Department of Chemistry, Duke University, Durham, NC, United States; Department of Polymer Science, The University of Akron, Akron, OH, United States.
Pharmaceutical Sciences, Merck & Co., Inc., West Point, PA, United States.
J Control Release. 2021 Jan 10;329:316-327. doi: 10.1016/j.jconrel.2020.11.052. Epub 2020 Dec 3.
Medical prescriptions for the alleviation of post-surgical pain are the most abundant source of opioids in circulation. As a systemic drug delivery source, opioids leave patients at high risk for side effects after being dosed. Given the significant rate of unauthorized use, distribution, addiction, and opioid related deaths, an alternative method of post-surgical analgesia is needed. Herein, we report the use of bio-resorbable poly(ester urea) (PEU) films that controllably deliver a non-opioid COX-2 inhibitor, etoricoxib, in vivo and in vitro as a model system for post-surgical pain control. PEU composition, drug-load, and film thickness were varied to selectively control etoricoxib elution. Elution data were fit to a Higuchi model, and the diffusion constant of etoricoxib was calculated in each of the films. Pharmacokinetic (pK) data from an in vivo rat model showed the local tissue concentration of etoricoxib at the study endpoint to be up to 23-fold higher in tissue then plasma. In a well-established mouse model of diabetic neuropathic pain in vivo film implantation showed effective relief of pain for more than 4 days post-implantation and efficacious local etoricoxib delivery. Overall, implementation of local drug delivery systems such as this could reduce the need for opioid prescriptions associated with current pain management strategies.
用于缓解术后疼痛的医疗处方是流通中阿片类药物的最主要来源。作为一种全身性药物输送源,阿片类药物在给药后使患者面临很高的副作用风险。鉴于阿片类药物的非授权使用、滥用、成瘾和相关死亡的发生率很高,因此需要一种替代的术后镇痛方法。在此,我们报告了使用可生物吸收的聚(酯脲)(PEU)膜,以体内和体外模型系统来控制非阿片类 COX-2 抑制剂依托考昔的释放,从而控制术后疼痛。改变 PEU 的组成、药物负载和膜厚度,以选择性地控制依托考昔的洗脱。将洗脱数据拟合到 Higuchi 模型中,并计算出每种膜中依托考昔的扩散常数。来自体内大鼠模型的药代动力学(PK)数据表明,在研究终点时,局部组织中的依托考昔浓度比血浆中的浓度高 23 倍。在糖尿病神经病理性疼痛的成熟体内小鼠模型中,植入膜后 4 天以上可有效缓解疼痛,并能有效局部递送依托考昔。总的来说,实施局部药物输送系统,如本文所述,可能会减少与当前疼痛管理策略相关的阿片类药物处方的需求。