Lycopene, the aliphatic hydrocarbon carotenoid with abundant bioactivities, has instability, extremely poor water solubility, and low oral bioavailability. The study aimed to develop a highly water-soluble and practical lycopene formulation to improve the oral bioavailability and efficiency of lycopene. Environment-friendly hot-melt extrusion (HME) technique was applied to fabricate lycopene-cyclodextrin-polyethylene glycol 6000 (PEG 6000) ternary systems, which possessed highly aqueous solubility (897.665 μg mL−1), almost 32-fold higher than that of the reported lycopene binary inclusion (27.1 ± 3.2 μg mL−1). The dissolution rate was significantly accelerated compared to pure lycopene. The molecular mechanism was further investigated by the integrated experimental and modeling tools. Molecular dynamics (MD) simulation revealed lycopene molecule was wrapped within the aggregates of hydroxypropyl-beta-cyclodextrin (HP-β-CD) and PEG 6000 through extensive hydrogen bond interactions, which was experimentally validated by DSC, XRD, and FTIR spectrum analysis. The third component PEG 6000 facilitated the process of HME and augmented hydrogen bond interactions with HP-β-CD. Moreover, lycopene inclusions exhibited significant antitumor activity via inhibiting cell proliferation and inducing apoptosis. The pharmacokinetic studies showed the relative bioavailability of lycopene ternary preparation was up to 313.08% and the Cmax was 4.9-fold higher than that of the marketed tablet. In conclusion, the lycopene cyclodextrin ternary formulation developed by the modified HME techniques is suitable for industrial production, while PEG 6000 plays a vital part in the multicomponent systems to increase solubility, dissolution rate, and oral bioavailability of lycopene. The combination of experimental and computational tools is able to benefit the development of multicomponent formulations accurately and effectively.
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The Science and Technology Program of Guangzhou, China (Grant numbers 201604020166 and 201904010110) supported this study.
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Yan Ma, Liuting Zhong, and Zhuo Peng share first authorship of this article
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Ma, Y., Zhong, L., Peng, Z. et al. Development of a Highly Water-Soluble Lycopene Cyclodextrin Ternary Formulation by the Integrated Experimental and Modeling Techniques. AAPS PharmSciTech 22, 5 (2021). https://doi.org/10.1208/s12249-020-01861-3
- ternary formulation
- hot-melt extrusion
- molecular dynamics simulation