Safety Evaluation of Spray-Dried Curcuma longa L. Extract for Pharmacopuncture: acute toxicity and neurobehavioral assessment in zebrafish

Objectives: Curcuma longa L. (CL) exhibits potent anti-inflammatory and analgesic properties suitable for pharmacopuncture; however, the clinical application of CL is severely hindered by poor aqueous solubility. Moreover, traditional ethanol-based extracts are unsuitable for safe parenteral administration due to the risk of tissue necrosis and neurotoxicity at sensitive acupoint sites. Thus, no systematic safety evaluation of water-soluble CL extract (CLE) formulations for injection has yet been conducted. Methods: Spray-dried CLE (SDCLE) was prepared by spray-drying CLE with lactose (1:9 w/w) as the microencapsulation agent. The curcuminoid composition was quantified using a validated high-performance thin-layer chromatography (HP-TLC) method. The solubility of SDCLE was compared with that of native CLE (NCLE). Acute toxicity (LC50), survival, and locomotor behavior were determined using probit regression and automated EthoVision XT tracking following a 96-hour exposure of adult zebrafish to SDCLE (0-500 mg/L). Results: SDCLE, formulated to contain 10% (w/w) NCLE, exhibited a curcumin content of 0.148 ± 0.02 mg/g. This formulation showed markedly enhanced aqueous solubility (91.30% at a 1:30 dilution) compared with NCLE alone (55.78% at the same dilution), yielding clear, homogeneous solutions suitable for parenteral administration. Post-exposure acute toxicity assessment in zebrafish revealed a time-dependent decrease in LC50 values, from 469.96 mg/L at 24 h to 288.13 mg/L at 96 h. Acute toxicity analysis identified a no-observed-effect concentration (NOEC) of 144.07 mg/L and a lowest-observed-effect concentration (LOEC) of 187.28 mg/L. Exposure to concentrations ≤ 200 mg/L resulted in 95% survival and preserved normal locomotor activity, whereas concentrations ≥ 300 mg/L induced pronounced neurobehavioral suppression, characterized by a 35% reduction in swimming distance and a six-fold increase in inactivity. Conclusion: Spray-drying overcame the solubility limitations of CLE, enabling aqueous reconstitution for pharmacopuncture applications. A 96-hour LC50 of 288.13 mg/L was employed to define mortality, while neurobehavioral endpoints indicated toxicity at sublethal concentrations, supporting the safety of concentrations ≤ 200 mg/L for rational SDCLE dose selection.

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