Mol Pharm. 2023 May 1;20(5):2452-2464. doi: 10.1021/acs.molpharmaceut.2c01056. Epub 2023 Apr 3.
In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by and evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.
在这项工作中，系统地开发了一种无定形固体分散体 (ASD) 配方，以同时提高所选晶型候选药物 GDC-0334 的生物利用度并降低其机械不稳定性风险。无定形溶解度优势计算用于了解无定形制剂对 GDC-0334 的溶解度增强潜力，结果表明其具有 2.7 倍的理论无定形溶解度优势。这与无定形 GDC-0334 与晶型 GDC-0334 在广泛 pH 缓冲液中的实验溶解度比（约 2 倍）相当吻合。在此无定形溶解度优势的指导下，然后进行了 ASD 筛选，重点关注过饱和度维持和溶解性能。结果发现，尽管聚合物载体的类型不会影响 ASD 性能，但添加 5%（w/w）十二烷基硫酸钠 (SDS) 可显著提高 GDC-0334 ASD 的溶解速率。在进行 ASD 组成筛选后，对选定的 ASD 粉末及其假设的片剂配方进行了稳定性研究。观察到具有或不具有片剂赋形剂的选定 ASD 原型的稳定性都非常出色。随后，制备了 ASD 片剂，并进行了 和 评价。与促进 ASD 粉末溶解的作用相似，添加的 SDS 提高了 ASD 片剂的崩解和溶解。最后，犬药代动力学研究证实，与 GDC-0334 晶型相比，开发的 ASD 片剂使 GDC-0334 的暴露量增加了 1.8 至 2.5 倍，这与 GDC-0334 的无定形溶解度优势一致。根据这项工作的实践，提出了一种用于实际药物应用的 ASD 制剂开发工作流程，可为其他新化学实体的 ASD 制剂开发提供潜在指导。
