High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions

Markus Selin (Corresponding Author), Sami Nummelin (Corresponding Author), Jill Deleu, Jarmo Ropponen, Tapani Viitala, Manu Lahtinen, Jari Koivisto, Jouni Hirvonen, Leena Peltonen, Mauri A. Kostiainen, Luis M. Bimbo (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3983-3993
Number of pages11
JournalBiomacromolecules
Volume19
Issue number10
DOIs
Publication statusPublished - 8 Oct 2018
MoE publication typeNot Eligible

Fingerprint

Dendrimers
Excipients
Suspensions
Pharmaceutical Preparations
Indomethacin
Stabilization
Crystals
Poloxamer
Surface plasmon resonance
Drug products
Contact angle
Electrostatics
Dissolution
Agglomeration
Crystallization
Adsorption
Kinetics
Water

Cite this

Selin, M., Nummelin, S., Deleu, J., Ropponen, J., Viitala, T., Lahtinen, M., ... Bimbo, L. M. (2018). High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions. Biomacromolecules, 19(10), 3983-3993. https://doi.org/10.1021/acs.biomac.8b00931
Selin, Markus ; Nummelin, Sami ; Deleu, Jill ; Ropponen, Jarmo ; Viitala, Tapani ; Lahtinen, Manu ; Koivisto, Jari ; Hirvonen, Jouni ; Peltonen, Leena ; Kostiainen, Mauri A. ; Bimbo, Luis M. / High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions. In: Biomacromolecules. 2018 ; Vol. 19, No. 10. pp. 3983-3993.
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abstract = "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.",
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Selin, M, Nummelin, S, Deleu, J, Ropponen, J, Viitala, T, Lahtinen, M, Koivisto, J, Hirvonen, J, Peltonen, L, Kostiainen, MA & Bimbo, LM 2018, 'High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions', Biomacromolecules, vol. 19, no. 10, pp. 3983-3993. https://doi.org/10.1021/acs.biomac.8b00931

High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions. / Selin, Markus (Corresponding Author); Nummelin, Sami (Corresponding Author); Deleu, Jill; Ropponen, Jarmo; Viitala, Tapani; Lahtinen, Manu; Koivisto, Jari; Hirvonen, Jouni; Peltonen, Leena; Kostiainen, Mauri A.; Bimbo, Luis M. (Corresponding Author).

In: Biomacromolecules, Vol. 19, No. 10, 08.10.2018, p. 3983-3993.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions

AU - Selin, Markus

AU - Nummelin, Sami

AU - Deleu, Jill

AU - Ropponen, Jarmo

AU - Viitala, Tapani

AU - Lahtinen, Manu

AU - Koivisto, Jari

AU - Hirvonen, Jouni

AU - Peltonen, Leena

AU - Kostiainen, Mauri A.

AU - Bimbo, Luis M.

PY - 2018/10/8

Y1 - 2018/10/8

N2 - 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.

AB - 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.

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U2 - 10.1021/acs.biomac.8b00931

DO - 10.1021/acs.biomac.8b00931

M3 - Article

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SP - 3983

EP - 3993

JO - Biomacromolecules

JF - Biomacromolecules

SN - 1525-7797

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