Novel double coated nanocapsules for intestinal delivery and enhanced oral bioavailability of tacrolimus, a P-gp substrate drug

This study proposes a new concept of double coated nanocapsules to improve the oral bioavailability of a P-glycoprotein (P-gp) substrate drug, tacrolimus, without modulating the physiological activity of the P-gp pump. Tacrolimus was incorporated in nanocapsules with different ratios of two polymethacrylate polymers followed by microencapsulation of these nanocapsules within hydroxypropylmethylcellulose using a spray drying technique. The influence of different formulations of tacrolimus administered orally to rats and pigs on the drug's absorption was investigated. Histopathological studies were performed on rats to follow the nanocapsule path in enterocytes. The novel formulations that released mostly drug loaded nanocapsules in the intestine were shown to enhance markedly the oral absorption of tacrolimus. The relative oral bioavailability of tacrolimus was 4.9 and 2.45 fold compared to the commercial product in rats and pigs respectively. Although there is no direct evidence that intact nanocapsules internalized in the enterocytes, numerous small oil cores were detected within the enterocytes showing the potential of P-gp substrates incorporated in such nanocarriers to escape the efflux pump. (C) 2008 Elsevier B.V. All rights reserved.