Department of Pharmaceutical Chemistry , University of Kansas , 2030 Becker Drive , Lawrence , Kansas 66047 , United States.
Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy , University of Minnesota , Minneapolis , Minnesota 55455 , United States.
Mol Pharm. 2019 Mar 4;16(3):1119-1131. doi: 10.1021/acs.molpharmaceut.8b01118. Epub 2019 Feb 18.
Oral administration is advantageous compared to the commonly used parenteral administration for local therapeutic uses of biologics or mucosal vaccines, since it can specifically target the gastrointestinal (GI) tract. It offers better patient compliance, even though the general use of such a delivery route is often limited by potential drug degradation in the GI tract and poor absorption. Using bovine serum albumin (BSA) and lysozyme as two model proteins, we studied their solid-state properties, mechanical properties, and tabletability as well as effects of compaction pressure, particle size, and humidity on protein degradation. It was found that BSA and lysozyme are highly hygroscopic, and their tablet manufacturability (powder caking, punch sticking, and tablet lamination) is sensitive to the humidity. BSA and lysozyme exhibited high plasticity and excellent tabletability and remained amorphous at high pressure and humidity. As for protein stability, lysozyme was resistant to high pressure (up to 300 MPa) and high humidity (up to 93%). In contrast, BSA underwent aggregation upon compression, an effect that was more pronounced for smaller BSA particles. High humidity accelerated the aggregation of BSA during incubation, but it did not further synergize with mechanical stress to induce protein degradation. Thus, compression can potentially induce protein aggregation, but this effect is protein-dependent. Therefore, strategies (e.g., the use of excipients, optimized manufacturing processes) to inhibit protein degradation should be explored before their tablet dosage form development.
与常用于局部治疗生物制剂或黏膜疫苗的肠外给药相比，口服给药具有优势，因为它可以专门针对胃肠道（GI）。它提供了更好的患者依从性，尽管这种给药途径的一般用途通常受到 GI 道中潜在药物降解和吸收不良的限制。我们使用牛血清白蛋白（BSA）和溶菌酶作为两种模型蛋白，研究了它们的固态特性、力学性能以及片剂的可压性，以及压缩压力、粒径和湿度对蛋白降解的影响。结果发现，BSA 和溶菌酶具有很强的吸湿性，其片剂的可制造性（粉末结块、冲头粘连和片剂分层）对湿度敏感。BSA 和溶菌酶表现出高塑性和优异的可压性，并在高压和高湿度下保持非晶态。至于蛋白质稳定性，溶菌酶耐受高压（高达 300 MPa）和高湿度（高达 93%）。相比之下，BSA 在压缩时会发生聚集，较小的 BSA 颗粒的聚集效果更为明显。高湿度会加速 BSA 在孵育过程中的聚集，但它不会与机械应力协同作用进一步导致蛋白质降解。因此，压缩可能会导致蛋白质聚集，但这种效应是蛋白质依赖性的。因此，在开发其片剂剂型之前，应该探索抑制蛋白质降解的策略（例如，使用赋形剂、优化的制造工艺）。
