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Download fileStructural and Spectroscopic Characterization of TPGS Micelles: Disruptive Role of Cyclodextrins and Kinetic Pathways
journal contribution
posted on 2017-04-16, 00:00 authored by Joan Puig-Rigall, Isabelle Grillo, Cécile A. Dreiss, Gustavo González-GaitanoThe
aggregation and structure of d-α-tocopheryl
polyethylene glycol succinate micelles, TPGS-1000, an amphiphilic
derivative of vitamin E, were characterized using scattering and spectroscopic
methods, and the impact of different cyclodextrins (CDs) on the self-assembly
was investigated, with the view of combining these two versatile pharmaceutical
excipients in drug formulations. Combined small-angle neutron scattering
(SANS), dynamic light scattering, and time-resolved and steady-state
fluorescence emission experiments revealed a core–shell architecture
with a high aggregation number (Nagg ≈
100) and a highly hydrated poly(ethylene oxide) corona (∼11
molecules of solvent per ethylene oxide unit). Micelles form gradually,
with no sharp onset. Structural parameters and hydration of the aggregates
were surprisingly stable with both temperature and concentration,
which is a critical advantage for their use in pharmaceutical formulations.
CDs were shown to affect the self-assembly of TPGS in different ways.
Whereas native CDs induced the precipitation of a solid complex (pseudopolyrotaxane),
methylated β-CDs led to different outcomes: constructive (micellar
expansion), destructive (micellar rupture), or no effect, depending
on the number of substituents and whether the substitution pattern
was regular or random on the rims of the macrocycle. Time-resolved
SANS studies on mixtures of TPGS with regularly dimethylated β-CD
(DIMEB), which ruptures the micelles, revealed an almost instantaneous
demicellization (<100 ms) and showed that the process involved
the formation of large aggregates whose size evolved over time. Micellar
rupture is caused by the formation of a TPGS–DIMEB inclusion
complex, involving the incorporation of up to three macrocycles on
the tocopherol, as shown by proton nuclear magnetic resonance (NMR)
and ROESY NMR. Analysis of NMR data using Hill’s equation revealed
that the binding is rather cooperative, with the threading of the
CD favoring the subsequent inclusion of additional CDs on the aliphatic
moiety.
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Keywords
fluorescence emission experimentsvitamin Edimethylated β- CDMicelles formMicellar ruptureethylene oxide unitROESY NMRaggregation numberNMR dataKinetic PathwaysDisruptive Rolealiphatic moietydrug formulationsDIMEBspectroscopic methodsTime-resolved SANS studies-α-tocopheryl polyethylene glycol succinate micellessmall-angle neutronStructural parametersSpectroscopic CharacterizationTPGS Micellessubstitution pattern