阿片类药物仍然是术后疼痛管理的主要手段,即使它们与包括成瘾在内的过多副作用有关,恶心,便秘,认知障碍,呼吸抑制,以及因服药过量而意外死亡.局部麻醉药可有效控制手术后的剧烈疼痛,但其作用持续时间短限制了其在术后疼痛管理中的临床应用。在这份手稿中,在试验台上表征了用于术后多日疼痛管理的优化的基于油凝胶的布比卡因注射制剂,并在两个临床相关的猪术后疼痛模型中进行了评估.台式表征验证了优化的油凝胶基布比卡因制剂设计,由于剪切稀化特性,证明了均匀稳定的油凝胶具有足够的可注射性,高载药量和一级药物释放动力学超过5天。在两个猪术后疼痛模型中的体内评估表明,基于油凝胶的布比卡因制剂可以在两种给药途径中提供统计学上显着的多日镇痛:直接局部滴注到手术部位和超声引导的周围神经阻滞注射。ALX005的药代动力学评估发现,Cmax值与盐酸布比卡因对照没有统计学差异,没有观察到局部麻醉全身毒性的临床迹象,当施用高达2.7倍和8.1倍的盐酸布比卡因对照剂量时。这项研究证明了基于油凝胶的可注射布比卡因制剂的临床前安全性和有效性,并探索了其作为单次给药长效局部麻醉产品用于术后疼痛管理的实用性,可用于局部和区域麻醉应用。
Opioid-based medications remain the mainstay of post-operative pain management, even though they are associated with a plethora of adverse effects including addiction, nausea, constipation, cognitive impairment, respiratory depression, and accidental death due to overdose. Local anesthetics are effective at controlling the intense pain after surgery but their short duration of effect limits their clinical utility in post-operative pain management. In this manuscript, an optimized injectable
oleogel-based formulation of bupivacaine for multi-day post-operative pain management was characterized on the benchtop and assessed in two clinically-relevant porcine post-operative pain models. Benchtop characterization verified the optimized
oleogel-based bupivacaine formulation design, demonstrating a homogenous stable
oleogel with sufficient injectability due to shear-thinning properties, high drug loading capacity and first-order drug release kinetics over 5 days. In vivo assessment in two pig post-operative pain models demonstrated that the
oleogel-based bupivacaine formulation can provide statistically significant multi-day analgesia in two routes of administration: local instillation directly into a surgical site and ultrasound-guided peripheral nerve block injection. Pharmacokinetic assessment of ALX005 found that Cmax values were not statistically different from the bupivacaine HCl control, with no clinical signs of local anesthetic systemic toxicity observed, when administering up to 2.7 and 8.1 times the control dose of bupivacaine HCl. This study demonstrates the pre-clinical safety and efficacy of an injectable
oleogel-based bupivacaine formulation and explores its utility as a single-administration long-acting local anesthetic product for post-operative pain management that can be used in both local and regional anesthetic applications.