title: A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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. 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.
  
  
  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.
authors.affiliation: Chiasma, 10 Hartom St., POB 45182, Jerusalem, 91450, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Tuvia
authors.forename: Dori
authors.initials: D
authors.lastname: Pelled
authors.forename: Karen
authors.initials: K
authors.lastname: Marom
authors.forename: Paul
authors.initials: P
authors.lastname: Salama
authors.forename: Maya
authors.initials: M
authors.lastname: Levin-Arama
authors.forename: Irina
authors.initials: I
authors.lastname: Karmeli
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Idelson
authors.forename: Isaac
authors.initials: I
authors.lastname: Landau
authors.forename: Roni
authors.initials: R
authors.lastname: Mamluk
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008252:Macaca fascicularis; D046911:Macromolecular Substances / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D015282:Octreotide / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013608:Tablets, Enteric-Coated
chemical_list: D046911:Macromolecular Substances; D013608:Tablets, Enteric-Coated; D015282:Octreotide