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Sustained-release ketamine-loaded lipid-particulate system: in vivo assessment in mice

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Abstract

Ketamine is used as an analgesic adjuvant in patients with chronic cancer–related pain. However, ketamine’s short half-life requires frequent dose administration. Our aim was to develop a sustained release formulation of ketamine with high loading and to evaluate the in vivo pharmacokinetics and biodistribution in mice. Here, ketamine hydrochloride sustained-release lipid particles (KSL) were developed using the thin-film hydration method. The mean (± SD) encapsulation efficiency (EE) and drug loading (DL) of KSL were 65.6 (± 1.7)% and 72.4 (± 0.5)% respectively, and the mean (± SD) size of the lipid particles and the polydispersity index were 738 (± 137) nm and 0.44 (± 0.02) respectively. The release period of KSL in pH 7.4 medium was 100% complete within 8 h in vitro but a sustained-release profile was observed for more than 5 days after intravenous injection in mice. Importantly, the KSL formulation resulted in a 27-fold increase in terminal half-life, a threefold increase in systemic exposure (AUC0-∞), and a threefold decrease in clearance compared with the corresponding pharmacokinetics for intravenous ketamine itself. Our findings demonstrate high encapsulation efficiency of ketamine in the sustained-release KSL formulation with prolonged release in mice after systemic dose administration despite 100% in vitro release within 8 h that requires future investigation.

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Acknowledgements

The authors acknowledge the Queensland Government Smart State Research Facilities Programme for supporting CIPDD research infrastructure. CIPDD is also supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. A special acknowledgement to Mohammad Mobasseri for his insight into the preparation of liposomes as a starting point for this research. We also thank The University of Queensland for the financial support to complete this research.

Funding

This work was supported by a collaborative seeding grant to FYH, TK, and JF from The University of Queensland, Australia. FYH and WX were supported financially by a National Health and Medical Research Council (NHMRC) Grant [APP1107723], Australia. This work also received financial support from the Australian Research Council (LE0775684, LE110100028, LE110100033, LE140100087, LE160100168). T.M.W also received support from the National Health and Medical Research Council (APP1118881).

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Authors and Affiliations

  1. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia

    Weizhi Xu, Andrew K. Whittaker & Felicity Y. Han

  2. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Weizhi Xu, Vinod Kumar, Cedric S. Cui, Trent M. Woodruff, Karin Borges, Maree T. Smith & Felicity Y. Han

  3. School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, QLD, Australia

    Faheem Maqbool & James R. Falconer

  4. ARC Centre of Excellence in Convergent Bio Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia

    Andrew K. Whittaker

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  1. Weizhi Xu
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Contributions

FYH initiated and with JRF conceived the project. FYH, JRF, and FM designed and developed the formulation and FM performed the formulation. WX and FM performed in vitro characterisation with the support from AKW. FYH and VK designed in vivo studies. VK, WX, and CSC performed pharmacokinetic (PK) studies and analysis with support from TMW. FYH, JRF, and WX wrote the manuscript with input from MTS, and all authors edited the final manuscript.

Corresponding authors

Correspondence to James R. Falconer or Felicity Y. Han.

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Ethics approval and consent to participate

Animal experiments were performed in accordance with approval from the University of Queensland Animal Ethics Committee, Australia (the approval number is 241/18, and date of approval is 21 Aug 2018).

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All authors have agreed to publish this work.

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The authors declare no competing interests.

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Xu, W., Maqbool, F., Kumar, V. et al. Sustained-release ketamine-loaded lipid-particulate system: in vivo assessment in mice. Drug Deliv. and Transl. Res. 12, 2518–2526 (2022). https://doi.org/10.1007/s13346-021-01093-3

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