title: Mucus permeating thiolated self-emulsifying drug delivery systems.
abstract: BACKGROUND
  Mucus represents a critical obstacle for self-emulsifying drug delivery systems (SEDDS) targeting the epithelial membrane site.
  
  
  OBJECTIVE
  The aim of the study was the development of a novel SEDDS to overcome the mucus barrier.
  
  
  METHODS
  Two novel conjugates N-dodecyl-4-mercaptobutanimidamide (thiobutylamidine-dodecylamine, TBA-D) and 2-mercapto-N-octylacetamide (thioglycolicacid-octylamine, TGA-O) were synthesized, incorporated into SEDDS and analyzed for stability, cytotoxicity and physico-chemical characteristics using dynamic light scattering. Mucus interaction studies were performed using in vitro assays based on multiple particle tracking, rotational silicone tubes and rheology.
  
  
  CONCLUSIONS
  TBA-D was synthesized using dodecylamine and iminothiolane as thiol precursor (yield=55 ± 5%). TGA-O was obtained via crosslinking of octylamine with SATA ((2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate) (yield=70 ± 6%). The chemical structure of target compounds was confirmed via NMR analysis. The thiol-conjugates were incorporated in an amount of 3% (m/m) into SEDDS (Cremophor EL 30%, Capmul MCM 30%, Captex 355 30% and propylene glycol 10%), namely thiolated SEDDS leading to a droplet size around 50 nm and zeta potential close to 0 mV. Thiolated SEDDS with an effective diffusion coefficient 〈Deff〉 of up to 0.871 ± 0.122 cm(2) s(-1) × 10(-9) were obtained. Rotational silicone studies show increased permeation of the thiolated SEDDS A in comparison with unthiolated control. Rheological studies confirmed the mucolytic activity of the thiol-conjugates which differed only by 3% from DTT (dithiothreitol) serving as positive control.
  
  
  CONCLUSIONS
  Low molecular weight thiol-conjugates were identified to improve the mucus permeation, leading to highly efficient mucus permeating SEDDS, which were superior to conventional SEDDS and might thus be a new carrier for lipophilic drug delivery.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Rohrer
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Partenhauser
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauptstein
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria.
authors.forename: Caroline Marie
authors.initials: CM
authors.lastname: Gallati
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Matuszczak
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK.
authors.forename: Muthanna
authors.initials: M
authors.lastname: Abdulkarim
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Gumbleton
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D045744:Cell Line, Tumor; D004058:Diffusion; D016503:Drug Delivery Systems; D045703:Emulsifying Agents / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009093:Mucus / Q000378:metabolism*; D010539:Permeability; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D045703:Emulsifying Agents; D013438:Sulfhydryl Compounds
keywords: Fatty acid derivatives; Low molecular weight thiolated compounds; Mucolytic