School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, QLD, Australia.
Drug Deliv Transl Res. 2022 Mar;12(3):676-694. doi: 10.1007/s13346-021-00991-w. Epub 2021 Apr 28.
Ketamine in sub-anaesthetic doses has analgesic properties and an opioid-sparing effect. Intrathecal (i.t.) delivery of analgesics bypasses systemic metabolism and delivers the analgesic agent adjacent to the target receptors in the spinal cord and so small doses are required to achieve effective pain relief. In order to relieve intractable cancer-related pain, sustained-release ketamine formulations are required in combination with a strong opioid because frequent i.t. injection is not practical. In this study, ketamine or ketamine-loaded porous silicon (pSi) were encapsulated into poly(lactic-co-glycolic acid) (PLGA) microparticles by a novel supercritical carbon dioxide (scCO) method, thereby avoiding the use of organic solvent. Multiple parameters including theoretical drug loading (DL), presence of pSi, size of scCO vessel, PLGA type, and use of co-solvent were investigated with a view to obtaining high DL and a sustained-release for an extended period. The most important finding was that the use of a large scCO vessel (60 mL) resulted in a much higher encapsulation efficiency (EE) compared with a small vessel (12 mL). In addition, pre-loading ketamine into pSi slightly improved the level of drug incorporation (i.e. EE and DL). Although the in vitro release was mainly affected by the drug payload, the use of the large scCO vessel reduced the burst release and extended the release period for PLGA microparticles with 10% or 20% ketamine loading. Together, our findings provide valuable information for optimization of drug delivery systems prepared with the aid of scCO.
亚麻醉剂量的氯胺酮具有镇痛作用，并具有阿片类药物节约效应。鞘内（i.t.）给药可绕过全身代谢，将镇痛剂递送至脊髓中的靶受体附近，因此只需小剂量即可实现有效的疼痛缓解。为了缓解顽固性癌症相关疼痛，需要与强效阿片类药物联合使用持续释放的氯胺酮制剂，因为频繁的 i.t. 注射是不切实际的。在这项研究中，通过一种新颖的超临界二氧化碳（scCO）方法将氯胺酮或负载氯胺酮的多孔硅（pSi）封装到聚乳酸-羟基乙酸共聚物（PLGA）微球中，从而避免了有机溶剂的使用。研究了多种参数，包括理论药物载药量（DL）、pSi 的存在、scCO 容器的大小、PLGA 类型以及共溶剂的使用，以期获得高 DL 和延长时间的持续释放。最重要的发现是，与小容器（12 毫升）相比，使用大 scCO 容器（60 毫升）可使包封效率（EE）大大提高。此外，预先将氯胺酮加载到 pSi 中可略微提高药物掺入水平（即 EE 和 DL）。尽管体外释放主要受药物载药量的影响，但使用大 scCO 容器可减少突释并延长载有 10%或 20%氯胺酮的 PLGA 微球的释放期。总之，我们的研究结果为借助 scCO 制备的药物传递系统的优化提供了有价值的信息。
