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Development and Characterisation of Ursolic Acid Nanocrystals Without Stabiliser Having Improved Dissolution Rate and In Vitro Anticancer Activity

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Abstract

Ursolic acid (UA), which is a natural pentacyclic triterpenoid, has the potential to be developed as an anticancer drug, whereas its poor aqueous solubility and dissolution rate limit its clinical application. The aim of the present study was to develop UA nanocrystals to enhance its aqueous dispersibility, dissolution rate and anticancer activity. Following the investigation on the effects of stabiliser, the ratio of organic phase to aqueous solution and drug concentration, the UA nanocrystals without stabiliser were successfully prepared by anti-solvent precipitation approach. The nanocrystals maintained similar crystallinity with particle size, polydispersion index and zeta potential values of 188.0 ± 4.4 nm, 0.154 ± 0.022, and −25.0 ± 5.9 mV, respectively. Compared with the raw material, the UA nanocrystals showed good aqueous dispensability and a higher dissolution rate, and they could be completely dissolved in 0.5% SDS solution within 120 min. Moreover, the suspension of UA nanocrystals was physically stable after storage at 4°C for 7 weeks. By inducing G2/M phase cell cycle arrest, the UA nanocrystals significantly induced stronger cell growth inhibition activity against MCF-7 cells compared with free drug in vitro, although the uptake of free UA was approximately twice higher than that of the UA nanocrystals. The UA nanocrystals may be used as a potential delivery formulation for intravenous injection with enhanced dissolution velocity and anticancer activity.

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Abbreviations

UA:

Ursolic acid

HPMC:

Hydroxypropyl methylcellulose

SDS:

Sodium dodecyl sulfate

Tween 80:

Polysorbate 80

F68:

Poloxamer 188

PVP:

Polyvinylpyrrolidone

TEM:

Transmission electron microscope

DSC:

Differential scanning calorimetry

PdI:

Polydispersity index

DLS:

Dynamic light scattering

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ACKNOWLEDGEMENTS

This work was supported by the Macao Science and Technology Development Fund (no. 044/2011/A2) and the research grant by University of Macau (MRG002/ZY/2012/ICMS). We would like to thank Professor Albert Chow, Dr. SF Chow and Dr. XR Zhang at the Chinese University of Hong Kong, and Dr. XP Chen and Mr. JB Sun at our institute for their valuable advice on the project and help with the TGA analysis.

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Authors and Affiliations

  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 2/F, Room 204A, Block 3, Av. Padre Tomás Pereira, S.J. Taipa, Macao,, SAR, China

    Ju Song, Yancai Wang, Yuelin Song, Hokman Chan, Chao Bi, Xiao Yang, Ru Yan, Yitao Wang & Ying Zheng

  2. School of Chemistry and Pharmaceutical Engineering, Shandong Polytechnic University, Jinan, 250353, China

    Yancai Wang

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  1. Ju Song
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  2. Yancai Wang
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  3. Yuelin Song
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  7. Ru Yan
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  9. Ying Zheng
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Correspondence to Ying Zheng.

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Song, J., Wang, Y., Song, Y. et al. Development and Characterisation of Ursolic Acid Nanocrystals Without Stabiliser Having Improved Dissolution Rate and In Vitro Anticancer Activity. AAPS PharmSciTech 15, 11–19 (2014). https://doi.org/10.1208/s12249-013-0028-0

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  • DOI: https://doi.org/10.1208/s12249-013-0028-0

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