| Cinnamic acid(CA) is a phenol compound widely presented in natural vegetable oils, which is mainly used as food flavors. In addition, cinnamic acid possesses a variety of pharmacological activities of anti-inflammatory, anti-bacterial, anti-cancer, anti-tumor and anti-oxidation effects. However, the characteristics of poor solubility and low bioavailability limit its formulation research. In this paper, solid dispersion technology and thin-film dispersion method were combined with two kinds of sustained release pellets to achieve the aim of improving solubility, enhancing stability and increasing bioavailability of cinnamic acid, in order to expand further widely clinical application. Herein, the main five parts of this paper were presented as follows.Part one: ReviewsThis part was a summary of main pharmacological effects and novel drug formulation study of cinnamic acid, such as aerosols, capsules and pellets. Together, the research progress of sustained-release pellets was introduced to lay the foundation for the subsequent studies.Part two: Preformulation studiesThe methodology HPLC was established to determine the contents of cinnamic acid in samples in vitro. In this study, the in vitro assay was turned to be in good specificity with a linear range of 0.5-100 μg·m L-1(n=3, R2 =0.999). The intra-day and inter-day precision coefficients of variation(RSD %) both were less than 2%. And the average recoveries of the samples were between 97% and 101%. The solubility increases with the p H value of dispersion medium in the equilibrium solubility study of cinnamic acid at different p H of the medium(water, p H1.2 and p H7.4). And the results showed that cinnamic acid is a water insoluble compound because of the scarce solubility(only 0.23 mg·m L-1 in water), which provided a theoretical basis for the study. Part three: Preparation and optimization of cinnamic acid sustained release pelletsIn this part, the technologies of solid dispersion and thin-film dispersion were adopted to improve the solubility of cinnamic acid. By these technologies, solid dispersion coating sustained-release pellets(CSDP) and liposome matrix sustained-release pellets(CLMP) of cinnamic acid were prepared with the methods of coating and extrusion spheronization, respectively. Based on single factor method, the optimal formulations were confirmed as followed: there were 5% cinnamic acid, 5% hydroxypropyl methyl cellulose(HPMC K100), 75% microcrystalline cellulose(MCC), 2.5% soya lecithin and 12.5% polyvinyl pyrrolidone(PVP K30) in the CSDP. While the formulation of sustained release coating solution was consisted of 5 g ethyl cellulose(EC), 1 g polyethylene glycol 4000(PEG4000) and 1.5 g talcum powder in 150 m L absolute ethyl alcohol. Ultimately, the formulation of CLMP was cinnamic acid(1.3%), soybean lecithin(14%), cholesterol(2%), sodium cholate(10%), isopropyl myristate(10%), hydroxypropyl methyl cellulose(HPMC K100)(10%) and microcrystalline cellulose(MCC)(52.7%). Part four: Characterization and in vitro evaluation of cinnamic acid sustained release pelletsThe morphology and properties of cinnamic acid sustained release pellets were characterized mainly including SEM morphology, X-ray diffraction analysis(XRD) and in vitro drug release characteristics investigation. Differential scanning calorimeter(DSC) and XRD confirmed that there was no crystalline cinnamic acid, which turned out that cinnamic acid displayed in amorphous form distribution in CSD. In the case of being uniformly dispersed in water, CL was displaying particle size of 29.62 nm, with the ploydispersity index being 0.150 and the zeta potential being-19.78 m V. CL was also observed by TEM to be uniform in diameter, and great redispersibility of cinnamic acid was displayed in CLMP. Uniformly distributed and smooth CSDP were observed in SEM images. What’s more, In vitro release curves of two kinds pellets showed that cinnamic acid was released at a relatively slow speed in 24 h significantly. Moreover, both of their cumulative release rates reached 80%. Part five: Pharmacokinetics of cinnamic acid sustained release pellets in New Zealand rabbitsThe in vivo analysis method of cinnamic acid in New Zealand rabbits was established, which was in good specificity, high degree of separation and was in line with the method requirements. And there was no interference between cinnamic acid and internal standard through the method for plasma samples. In the pharmacokinetic study, no significant differences were observed in Tmax and t1/2 of CSD compared with that of free drug, while the Cmax and AUC0-24 h were greatly improved. The Cmax, Tmax and t1/2 of CL, CSDP and CLMP after oral administration were extended compared with unformulated cinnamic acid; therefore by maintain the effective blood concentration for a long time. Meanwhile, the AUC0-24 h increased to 20.6625 ± 0.03129, 20.4871 ± 0.03105 and 22.7488 ± 0.05729 μg·h·m L-1, respectively. It was obviously shown that the relative oral bioavailability of CSD, CL, CSDP and CLMP was 216.43%, 479.17%, 475.11% and 527.56%, respectively, compared with free cinnamic acid. In addition, both of the two kinds sustained release pellets significantly prolonged cinnamic acid action time. Meanwhile, half life(t1/2) was increased to 6.87 h and 8.49 h respectively. |
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