Discovery of a long-acting nanocrystal formulation of INND-2201, a new co-drug of pregabalin and palmitoylethanolamide with synergistic analgesic effects

Abstract

Chronic pain is a global health problem affecting approximately 30% of the adult population worldwide. Currently available painkillers often showed limited efficacy or serious adverse effects and require frequent administration to maintain therapeutic effects. To develop new long-acting analgesics with synergistic antinociceptive effects, a new co-drug INND-2201 of pregabalin and palmitoylethanolamide (PEA) was synthesized, characterized and prepared as a nanocrystal formulation. INND-2201 was slowly metabolized into pregabalin and PEA in microsomal stability test, and oral INND-2201 exhibited significant and synergistic antinociceptive effects for inflammatory and neuropathic pain with ED₅₀ values of 4.43 and 5.54mg/kg, respectively. Nanocrystals (NCs) of INND-2201 were then prepared by the ball milling method with the particle size of 107.1±2.7 nm. Intramuscular administration of INND-2201 NCs demonstrated prolonged pain relief lasting up to 5 days for chronic inflammatory pain in mice. Acute toxicity test, muscular irritation evaluation, rotarod test and open field test indicated that INND-2201 had a good safety profile. Taken together, INND-2201 NCs exerted long-acting analgesic effects and provided a promising strategy for the management of chronic pain.

Keywords

Chronic pain / Co-drug / Nanocrystals / Pregabalin / Synergistic analgesic effects

CRediT authorship contribution statement

Xiao-Min Han: Writing - original draft, Validation, Investigation, Formal analysis, Data curation. Yang Xiao: Writing - original draft, Investigation. Chao-Nan Huang: Writing - original draft, Investigation. Ming-Yue Yin: Visualization, Software. Ben Xu: Formal analysis. YangYang Song: Formal analysis. Tao Zhuang: Writing - review & editing, Writing - original draft, Methodology, Formal analysis, Data curation, Conceptualization. Gui-Sen Zhang: Writing - review & editing, Conceptualization.

Ethical approval

All animal experiments were executed in accordance with the protocol approved by the Ethical Committee of Jiangsu Ocean University (Approval No. 202200029).

Declaration of generative AI in scientific writing

Not applicable.

Funding information

This research was supported by National Natural Science Foundation of China (82304275) and Postgraduate Research & Practice Innovation Program of Jiangsu Ocean University (KYCX2024-19).

Data availability

Data will be made available on request.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank Zongzheng Li for his assistance with NMR data interpretation.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.pscia.2025.100099.

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