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Merck

Therapeutic surfactant-stripped frozen micelles.

Nature communications (2016-05-20)
Yumiao Zhang, Wentao Song, Jumin Geng, Upendra Chitgupi, Hande Unsal, Jasmin Federizon, Javid Rzayev, Dinesh K Sukumaran, Paschalis Alexandridis, Jonathan F Lovell
ABSTRACT

Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like 'top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and 'bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2-3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
TERGITOL solution, Type NP-40, 70% in H2O
General Purpose Viscosity Standard; UKAS ISO/IEC17025 and ISO 17034 certified, viscosity 990.0 mPa.s (25 °C)
Sigma-Aldrich
Castor oil
Sigma-Aldrich
Brij® L23, main component: tricosaethylene glycol dodecyl ether