High-generation amphiphilic Janus-dendrimers as stabilizing agents for drug suspensions

Pharmaceutical nanosuspensions are formed when drug crystals are suspended in aqueous media in the presence of stabilizers. This technology offers a convenient way to enhance the dissolution of poorly water-soluble drug compounds. The stabilizers exert their action through electrostatic or steric interactions, however, the molecular requirements of stabilizing agents have not been studied extensively. Here, four structurally related amphiphilic Janus-dendrimers were synthesized and screened to determine the roles of different macromolecular domains on the stabilization of drug crystals. Physical interaction and nanomilling experiments have substantiated that Janus-dendrimers with fourth generation hydrophilic dendrons were superior to third generation analogues and Poloxamer 188 in stabilizing indomethacin suspensions. Contact angle and surface plasmon resonance measurements support the hypothesis that Janus-dendrimers bind to indomethacin surfaces via hydrophobic interactions and that the number of hydrophobic alkyl tails determines the adsorption kinetics of the Janus-dendrimers. The results showed that amphiphilic Janus-dendrimers adsorb onto drug particles and thus can be used to provide steric stabilization against aggregation and recrystallization. The modular synthetic route for new amphiphilic Janus-dendrimers offers, thus, for the first time a versatile platform for stable general-use stabilizing agents of drug suspensions.

Publication year: 2018
Authors: Selin M. 1, Nummelin S. 2, Deleu J. 1,3, Ropponen J. 4, Viitala T. 5, Lahtinen M. 6, Koivisto J. 7, Hirvonen J. 1, Peltonen L. 1, Kostinainen M.A. 2,8, Bimbo L.M. 1,9
1 – Division of Pharmaceutical Chemistry and Technology, Faculty of PharmacyUniversity of Helsinki, FI-00014, Finland
2 – Biohybrid Materials, Department of Bioproducts and BiosystemsAalto University, FI-00076, Finland
3 – Faculty of Pharmaceutical SciencesGhent University, 9000 Ghent, Belgium
4 – VTT-Technical Research Centre of Finland Ltd, P.O. Box 1000, FI-02044 VTT Finland
5 – Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland
6 – Department of Chemistry, University of Jyväskylä, FI-40014, Finland
7 – Department of Chemistry and Materials ScienceAalto University, FI-00076, Finland
8 – HYBER Center of Excellence, Department of Applied PhysicsAalto University, FI-00076, Finland
9 – Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 ORE, United Kingdom
Published in: Biomacromolecules, 2018, Vol. 19 (10), p. 3983–3993 doi: 10.1021/acs.biomac.8b00931
DOI: 10.1021/acs.biomac.8b00931


adsorption kinetics desorption drug stabilization drug-dendrimer interaction solid-liquid interface interaction


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