Pharmaceutical Research 2014-08-01

A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms.

Shmuel Tuvia, Dori Pelled, Karen Marom, Paul Salama, Maya Levin-Arama, Irina Karmeli, Gregory H Idelson, Isaac Landau, Roni Mamluk

Index: Pharm. Res. 31(8) , 2010-21, (2014)

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Abstract

Medium chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. Novel oily suspension (OS) formulation disperses a powder containing sodium caprylate and macromolecules such as octreotide or fluorescent dextran (FD). Formulation safety, macromolecule absorption and pharmacokinetic (PK)/pharmacodynamic (PD) were evaluated.Octreotide/OS toxicity was evaluated in monkeys following 9 months of daily oral enteric-coated capsule administration. The OS permeation effect was also assessed in rats, using FD/OS and octreotide/OS preparations. Octreotide/OS effects on circulating growth hormone (GH) levels were also measured.Safety assessment of octreotide/OS in monkeys after 9 months showed minor drug-related findings, comparable to the injectable octreotide. Octreotide exposure levels were similar across the treatment periods. In rats, OS facilitated FD permeation up to 70 kDa in a reversible, spatial and dose-dependent manner, independent of the intestinal dosing site. Following OS administration, the staining pattern of the tight-junction protein, ZO-1, changed transiently, and a paracellular penetration marker, LC-biotin, permeated between adjacent epithelial cells. Enteral octreotide/OS absorption was dose-dependent and suppressed rat GH levels.Oral octreotide/OS dosing was shown to be safe in monkeys. OS enhances intestinal absorption of active octreotide, likely by transient alteration of the tight junction protein complex.