Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion.
Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion.
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吞噬的氯法齐明生物晶体可以通过抑制 TNFα 和促进 IL-1RA 分泌来调节先天免疫信号。
DOI：
10.1021/acs.molpharmaceut.5b00035
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发表时间：
2015
影响因子：
4.9
通讯作者：
Rosania,GusR
中科院分区：
文献类型：
--
作者：
Yoon,GiS;Sud,Sudha;Keswani,RahulK;Baik,Jason;Standiford,TheodoreJ;Stringer,KathleenA;Rosania,GusR
口腔黏膜粘附膜(MBF)提供了一种创新的方法，可以促进活性化合物的有效部位特异性输送，同时将病变与口腔环境分开。以环氧乙烷(CPX)在聚环氧乙烷(PEO)基质中的分子束流动为例，展示了这些复杂的多组分多相体系的结构多样性，以及在分子尺度和原子分辨率上表征其结构的实验策略。在详细描述CPX/PEO膜的每一组分之后，分析了每一组分与MBF的物理化学性质之间的关系。通过固体核磁共振谱鉴定了两种不同的MBF：(I)在低API(活性药物成分)负载时，CPX分子分散在无定形PEO基质中的纳米非均相固溶体生成；(Ii)在高API负载时，CPX-2-氨基乙醇纳米晶被引入结晶PEO基质的片层间隙中。这些结构上的差异被发现与所制备的MBF的机械和物理化学性质密切相关。在低API负载量下，PEO的聚合物链提供了足够数量的结合位来稳定分子分散在高度无定形半柔性聚合物基质中的CPX。因此，所得到的MBF是柔软的，具有较低的拉伸强度、可塑性和膨胀指数，支持药物的快速释放。然而，当CPX含量较高时，活性化合物和聚合物链同时共晶，使得CPX形成直接在PEO球晶内生长的纳米晶。因此，界面聚合物-药物相互作用不仅导致体系的可塑性显著提高，而且还导致CPX以热力学上最稳定的晶型I的形式唯一结晶，表现出较低的溶解动力学。因此，通过诱导CPX醇胺在聚合物基质中的完全分散和/或微分离和纳米结晶，可以有效地控制以PEO为基础的MBF的CPX醇胺的生物利用度。固体核磁共振波谱是探索这些复杂药物固体的结构-性质关系的有效工具。
Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX–2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer–drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure–property relationships in these complex pharmaceutical solids.