestinal transport of FD4, indicating that absorption enhancing actions of HP-β-CD-PEI polymers were possibly performed by loosening tight junctions of intestinal epithelium cells, thereby increasing drug permeation via a paracellular pathway. A good liner relationship between absorption enhancing effects of HP-β-CD-PEI polymers and their zeta potentials suggested the contribution of positive charge on the surface of these polymers to their absorption enhancing effects.

CONCLUSION: HP-β-CD-PEI polymers might be potential and safe absorption enhancers for improving oral delivery of poorly absorbable macromolecules including peptides and proteins.