Purpose

For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection.

Methods

A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain.

Results

The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 μg. Co-administration of ketamine-loaded NPs at 340 μg did not increase the duration of analgesia significantly.

Conclusions

The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.

中文翻译：

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使用微流控技术制造可溶蚀的含氢吗啡酮或氯胺酮的脂质杂化纳米颗粒，以缓解顽固性疼痛

目的

对于患有难治性癌症相关疼痛的患者，通过鞘内途径在目标受体/离子通道附近给予强效阿片类镇痛药和辅助剂可恢复疼痛缓解。因此，本研究的目的是使用可生物蚀解的聚合物来封装阿片类镇痛药（氢吗啡酮）和辅助药物（氯胺酮）以生产用于注射的延长释放制剂。

方法

使用两阶段的微流体方法来制造纳米粒子（NPs）。使用动态光散射和透射电子显微镜对物理性质进行表征。在周围神经性疼痛的大鼠模型中进行了一项体内试验研究。

结果

在体外从与聚合物混合物（CPP-SA / PLGA 50:50）产生的NP封装有效载荷的释放是持续28天。在一项体内试验研究中，以50μg注射了氢吗啡酮的NP注射后，镇痛持续了三天。并用340μg氯胺酮的NP并用不会明显增加镇痛时间。

结论

两阶段的微流控方法可以有效生产载有止痛药/辅助药的NP。我们的原则上的体内研究表明，单次注射后氢吗啡酮的镇痛作用延长了78小时。在给药剂量下，从NP释放的氯胺酮不足以增强氢吗啡酮镇痛作用。