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

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

doi:10.1007/s11095-014-1303-9

Abstract

PurposeMedium 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.MethodsOctreotide/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.ResultsSafety 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.ConclusionsOral 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.

Highlights

Passive intestinal absorption of hydrophilic macromolecules such as proteins or peptides (> 3 amino acids) [1] is limited due to low intestinal permeability and intraluminal enzymatic degradation [2,3]
The tight junction permeation is enhanced by dietary components and/or other naturally occurring substances affirmed as Generally Recognized As Safe (GRAS) such asglycerides, acylcarnitines, bile salts, and medium chain fatty acids [See review in [9]]
Oral dosing of enteric coated oily suspension (OS)-filled capsules with octreotide acetate for 9 months had no effect on bodyweight, electrocardiogram, ophthalmological, hematological, or clinical pathology

Summary

Results

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. 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. Conclusions 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. KEY WORDS absorption enhancer . intestinal permeability . oral drug delivery . sodium caprylate . tight junction

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION