| Objective:To improve the concentration of drug in the therapeutic area and patient compliance, Paeonol-β-cyclodextrin (Pae-β-CYD) inclusion complex coated tablets were prepared for colon-specific release, the pharmaceutical profiles in vitro and pharmacokinetic parameters were evaluated after oral administration into rabbits.Method:Paeonol-β-cyclodextrin inclusion complex was prepared by saturated water solution-ultrasonication method. The effect of different factors such as ratio of Paeonol andβ-cyclodextrin, Paeonol concentration, ultrasonication times and frequency on the recovery rate of inclusion complex and Paeonol content were investigated and optimized using Uniform Design U13*(134) table. Infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction (X-RD) were routinely used to verify the formation of inclusion complex and to compare the change of physical and chemical properties before and after inclusion. The core tablets were prepared with the mixture of Pae-β-CYD inclusion complex, pectin and calcium acetate, which could cross linked in situ.. The effects of different pH, ratio of pectin and calcium acetate, core hardness, drying time and amount of pectinase on the release of drug were observed. Based on the previous results, the core tablets were coated with Eudragit S100. The effects of coating weight, curing temperature, curing time, type and amount of plasticizers on the release of drug from the coated tablets were evaluated in vitro to optimize the coating process. Furthermore, New Zealand rabbits were used as animal model, the pharmacokinetic studies of inclusion complex coated tablets and self-made conventional tablets were performed to assess the colon-targeting delivery effect.Results:(1) According to the Uniform Design, the optimal preparation process of Pae-β-CYD was as follows: when the saturated water solution-ultrasonication method was used, the ratio of Paeonol toβ-cyclodextrin was 3:1, the concentration of Paeonol was 60mg·mL-1. Ultrasonic times, frequency and treatment time were 90, 400 MHZ and 1 second interval per second, respectively. Entrapment efficiency of the inclusion complex was 10.7±0.5% and inclusion compound yield was 26.9±1.3%. The results of FT-IR, DSC, X-RD confirmed the formation of inclusion complex. (2) The addition of calcium acetate into the core of pectin tablets decreased the cumulative drug release percentage from 51% to 28%. Factors including coating weight, curing temperature and plasticizer type showed significant effect on the release of Paeonol. The release of Paeonol was not detected in simulated gastric fluid (pH 1.2, 2h) and followed small intestine (pH 6.8, 2h). But the coating membrane ruptured at higher pH conditions and the drug release was increased from the core tablets under the existence of pectinase, the lag time of colon-targeted tablets was about 5-6 hours. (3) Paeonol concentration in rabbit plasma was assayed by HPLC method. Tmax and Cmax of Paeonol conventional tablets were (0.9±0.7)h and (2554.5±1534.7)ng·mL-1, and interestingly changed to (3.2±0.8)h and (488.2±214.7)ng·mL-1 in the case of colon-targeted tablets accompanied with relative bioavailability was 60.8%. In addition, the data of Tlag (2.3±0.6)h showed retarded release of drug from colon-targeted tablets. The pharmacokinetic parameters of Paeonol in rabbit indicated that there were significant differences between the two preparations.Conclusion:The analysis methods of Paeonol were established in vitro and in vivo. On the basis of Pae-β-CYD inclusion compound, a novel colon-targeted tablet was successfully formulated and paeonol release could be controlled at the end of small intestine using pectin and calcium acetate as enzymatic degradation materials. Pharmacokinetic result showed that the novel coated tablet had an ideal colon-specific effects.
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