A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms

作者：Tuvia Shmuel; Pelled Dori; Marom Karen; Salama Paul; Levin Arama Maya; Karmeli Irina; Idelson Gregory H; Landau Isaac; Mamluk Roni^*

来源：Pharmaceutical Research, 2014, 31(8): 2010-2021.

DOI：10.1007/s11095-014-1303-9

• absorption enhancer
• intestinal permeability
• oral drug delivery
• sodium caprylate
• tight junction

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.

• 出版日期2014-8