School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Gülhane Education and Research Hospital, Department of Pharmaceutical Sciences, 06010 Etlik, Ankara, Turkey.
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Wallace Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA.
J Control Release. 2017 Dec 28;268:159-165. doi: 10.1016/j.jconrel.2017.10.021. Epub 2017 Oct 16.
Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108±9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259±917ng/mL min) was not significantly different (p>0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5min for both delivery methods and t value of MNPs (38±23min) showed no significant difference (p>0.05) compared to subcutaneous injection (24±13min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability.
偏头痛是一种广泛存在的神经系统疾病，会对生活质量和生产力产生负面影响。中重度急性偏头痛发作可以用二氢麦角胺甲磺酸盐（DHE）治疗，它是一种麦角衍生物，对曲坦衍生物无反应者尤其有效。为了克服当前 DHE 制剂在皮下注射和鼻喷中的局限性，如疼痛、不良反应和生物利用度差，需要一种新的 DHE 递送方法，实现无痛自我给药、快速起效和高生物利用度。在这项研究中，我们开发了一种由聚乙烯吡咯烷酮制成的溶解微针贴片（MNP），由于其高水溶性和增溶性质，使用了先前显示无痛且易于给药的 MNP 设计。载有 DHE 的 MNPs 的含量均匀度为 108±9%，具有足够的机械强度，可用于插入猪皮的体外和在 2 分钟内溶解。在无毛大鼠中进行了体内药代动力学研究，并通过液相色谱-串联质谱（LC-MS/MS）测定 DHE 血浆水平。MNP 给药后的曲线下面积（AUC）值（1259±917ng/mL min）与皮下注射无显著差异（p>0.05），相对生物利用度为 97%。此外，两种给药方式都在 5 分钟内观察到可观的 DHE 血浆水平，MNP 的 t 值（38±23min）与皮下注射（24±13min）相比无显著差异（p>0.05）。这些结果表明，载有 DHE 的 MNPs 有望成为一种替代 DHE 给药方法，可以无痛自我给药，快速起效，生物利用度高。
