Chamsai Benchawan, Limmatvapirat Sontaya, Sungthongjeen Srisagul, Sriamornsak Pornsak
a Department of Pharmaceutical Technology, Faculty of Pharmacy , Silpakorn University , Nakhon Pathom , Thailand.
b Pharmaceutical Biopolymer Group (PBiG), Faculty of Pharmacy , Silpakorn University , Nakhon Pathom , Thailand.
Drug Dev Ind Pharm. 2017 Dec;43(12):2064-2075. doi: 10.1080/03639045.2017.1371731. Epub 2017 Sep 10.
Low bioavailability of oral manidipine (MDP) is due to its low water solubility.
The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone.
In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated.
The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo.
The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.
口服马尼地平（MDP）的生物利用度低是由于其水溶性差。
本研究的目的是通过用d-α-生育酚聚乙二醇1000琥珀酸酯和共聚维酮制备三元固体分散体（tSD）来提高MDP的溶解度和生物利用度。
在本研究中，应用固体三元相图来检查通过用干冰熔融和固化制备的tSD的均匀性。通过差示扫描量热法（DSC）、粉末X射线衍射（PXRD）、傅里叶变换红外光谱（FTIR）和热台显微镜测定不同制剂的物理化学性质。还研究了它们的溶解度、溶出度、稳定性和生物利用度。
结果表明，从三元相图获得的tSD分为均匀区域和非均匀区域。在均匀区域，观察到tSD的透明特性并将其视为玻璃溶液，其MDP溶解度高于非均匀区域。热台显微镜、DSC和PXRD证实形成了固体分散体，其中MDP分子分散在载体中，特别是在相图的均匀区域。FTIR分析表明MDP的胺基与共聚维酮的羰基之间存在强氢键，这支持了tSD更高的溶解度和溶出度。在Wistar大鼠中的药代动力学研究表明，tSD对口服生物利用度的影响最大。在体内也观察到tSD的即时降压作用。
使用tSD技术可以提高MDP的稳定性、溶出度和口服生物利用度。
