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<p>Paracetamol (PCM) overdosing-induced hepatotoxicity is a chief cause of acute liver toxicity. Andrographolide (APD) upregulates the Nrf2 level in hepatocytes, inhibits activation of NF-kB pathway and lipid peroxidation, as well as mitigates the release of pro-inflammatory mediators. However, APD meets several challenges, such as limited oral bioavailability (15.87 ± 3.84%), poor solubility (3.29 ± 0.73&#xa0;µg.mL<sup>− 1</sup>), and gastric <i>milieu</i> susceptibility. Therefore, in the present investigation, parenteral poly(ε-caprolactone) microparticles of andrographolide <b>(</b>APD-PCL-MPs) were engineered using an oil-in-water (O/W) emulsion solvent evaporation method under optimized processing conditions assessed by Box-Behnken Design (BBD; 3-factors, 3-levels). The APD-PCL-MPs exhibited a particle size of 1.47 ± 0.19&#xa0;μm, ζ-potential of -29.44 ± 0.92 mV, 4.57 ± 0.03% drug loading (% DL), and 70.40 ± 1.35% entrapment efficiency (% EE). Comprehensive characterizations by FTIR, TGA, DSC, and P-XRD analyses authenticated efficient entrapment, enriched thermal stability, and molecular amorphous dispersion of the therapeutic entity post-microencapsulation. The in-vitro drug release profile verified sustained drug release up to 96&#xa0;h by following Higuchi and Korsmeyer-Peppas kinetics. Further, andrographolide loaded poly(ε-caprolactone) microparticles once a day through intravenous route at the dose of 10&#xa0;mg/kg for 7 days attenuated PCM (3&#xa0;g/kg)-induced hepatotoxicity owing to targeted and sustained release of therapeutic entity, as evidenced by normalization of biochemical markers, hepatic antioxidant enzyme levels, lipid peroxidation, and proinflammatory mediators (IL-6 and TNF-α). Andrographolide-loaded poly(ε-caprolactone) microparticles once a day through the intravenous route preserved hepatic cytoarchitecture with markedly reduced necrosis, vascular congestion, diffused sinusoidal dilation, and inflammatory infiltration. In conclusion, andrographolide-loaded poly(ε-caprolactone) microparticles once a day through the intravenous route may be a promising therapeutic modality for translating into a clinically viable product.</p> Graphical Abstract <p></p>

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Poly(ε-Caprolactone) Microparticles of Andrographolide for Paracetamol-Induced Liver Iinjury: Box-Behnken Design Based Optimization, In Vitro and In Vivo Studies

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Nitin Wadate,
  • Pawan Devangan,
  • Pankaj Kumar,
  • Gopal Bajad,
  • Jitender Madan

摘要

Paracetamol (PCM) overdosing-induced hepatotoxicity is a chief cause of acute liver toxicity. Andrographolide (APD) upregulates the Nrf2 level in hepatocytes, inhibits activation of NF-kB pathway and lipid peroxidation, as well as mitigates the release of pro-inflammatory mediators. However, APD meets several challenges, such as limited oral bioavailability (15.87 ± 3.84%), poor solubility (3.29 ± 0.73 µg.mL− 1), and gastric milieu susceptibility. Therefore, in the present investigation, parenteral poly(ε-caprolactone) microparticles of andrographolide (APD-PCL-MPs) were engineered using an oil-in-water (O/W) emulsion solvent evaporation method under optimized processing conditions assessed by Box-Behnken Design (BBD; 3-factors, 3-levels). The APD-PCL-MPs exhibited a particle size of 1.47 ± 0.19 μm, ζ-potential of -29.44 ± 0.92 mV, 4.57 ± 0.03% drug loading (% DL), and 70.40 ± 1.35% entrapment efficiency (% EE). Comprehensive characterizations by FTIR, TGA, DSC, and P-XRD analyses authenticated efficient entrapment, enriched thermal stability, and molecular amorphous dispersion of the therapeutic entity post-microencapsulation. The in-vitro drug release profile verified sustained drug release up to 96 h by following Higuchi and Korsmeyer-Peppas kinetics. Further, andrographolide loaded poly(ε-caprolactone) microparticles once a day through intravenous route at the dose of 10 mg/kg for 7 days attenuated PCM (3 g/kg)-induced hepatotoxicity owing to targeted and sustained release of therapeutic entity, as evidenced by normalization of biochemical markers, hepatic antioxidant enzyme levels, lipid peroxidation, and proinflammatory mediators (IL-6 and TNF-α). Andrographolide-loaded poly(ε-caprolactone) microparticles once a day through the intravenous route preserved hepatic cytoarchitecture with markedly reduced necrosis, vascular congestion, diffused sinusoidal dilation, and inflammatory infiltration. In conclusion, andrographolide-loaded poly(ε-caprolactone) microparticles once a day through the intravenous route may be a promising therapeutic modality for translating into a clinically viable product.

Graphical Abstract