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Oleanolic acid is a pentacyclic triterpenoid compound that exists widely in medicinal herbs and other plants. Because of the extensive pharmacological activity, oleanolic acid has attracted more and more attention. However, the structural characteristics of oleanolic acid prevent it from being directly made into new drugs, which limits the application of oleanolic acid. Through the application of modern preparation techniques and methods, different oleanolic acid dosage forms and derivatives have been designed and synthesized. These techniques can improve the water solubility and bioavailability of oleanolic acid and lay a foundation for the new drug development. In this review, the recent progress in understanding the oleanolic acid dosage forms and its derivatives are discussed. Furthermore, these products were evaluated comprehensively from the perspective of characterization and pharmacokinetics, and this work may provide ideas and references for the development of oleanolic acid preparations.

Yue Sun,1 Lingjun Li,1 Huichao Xie,2 Yuzhen Wang,1 Shuang Gao,1 Li Zhang,1 Fumin Bo,1 Shanjing Yang,1 Anjie Feng1 1College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, People’s Republic of China; 2School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaCorrespondence: Lingjun Li Email sdzyylilingjun@163.comBackground: Paeonol (PAE) is a potential central neuroprotective agent with poor water solubility and rapid metabolism in vivo. The key to improve the clinical application of PAE in the treatment of neurodegenerative diseases is to improve the brain delivery of it. The purpose of this study was to construct a paeonol-solid lipid nanoparticles-in situ gel (PAE-SLNs-ISG) drug delivery system based on nose-brain transport pathway.Materials and Methods: In this study, the stability of PAE in simulated biological samples was studied firstly in order to clarify the reasons for low oral bioavailability. Paeonol-solid lipid nanoparticles (PAE-SLNs) were prepared by high-temperature emulsification–low-temperature curing combined with ultrasound. The PAE-SLNs-ISG drug delivery system was constructed, and related formulation optimization, preparation characterization, cell evaluation and in vivo evaluation were performed.Results: The metabolic mechanism of PAE incubated in the liver microsomes metabolic system was in accordance with the first-order kinetics, and the half-life was 0.23 h. PAE-SLNs were polyhedral or spherical particles with good dispersion and the particle size was 166.79 nm ± 2.92 nm. PAE-SLNs-ISG solution was a Newtonian fluid with a viscosity of 44.36 mPa · S ± 2.89 mPa · S. The viscosity of PAE-SLNs-ISG gel was 1542.19 mPa · S ± 19.30 mPa · S, and the rheological evaluation showed that the gel was a non-Newtonian pseudoplastic fluid with shear thinning, thixotropy and yield value. The release mechanism of PAE from PAE-SLNs was drug diffusion; the release mechanism of PAE from PAE-SLNs-ISG was a synergistic effect of skeleton erosion and drug diffusion. The cell viabilities of PAE-SLNs and PAE-SLNs-ISG in the concentration range of 0.001 μg/mL to 10 μg/mL were higher than 90%, showing a low level of cytotoxicity. The geometric mean fluorescent intensities of RPMI 2650 cells incubated with fluorescein isothiocyanate-solid lipid nanoparticles (FITC-SLNs) for 1 h, 4 h and 6 h were 1841 ± 24, 2261 ± 27 and 2757 ± 22, respectively. Cyanine7 NHS ester-solid lipid nanoparticles-in situ gel (Cy7-SLNs-ISG) accumulated effectively in the brain area after administration through the olfactory area, and the fluorescence response was observed in olfactory bulb, cerebellum and striatum.Conclusion: SLNs-ISG nose-brain drug delivery system can effectively deliver SLNs to brain regions, and it is a potentially effective strategy to realize the brain region delivery of PAE.Keywords: paeonol, in vitro metabolism, solid lipid nanoparticles, in situ gel, nose-brain transport