Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439.
J Pharm Sci. 2019 Dec;108(12):3859-3869. doi: 10.1016/j.xphs.2019.09.014. Epub 2019 Sep 19.
Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has gained popularity as a carrier for amorphous solid dispersion because of its ability to maintain drugs in supersaturated state after dissolution in aqueous media. In part I and II of this series of articles, we have demonstrated that amorphous solid dispersions containing HPMCAS may be prepared using surfactants as plasticizers to reduce processing temperature (Solanki et al., J Pharm Sci. 2019; 108:1453-65), where surfactants also increase dissolution rate and degree of supersaturation (Solanki et al., J Pharm Sci. 2019; 108: 3063-73). The present investigation was undertaken to develop melt extrudates of itraconazole-HPMCAS and itraconazole-surfactant-HPMCAS mixtures into tablets having tensile strength ≥2 MPa, where poloxamer 407 and d-α-tocopherol polyethylene glycol 1000 succinate were used as surfactants. Milled filaments were sieved to collect <212-μm particles, which were then compressed into tablets with different excipients (silicified microcrystalline cellulose [MCC], Avicel PH-102, dicalcium phosphate, lactose, and Starch 1500). Initial screening of various diluents showed that only silicified MCC and Avicel PH-102 could provide the target tensile strength of ≥2 MPa. Tabletability (tensile strength vs. compaction pressure), compressibility (porosity vs. compaction pressure), and compactibility (tensile strength vs. porosity) were then studied for tablet formulations. The desired tensile strength could be obtained at the diluent level of 50%-70%, where silicified MCC provided better hardness than Avicel PH-102. Tablets disintegrated in <2 min, and drug release from tablets was comparable to that of milled filaments.
羟丙甲纤维素醋酸琥珀酸酯（HPMCAS）因其在水介质中溶解后能够将药物维持在过饱和状态而成为制备无定形固体分散体的热门载体。在本系列文章的第一部分和第二部分中，我们已经证明可以使用表面活性剂作为增塑剂来制备含有 HPMCAS 的无定形固体分散体，以降低加工温度（Solanki 等人，J Pharm Sci. 2019; 108:1453-65），其中表面活性剂还可以提高药物的溶解速率和过饱和度（Solanki 等人，J Pharm Sci. 2019; 108: 3063-73）。本研究旨在将伊曲康唑-HPMCAS 和伊曲康唑-表面活性剂-HPMCAS 混合物制成熔融挤出物，然后压制成拉伸强度≥2 MPa 的片剂，其中聚氧乙烯 407 和生育酚聚乙二醇 1000 琥珀酸酯用作表面活性剂。将研磨的细丝过筛，收集<212-μm 的颗粒，然后用不同的赋形剂（硅化微晶纤维素 [MCC]、Avicel PH-102、磷酸二钙、乳糖和淀粉 1500）将其压缩成片剂。对各种稀释剂的初步筛选表明，只有硅化 MCC 和 Avicel PH-102 才能提供≥2 MPa 的目标拉伸强度。然后研究了片剂配方的可压性（拉伸强度与压缩压力的关系）、可压缩性（孔隙率与压缩压力的关系）和可压实性（拉伸强度与孔隙率的关系）。在稀释剂水平为 50%-70%时，可以获得所需的拉伸强度，其中硅化 MCC 比 Avicel PH-102 提供更好的硬度。片剂在<2 分钟内崩解，片剂的药物释放与研磨细丝相当。
