Sustained release ketamine-loaded porous silicon-PLGA microparticles prepared by an optimized supercritical CO2 process

• DOI: 10.1007/s13346-021-00991-w
• Publication Date: 2021-04-28T00:03:10Z
• Authors: Weizhi Xu; Zonglan Zhao; James Falconer; Andrew K. Whittaker; Amirali Popat; Maree T. Smith; Tushar Kumeria; Felicity Y. Han
• Keywords: Analgesics; Silicon; 0303 health sciences; Carbon Dioxide; 3. Good health; 12. Responsible consumption; Analgesics, Opioid; 03 medical and health sciences; Polylactic Acid-Polyglycolic Acid Copolymer; Delayed-Action Preparations; Solvents; Ketamine; Particle Size; Porosity

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 (scCO2) method, thereby avoiding the use of organic solvent. Multiple parameters including theoretical drug loading (DL), presence of pSi, size of scCO2 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 scCO2 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 scCO2 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 scCO2.