Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach/Riß, Germany.
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach/Riß, Germany.
Mol Pharm. 2024 Mar 4;21(3):1309-1320. doi: 10.1021/acs.molpharmaceut.3c00696. Epub 2024 Feb 12.
Producing amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is favorable from an economic and ecological perspective but also limited to thermostable active pharmaceutical ingredients (APIs). A potential technology shift from spray-drying to hot-melt extrusion at later stages of drug product development is a desirable goal, however bearing the risk of insufficient comparability of the and performance of the final dosage form. Hot-melt extrusion was performed using API/polymer/surfactant mixtures with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the polymer and evaluated regarding the extrudability of binary and ternary amorphous solid dispersions (ASDs). Additionally, spray-dried ASDs were produced, and solid-state properties were compared to the melt-extruded ASDs. Tablets were manufactured of a ternary ASD lead candidate comparing their dissolution and performance. The extrudability of HPMCAS was improved by adding a surfactant as plasticizer, thereby lowering the high melt-viscosity. d-α-Tocopheryl polyethylene glycol succinate (TPGS) as surfactant showed the most similar solid-state properties between spray-dried and extruded ASDs compared to those of poloxamer 188 and sodium dodecyl sulfate. The addition of TPGS, however, barely affected API/polymer interactions. The dissolution experiment and dog study revealed a higher drug release of tablets manufactured from the spray-dried ASD compared to the melt-extruded ASD; this was attributed to the different particle size. We could further demonstrate that the drug release can be controlled by adjusting the particle size of melt-extruded ASDs leading to a similar release profile compared to tablets containing the spray-dried dispersion, which confirmed the feasibility of a technology shift from spray-drying to HME upon drug product development.
采用热熔挤出（HME）制备无定形固体分散体（ASD）从经济和生态角度来看是有利的，但也仅限于热稳定的活性药物成分（API）。在药物产品开发的后期，将喷雾干燥技术向热熔挤出技术转变是一个理想的目标，但存在最终剂型的和性能缺乏充分可比性的风险。使用 API/聚合物/表面活性剂混合物进行热熔挤出，其中以羟丙甲纤维素醋酸琥珀酸酯（HPMCAS）为聚合物，并评估二元和三元无定形固体分散体（ASD）的可挤出性。此外，还制备了喷雾干燥的 ASD，并将其固态性质与熔融挤出的 ASD 进行比较。比较了三元 ASD 先导候选药物的片剂，比较了它们的溶解和性能。通过添加表面活性剂作为增塑剂来改善 HPMCAS 的可挤出性，从而降低高熔体粘度。与泊洛沙姆 188 和十二烷基硫酸钠相比，作为表面活性剂的 d-α-生育酚聚乙二醇琥珀酸酯（TPGS）在喷雾干燥和挤出 ASD 之间显示出最相似的固态性质。然而，添加 TPGS 几乎不会影响 API/聚合物相互作用。溶解实验和犬研究表明，由喷雾干燥 ASD 制成的片剂的药物释放率高于熔融挤出 ASD，这归因于粒径不同。我们进一步证明，可以通过调整熔融挤出 ASD 的粒径来控制药物释放，从而与含有喷雾干燥分散体的片剂具有相似的释放曲线，这证实了在药物产品开发过程中，从喷雾干燥向 HME 技术转变的可行性。
