Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germany.
Novartis Pharma AG, Lichtstraße 35, 4002 Basel, Switzerland.
J Control Release. 2017 Dec 28;268:314-322. doi: 10.1016/j.jconrel.2017.10.040. Epub 2017 Oct 31.
Poor water solubility of drugs fuels complex formulations and jeopardizes patient access to medication. Simplifying these complexities we systematically synthesized a library of 36 sterically demanding counterions and mapped the pharmaceutical design space for amorphous ionic liquid strategies for Selurampanel, a poorly water soluble drug used against migraine. Patients would benefit from a rapid uptake after oral administration to alleviate migraine symptoms. Therefore, we probed the ionic liquids for the flux, supersaturation period and hygroscopicity leading to algorithms linking molecular counterion descriptors to predicted pharmaceutical outcome. By that, 30- or 800-fold improvements of the supersaturation period and fluxes were achieved as were immediate to sustained release profiles through structural counterions' optimization compared to the crystalline free acid of Selurampanel. Guided by ionic liquid structure, in vivo profiles ranged from rapid bioavailability and high maximal plasma concentrations to sustained patterns. In conclusion, the study outlined and predicted the accessible pharmaceutical design space of amorphous ionic liquid based and excipient-free formulations pointing to the enormous pharmaceutical potential of ionic liquid designs.
药物的水溶性差导致配方复杂，并危及患者获得药物的机会。为了简化这些复杂性，我们系统地合成了 36 种具有空间位阻的抗衡离子库，并为 Selurampanel 的无定形离子液体策略绘制了药物设计空间，Selurampanel 是一种用于偏头痛的水溶性差的药物。患者将从口服后快速吸收中受益，以缓解偏头痛症状。因此，我们研究了离子液体的通量、过饱和度期和吸湿性，从而得出将分子抗衡离子描述符与预测药物结果联系起来的算法。通过这种方式，与 Selurampanel 的结晶游离酸相比，过饱和度期和通量提高了 30 倍或 800 倍，通过结构抗衡离子的优化实现了即刻到持续释放的曲线。通过离子液体的结构指导，体内曲线从快速生物利用度和高最大血浆浓度到持续模式。总之，该研究概述并预测了基于无定形离子液体和无赋形剂的制剂的可及药物设计空间，指出了离子液体设计的巨大药物潜力。
