Preparation and in vivo and in vitro Study of Piperine-Theanine Co-Amorphous Complex
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摘要: 目的 将胡椒碱(PIP)和茶氨酸(THE)联合制备成胡椒碱-茶氨酸共无定型复合物(PIP-THE CAC)，提高PIP的溶出度以及生物利用度。方法 通过淬火冷却法制备PIP-THE CAC，采用差示扫描量热分析(DSC)、粉末X-射线衍射(XRPD)、傅里叶红外光谱(FTIR)和扫描电镜(SEM)对制备的PIP-THE CAC进行表征分析，对PIP-THE CAC在漏槽和非漏槽条件下的体外溶出进行评价，并考察PIP-THE CAC的物理稳定性。此外，在大鼠体内进行PIP-THE CAC的药代动力学研究。结果 DSC和XRPD结果表明成功制备PIP-THE CAC。FTIR证实在PIP-THE CAC中，PIP与THE之间发生了分子间氢键相互作用，导致PIP-THE CAC具有良好的物理稳定性。SEM观察发现PIP-THE CAC呈不规则块状、颗粒状，已不见PIP和THE的特征。体外溶出实验表明，与PIP原料药及PIP-THEPM相比，PIP-THE CAC具有更高的溶出速率和溶出度并且可维持长时间的超饱和程度。药代动力学实验结果表明，与PIP原料药组比较，PIP-THE CAC组Cmax、tmax、AUC0-24 h、AUC0-∞显著增加(P < 0.01)，PIP的Cmax和生物利用度分别提高了2.03、1.93倍(P < 0.01)。结论 将PIP和THE联合制备成的PIP-THE CAC能有效地改善PIP的溶解度、体外溶出度以及生物利用度。Abstract: OBJECTIVE To prepare piperine-theanine co-amorphous complex (PIP-THE CAC) and improve dissolution and bioavailability of PIP.METHODS The PIP-THE CAC was prepared by quench cooling, characterized by DSC, XRPD, FTIR, SEM and evaluated by in vitro dissolution under sink and non-sink conditions. The physical stability of PIP-THE CAC was also investigated. Besides, the bioavailability study of PIP-THE CAC was conducted by pharmacokinetic tests in rats.RESULTS DSC and XRPD indicated that PIP-THE CAC was successfully prepared. FTIR confirmed that there was intermolecular hydrogen bond interaction between PIP and THE in the prepared CAC, resulting in excellent physical stability. SEM showed that the CAC was irregular, lumpy and granular, and the characteristics of PIP and THE were disappeared. Besides, compared with pure PIP and PIP-THE physical mixture, PIP-THE CAC possessed a higher dissolution rate and a higher dissolution degree, and maintained supersaturated degree for long time in vitro dissolution experiments. Pharmacokinetic results showed that Cmax, tmax, AUC0-24 h and AUC0-∞ of PIP-THE CAC group increased significantly (P < 0.01) compared with raw PIP, and the Cmax and bioavailability of PIP increased by 2.03 and 1.93 times, respectively (P < 0.01).CONCLUSION PIP-THE CAC prepared by THE co-amorphization with PIP can effectively improve the solubility/dissolution and oral bioavailability of PIP.
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Key words:
- piperine /
- theanine /
- co-amorphous complex /
- in vitro dissolution /
- stability /
- bioavailability
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图 5 PIP原料药、PIP-THE PM和PIP-THE CAC在漏槽条件下的溶出曲线
注：A.0.5%吐温-80的pH 1.2盐酸缓冲溶液; B.0.5%吐温-80的pH 6.8磷酸盐缓冲液; 与PIP原料药比较，*P＜0.05，**P＜0.01。
图 6 PIP原料药、PIP-THE PM和PIP-THE CAC在非漏槽条件下的溶出曲线
注：A.0.5%吐温-80的pH 1.2盐酸缓冲溶液; B.0.5%吐温-80的pH 6.8磷酸盐缓冲液；与PIP原料药组比较，*P＜0.05，**P＜0.01。
图 7 在40 ℃ 75%相对湿度下的1 d无定型PIP(a)、PIP-THE CAC(b)，15 d PIP-THE CAC(c)，30 d PIP-THE CAC(d)的XRPD图
表 1 PIP原料药组、PIP-THE PM组和PIP-THE CAC组中PIP的药代动力学参数(x±s, n=6)
药代动力学参数 PIP PIP-THE PM PIP-THE CAC Cmax(μg·mL-1) 9.67±2.37 8.89±0.50 19.65±1.13**## tmax(h) 3.83±1.17 3.92±1.84 2.33±0.52*# t1/2(h) 6.22±2.67 5.50±1.37 6.27±2.12 AUC0-24 h(μg·h·mL-1) 105.40±33.37 101.92±20.91 203.25±15.96**## AUC0-∞(μg·h·mL-1) 119.50±54.44 112.54±17.18 224.30±28.61**## 注：与PIP原料药比较，*P < 0.05，**P < 0.01；与PIP-THE PM组比较，#P < 0.05，##P < 0.01。 
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