Abstract：
Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous \"30 wt % ASD\" prepared by spray drying, as well as inhomogeneous \"30 wt % PM\" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug-polymer interaction mechanism and \"apparent\" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single Tg in 30 wt % ASD confirmed its homogeneous phase. 1H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous \"30 wt % ASD\" has more numbers of interacting drug-polymer pairs, and thus exhibits stronger \"apparent\" interaction strength comparing with that of inhomogeneous \"30 wt % PM\". Unexpectedly,in the in vitro dissolution studies, inhomogeneous \"30 wt % PM\" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous \"30 wt % ASD\". However, drug precipitate recrystallized much slower in homogeneous \"30 wt % ASD\", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous \"30 wt % ASD\" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (Cmax) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous \"30 wt % PM\". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug-polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.
摘要：
不均匀性是显著影响无定形固体分散体(ASD)溶解行为的关键因素。然而,不均匀相对ASDs溶出特性和生物利用度影响的潜在机制尚不清楚.在这项研究中,制备了两种类型的基于非洛地平/PVPVA的ASD，其具有30wt％的载药量，但均一性不同：通过喷雾干燥制备的均匀的“30wt％ASD”，以及通过将喷雾干燥的70重量%ASD与PVPVA物理混合而制备的不均匀的“30重量%PM”。我们旨在研究（1）两种ASD中的药物-聚合物相互作用机制和“表观”相互作用强度，以及（2）两种ASD的溶解机制以及体内性能。DSC热谱图显示30重量%ASD中的单个Tg证实了其均匀相。1HNMR,FT-IR,和DVS研究共同证明，在ASD中，非洛地平和PVPVA之间形成了强烈的氢键相互作用。此外，均匀的“30重量%ASD”具有更多数量的相互作用的药物-聚合物对，因此，与不均匀的“30重量%PM”相比，表现出更强的“表观”相互作用强度。出乎意料的是,在体外溶出研究中，不均匀的“30wt％PM”显示出比均匀的“30wt％ASD”更快的溶解，并且产生的药物浓度〜4.4倍。然而,药物沉淀在均匀的“30重量%ASD”中重结晶慢得多大概是因为在这个系统中有更多的聚合物与无定形药物共沉淀，这有助于抑制药物结晶。令人惊讶的是,均匀的“30wt％ASD”在体内药代动力学研究中显示出明显更高的生物利用度，最大血浆浓度（Cmax）和曲线下面积（AUC）值比不均匀的“30wt％PM”高约2.7和2.3倍。以上发现表明药物沉淀的无定形状态显著有助于提高ASDs的生物利用度,而传统的体外溶出研究，例如,如果我们只比较溶液中溶解的药物或ASD产生过饱和的能力，不足以预测ASD的体内性能。总之,ASD的相行为直接影响药物-聚合物相互作用的形成，它不仅控制溶液中的药物过饱和，而且控制沉淀物中的药物结晶，并最终影响ASD的体内性能。
