Purpose

Opioids have been the main factor for drug overdose deaths in the United States. Current naloxone delivery systems are effective in mitigating the opioid effects only for hours. Naloxone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared as quick- and long-acting naloxone delivery systems to extend the naloxone effect as an opioid antidote.

Methods

The naloxone-PLGA microparticles were made using an emulsification solvent extraction approach with different formulation and processing parameters. Two PLGA polymers with the lactide:glycolide (L:G) ratios of 50:50 and 75:25 were used, and the drug loading was varied from 21% to 51%. Two different microparticles of different sizes with the average diameters of 23 μm and 50 μm were produced using two homogenization-sieving conditions. All the microparticles were critically characterized, and three of them were evaluated with β-arrestin recruitment assays.

Results

The naloxone encapsulation efficiency (EE) was in the range of 70–85%. The EE was enhanced when the theoretical naloxone loading was increased from 30% to 60%, the L:G ratio was changed from 50:50 to 75:25, and the average size of the particles was reduced from 50 μm to 23 μm. The in vitro naloxone release duration ranged from 4 to 35 days. Reducing the average size of the microparticles from 50 μm to 23 μm helped eliminate the lag phase and obtain the steady-state drug release profile. The cellular pharmacodynamics of three selected formulations were evaluated by applying DAMGO, a synthetic opioid peptide agonist to a μ-opioid receptor, to recruit β-arrestin 2.

Conclusions

Naloxone released from the three selected formulations could inhibit DAMGO-induced β-arrestin 2 recruitment. This indicates that the proposed naloxone delivery system is adequate for opioid reversal during the naloxone release duration.

中文翻译：

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设计用于治疗阿片类药物过量的快速和长效纳洛酮输送系统

目的

阿片类药物一直是美国药物过量死亡的主要因素。目前的纳洛酮给药系统仅能在数小时内有效减轻阿片类药物的影响。负载纳洛酮的聚(丙交酯-共-乙交酯) (PLGA) 微粒被制备为速效和长效纳洛酮递送系统，以延长纳洛酮作为阿片类药物解毒剂的作用。

方法

纳洛酮-PLGA 微粒是使用乳化溶剂萃取方法制备的，具有不同的配方和加工参数。使用了两种丙交酯:乙交酯 (L:G) 比例为 50:50 和 75:25 的 PLGA 聚合物，载药量从 21% 变化到 51%。使用两种均质筛分条件制备了平均直径为 23 μm 和 50 μm 的两种不同尺寸的不同微粒。所有微粒都经过严格表征，其中三个用 β-抑制蛋白募集测定法进行了评估。

结果

纳洛酮封装效率 (EE) 在 70-85% 的范围内。当理论纳洛酮负载量从 30% 增加到 60%，L:G 比从 50:50 到 75:25 时，EE 得到增强，颗粒的平均尺寸从 50 μm 减小到 23 μm。体外纳洛酮释放持续时间为 4 至 35 天。将微粒的平均尺寸从 50 μm 减小到 23 μm 有助于消除滞后期并获得稳态药物释放曲线。通过将合成的阿片肽激动剂 DAMGO（一种用于 μ-阿片受体的合成阿片肽激动剂）募集 β-抑制素 2，评估了三种选定制剂的细胞药效学。

结论

从三种选定的配方中释放的纳洛酮可以抑制 DAMGO 诱导的 β-arrestin 2 募集。这表明所提出的纳洛酮递送系统足以在纳洛酮释放期间逆转阿片样物质。