Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery
Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery
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DOI：
10.1016/j.jconrel.2020.03.026
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发表时间：
2020-06-10
影响因子：
10.8
通讯作者：
Donnelly, Ryan F.
中科院分区：
文献类型：
--
作者：
Courtenay, Aaron J.;McAlister, Emma;Donnelly, Ryan F.
根据定义，难治性抑郁症很难使用标准治疗干预措施进行治疗。最近，艾司氯胺酮已被证明是抑郁危机状态患者的一种可行的补救治疗选择。然而，IV给药存在许多缺点，先进的给药平台可以为患者提供艾司氯胺酮给药的替代胃肠外途径。水凝胶形成微针阵列通过穿透皮肤表面的外层、吸收皮肤间质流体和溶胀来促进药物的经皮递送。这随后促进药物渗透到皮肤微循环中。本文概述了含艾司氯胺酮的水凝胶形成微针阵列的体外处方开发。根据人用药品注册技术要求国际协调会标准，开发并验证了艾司氯胺酮检测和定量的分析方法。水凝胶形成微针阵列的机械强度和皮肤插入性能进行了充分表征。此外，评估了一系列含艾司氯胺酮的聚合物膜和冻干贮库作为候选药物贮库。进行溶出试验和药物回收率，然后在改良的Franz池装置中使用350 μ m厚的新生猪皮进行渗透研究。根据测得的理化性质选择铅储库候选物，并在雌性Sprague-Dawley大鼠中进行试验。使用反相高效液相色谱法分析血浆样品中的艾司氯胺酮。聚合物薄膜和冻干储库候选贴剂在24小时内的艾司氯胺酮血浆浓度均高于目标浓度0.15-0.3 μ g/ml。在大鼠中，具有药物储库F3和LW 3的微针贴剂贴敷后24小时的平均血浆浓度分别为0.260 μ g/ml和0.498 μ g/ml。这项开发研究强调了水凝胶形成微针阵列作为埃斯克经皮给药平台的潜在成功，并支持在更大的动物模型中进行体内试验。
Treatment resistant depression is, by definition, difficult to treat using standard therapeutic interventions. Recently, esketamine has been shown as a viable rescue treatment option in patients in depressive crisis states. However, IV administration is associated with a number of drawbacks and advanced delivery platforms could provide an alternative parenteral route of esketamine dosing in patients. Hydrogel-forming microneedle arrays facilitate transdermal delivery of drugs by penetrating the outer layer of the skins surface, absorbing interstitial skin fluid and swelling. This subsequently facilitates permeation of medicines into the dermal microcirculation. This paper outlines the in vitro formulation development for hydrogel-forming microneedle arrays containing esketamine. Analytical methods for the detection and quantitation of esketamine were developed and validated according to International Conference on Harmonisation standards. Hydrogel-forming microneedle arrays were fully characterised for their mechanical strength and skin insertion properties. Furthermore, a series of esketamine containing polymeric films and lyophilised reservoirs were assessed as drug reservoir candidates. Dissolution testing and content drug recovery was carried out, followed by permeation studies using 350 mu m thick neonatal porcine skin in modified Franz cell apparatus. Lead reservoir candidates were selected based on measured physicochemical properties and brought forward for testing in female Sprague-Dawley rats. Plasma samples were analysed using reverse phase high performance liquid chromatography for esketamine. Both polymeric film and lyophilised reservoirs candidate patches achieved esketamine plasma concentrations higher than the target concentration of 0.15-0.3 mu g/ml over 24 h. Mean plasma concentrations in rats, 24 h postapplication of microneedle patches with drug reservoir F3 and LW3, were 0.260 mu g/ml and 0.498 mu g/ml, respectively. This developmental study highlights the potential success of hydrogel-forming microneedle arrays as a transdermal drug delivery platform for ESK and supports moving to in vivo tests in a larger animal model.