Department of Chemistry , University of Minnesota , 207 Pleasant St. SE , Minneapolis , Minnesota 55455-0431 , United States.
Mol Pharm. 2019 Nov 4;16(11):4423-4435. doi: 10.1021/acs.molpharmaceut.9b00002. Epub 2019 Oct 21.
Amorphous solid dispersions of polymers and drugs have been shown to improve supersaturation maintenance of poorly water-soluble drugs. Herein, amorphous spray-dried dispersions (SDDs) of poly(acrylic acid)-polystyrene (PS--PAA) diblock copolymers with differing degrees of polymerization were prepared in aggregated and nonaggregated states with the Biopharmaceutical Classification System Class II drug, probucol (PBC). Specifically, PS--PAA, PS--PAA, PS--PAA, and PS--PAA amphiphilic block polymers that covered a compositional range in the area of oral drug delivery were prepared to examine the role of molecular weight and controlled aggregation in promoting drug supersaturation and maintenance. In addition, hydrophilic homopolymers PAA, PAA, PAA, and PAA were prepared as controls to evaluate the role of the block copolymer-based SDDs in PBC solubilization. Characterization such as powder X-ray diffraction, scanning electron microscopy, and dissolution tests under nonsink conditions were then performed to evaluate the SDDs. When comparing the block copolymer systems, polymers that were preaggregated into micellular structures prior to spray drying with the drug promoted higher drug solubility and maintenance than when the drug was formulated with molecularly dissolved PS-PAA block polymer. Interestingly, the aggregated PS--PAA SDD with 25 wt % PBC achieved 100% burst release and maintained full supersaturation of PBC at pH 6.5 (physiological pH in the small intestine). Dissolution studies conducted at the pH of the stomach (pH = 1.2) show that a minimal amount of drug (∼10 μg/mL) was released, which could be used for protecting drugs from acidic environments (stomach) before reaching the small intestine. To evaluate drug bioavailability, in vitro Caco-2 cell assays were performed, which reveal that PAA-based excipients do not hinder drug permeation across the epithelial membrane and that PS--PAA SDD with 25 wt % PBC achieved the highest membrane permeability coefficient. This work demonstrates that block copolymer-based SDDs capable of preaggregating into nanostructures may be a tunable drug-delivery platform that can improve solubility and supersaturation maintenance of Class II pharmaceutics while also not prohibiting bioavailability through model intestinal membranes. Indeed, this concept may be extended to accommodate a myriad of pharmaceutical and excipient structures.
聚合物和药物的无定形固体分散体已被证明可以提高低水溶性药物的过饱和度维持。本文中，用生物药剂学分类系统 II 类药物普罗布考（PBC），制备了不同聚合度的聚（丙烯酸）-聚苯乙烯（PS-PAA）嵌段共聚物的无定形喷雾干燥分散体（SDD），其处于聚集态和非聚集态。具体而言，制备了 PS-PAA、PS-PAA、PS-PAA 和 PS-PAA 两亲嵌段聚合物，涵盖了口服药物递送领域的组成范围，以考察分子量和控制聚集在促进药物过饱和和维持中的作用。此外，还制备了亲水性均聚物 PAA、PAA、PAA 和 PAA 作为对照，以评估基于嵌段共聚物的 SDD 在 PBC 增溶中的作用。然后进行粉末 X 射线衍射、扫描电子显微镜和非饱和条件下的溶解试验等表征，以评估 SDD。在比较嵌段共聚物体系时，与药物一起喷雾干燥前预聚集形成胶束结构的聚合物比药物与分子溶解的 PS-PAA 嵌段聚合物一起时能提高药物的溶解度和维持度。有趣的是，25wt%PBC 的聚集 PS-PAA SDD 实现了 100%的突释，并在 pH6.5（小肠中的生理 pH）下维持 PBC 的完全过饱和度。在胃的 pH（pH=1.2）下进行的溶解研究表明，仅释放了最小量的药物（约 10μg/mL），这可用于在到达小肠之前保护药物免受酸性环境（胃）的影响。为了评估药物的生物利用度，进行了体外 Caco-2 细胞测定，结果表明基于 PAA 的赋形剂不会阻碍药物穿过上皮膜的渗透，并且 25wt%PBC 的 PS-PAA SDD 实现了最高的膜渗透系数。这项工作表明，能够预聚集形成纳米结构的嵌段共聚物 SDD 可能是一种可调节的药物递送平台，可提高 II 类药物的溶解度和过饱和度维持度，同时通过模型肠膜不阻碍生物利用度。实际上，这个概念可以扩展到容纳无数的药物和赋形剂结构。
