Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.
Nat Commun. 2016 May 19;7:11649. doi: 10.1038/ncomms11649.
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.
疏水性药物通常溶解在表面活性剂和非水溶剂中，这可能会引起负面的副作用。一些替代方法，如无赋形剂注射药物混悬剂的“自上而下”精细研磨，目前在临床上还不可行，而“自下而上”的自组装递药系统通常用一种增溶剂替代另一种增溶剂，带来了新的需要考虑的问题。在这里，我们表明 Pluronic（泊洛沙姆）嵌段共聚物适合低温处理，以去除所有游离的和松散结合的表面活性剂，留下浓缩的、动力学冻结的药物胶束，其中含有最小量的增溶剂。该方法已经通过叶绿醌、环孢素、十一酸睾酮、卡巴他赛和其他七种生物活性分子进行了验证，得到的粒径在 45nm 到 160nm 之间，药物与增溶剂的摩尔比比目前的制剂高 2-3 个数量级。在某些情况下，高渗盐水或共载货物被发现可以防止聚集。使用表面活性剂去除胶束避免了与其他注射制剂相关的潜在风险。阐明了机制见解，并证明了治疗剂量反应。
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