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Enhancing Betulinic Acid Dissolution Rate and Improving Antitumor Activity via Nanosuspension Constructed by Anti-Solvent Technique

Authors Li S, Zhang J, Fang Y, Yi J, Lu Z, Chen Y, Guo B

Received 8 October 2019

Accepted for publication 22 December 2019

Published 16 January 2020 Volume 2020:14 Pages 243—256

DOI https://doi.org/10.2147/DDDT.S233851

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Tuo Deng


Shuqi Li, 1–3 Jie Zhang, 1–3 Yuqi Fang, 1–3 Jun Yi, 1 Zhufen Lu, 2, 3 Yanzhong Chen, 2, 3 Bohong Guo 1–3

1Department of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 3R&D Team for Formulation Innovation, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China

Correspondence: Yanzhong Chen
Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China
Tel +86 20 3935 2678
Fax +86 20 3935 2501
Email doctor.c@163.com

Bohong Guo
Department of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, 280 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, People’s Republic of China
Tel +86 20 3935 2117
Fax +86 20 3935 2129
Email guobohong@gdpu.edu.cn

Purpose: The aim of this study was to prepare and evaluate betulinic acid nanosuspension (BA-NS) for new drug delivery to enhance its solubility and in vitro anti-tumor activity.
Methods: BA-NS was formulated by an anti-solvent precipitation method using the Box-Behnken design (BBD). Particle size (PS) and Zeta potential were measured by laser particle size analysis. The drug solid state after freeze drying was characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) after freeze drying. The saturation solubility and dissolution rate were determined by solubility assay and in vitro dissolution studies, respectively. The in vitro cytotoxicity assay was performed using 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT) method.
Results: The PS was 129.7± 12.2 nm having a Zeta potential of − 28.1± 4.5 mV and the polydispersity index (PDI) was 0.231± 0.013, which confirmed that the nanosuspension was in the stable amorphous state. A series of characterization experiments demonstrated that nanoparticles retained original effective structure and existed as spherical or near-spherical nanoparticles in the nanosuspension, but the drug transferred from the crystal state to the amorphous state. The form of lyophilized BA-NS was very successful in enhancing the dissolution rate in PH-dependent way. The cytotoxicity assay revealed that BA-NS could significantly enhance the in vitro anti-proliferation against tumor cells compared to the BA suspension (BA-S).
Conclusion: The BA-NS can remarkably improve solubility and in vitro antitumor activity, which seems very promising for the treatment of cancers in practical application.

Keywords: betulinic acid, nanosuspension, anti-solvent precipitation, Box-Behnken design, cytotoxicity


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