Ripple Therapeutics, Toronto, ON, Canada.
School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada.
Nat Commun. 2021 May 17;12(1):2875. doi: 10.1038/s41467-021-23232-7.
Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.
聚合物药物载体被广泛用于提供药物递送的时间和/或空间控制，其中皮质类固醇是受益于其用于治疗炎症介导疾病的一类药物。然而，这些基于聚合物的系统通常具有有限的载药能力、不理想的释放动力学和/或促进不良的炎症反应。本文研究并描述了一种实现皮质类固醇控制释放的策略，该策略基于一个发现，即低分子量皮质类固醇二聚体可以使用广泛的现有制造方法加工成药物输送植入材料，而无需使用聚合物或赋形剂。这些植入物经历表面侵蚀，在体外实现了紧密控制和可重复的药物释放动力学。例如，当用作大鼠眼部植入物时，地塞米松二聚体植入物被证明可有效抑制脂多糖诱导的炎症。在兔模型中，地塞米松二聚体玻璃体内植入物表现出可预测的药代动力学，并与一种领先的商业聚合物地塞米松释放植入物相比，显著延长了药物释放持续时间和疗效（>6 个月）。
