Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
J Control Release. 2020 Jan 10;317:142-153. doi: 10.1016/j.jconrel.2019.11.033. Epub 2019 Nov 27.
Amorphous solid dispersion (ASD) is a well-established approach to improve the dissolution rate of the drugs with low water solubility. However, the application of the ASD was hindered by the low drug content and high risk of re-crystallization of drugs. The purpose of this research was to develop an ASD film with high content of amorphous olanzapine (OLN) for oral delivery. To overcome the high crystallization tendency of OLN in polyvinyl alcohol (PVA) films, three dicarboxylic acids (succinic acid (Suc), fumaric acid (Fum) and malic acid (Mal)) were introduced in the drug-in-polymer system as linkers between the drug and the polymer. The influence of the linkers on the re-crystallization of OLN in PVA films was evaluated by polarized light microscopy (PLM) and x-ray diffraction (XRD). Then, the possible mechanisms of crystallization inhibition were discussed based on the results of dielectric spectroscopy (DES), differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), Raman spectroscopy and molecular modeling. Finally, the effect of the linkers on the in vitro dissolution of the OLN-in-PVA films was studied in simulant saliva, and the in vivo performance of the optimal formulation was evaluated in rats. The results showed that OLN-in-PVA film have lower molecular mobility, lower electrical conductivity and stronger intermolecular interactions with the existence of Mal, which led to a better crystallization inhibition of OLN in PVA films. The re-crystallization of OLN in PVA films decreased the dissolution rate of OLN in simulant saliva. The in vivo performance of the optimal formulation was similar with that of OLN solution in rats. This study introduced a novel strategy to reduce the risk of drug re-crystallization in ASD, and also provided a deeper insight into the mechanisms of crystallization inhibition in ASD. The results will improve the judicious selection of excipients in pharmaceutical formulations.
无定形固体分散体（ASD）是提高低水溶性药物溶解速率的一种成熟方法。然而，ASD 的应用受到药物含量低和药物再结晶风险高的限制。本研究旨在开发一种用于口服递送的高含量无定形奥氮平（OLN）的 ASD 薄膜。为了克服 OLN 在聚乙烯醇（PVA）薄膜中结晶倾向高的问题，在药物-聚合物体系中引入了三种二羧酸（琥珀酸（Suc）、富马酸（Fum）和苹果酸（Mal））作为药物与聚合物之间的连接体。通过偏光显微镜（PLM）和 X 射线衍射（XRD）评估连接体对 OLN 在 PVA 薄膜中再结晶的影响。然后，根据介电光谱（DES）、差示扫描量热法（DSC）、衰减全反射傅里叶变换红外（ATR-FTIR）、拉曼光谱和分子建模的结果，讨论了可能的结晶抑制机制。最后，研究了连接体对 OLN 在 PVA 薄膜中的体外溶解性能的影响，并在大鼠体内评估了最佳配方的性能。结果表明，Mal 的存在使 OLN-PVA 薄膜具有较低的分子迁移率、较低的电导率和较强的分子间相互作用，从而更好地抑制了 OLN 在 PVA 薄膜中的结晶。OLN 在 PVA 薄膜中的再结晶降低了 OLN 在模拟唾液中的溶解速率。最佳配方的体内性能与大鼠中 OLN 溶液的体内性能相似。本研究为降低 ASD 中药物再结晶的风险提供了一种新策略，并深入了解了 ASD 中结晶抑制的机制。研究结果将改善药物制剂中赋形剂的合理选择。
