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Mucus permeating thiolated self-emulsifying drug delivery systems

Rohrer, Julia, Partenhauser, Alexandra, Hauptstein, Sabine, Gallati, Caroline, Matuszczak, Barbara, Abdulkarim, Muthanna, Gumbleton, Mark and Bernkop-Schnürch, Andreas 2016. Mucus permeating thiolated self-emulsifying drug delivery systems. European Journal of Pharmaceutics and Biopharmaceutics 98 , pp. 90-97. 10.1016/j.ejpb.2015.11.004

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Context 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. Materials and methods Two novel conjugates N-dodecyl-4-mercaptobutanimidamide (thiobutylamidine-dodecylamine, TBA-D) and 2-mercapto-N-octylacetamide (thioglycolic-acid-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. Results and discussion 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 cm2 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. Conclusion 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Mucolytic; Low molecular weight thiolated compounds; Fatty acid derivatives
Publisher: Elsevier
ISSN: 0939-6411
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 9 November 2015
Last Modified: 01 Jul 2019 14:08

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