Delivery Device and Connected Systems, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
AAPS PharmSciTech. 2018 May;19(4):1827-1836. doi: 10.1208/s12249-018-1000-9. Epub 2018 Apr 9.
This study aimed to elucidate the mechanisms and kinetics of coating failure for enteric coated beads exposed to high-humidity conditions at different storage temperatures. Enteric coated beads were placed on high-humidity conditions (75 to 98% relative humidity (RH)) in the temperature range of 5 to 40°C. These stability samples of beads were tested for acid dissolution and water activity and also analyzed with SEM, X-ray CT, and DMA. Exposure of enteric coated beads to high humidity led to increased gastric release of drug which eventually failed the dissolution specification. SEM showed visible cracks on the surface of beads exposed to 5°C/high humidity and fusion of enteric beads into agglomerates at 40°C/high humidity. In a non-destructive time elapse study, X-ray CT demonstrated swelling of microcrystalline cellulose cores, crack initiation, and propagation through the API layer within days under 5°C/98% RH storage conditions and ultimately fracture through the enteric coating. DMA data showed a marked reduction in T of the enteric coating materials after exposure to humidity. At 5°C/high humidity, the hygroscopic microcrystalline cellulose core absorbed moisture leading to core swelling and consequent fracture through the brittle API and enteric layers. At 40°C (high humidity) which is above the T of the enteric polymer, enteric coated beads coalesced into agglomerates due to melt flow of the enteric coating. We believe it is the first report on two distinct failure models of enteric coated dosage forms.
本研究旨在阐明在不同储存温度下高湿度条件下肠溶性包衣丸剂涂层失效的机制和动力学。将肠溶性包衣丸剂置于 5 至 40°C 的高湿度条件（75 至 98%相对湿度（RH））下。对这些稳定性样品丸剂进行酸溶解和水活度测试，并通过 SEM、X 射线 CT 和 DMA 进行分析。肠溶性包衣丸剂暴露于高湿度会导致药物在胃中的释放增加，最终导致溶解规范失败。SEM 显示，暴露于 5°C/高湿度条件下的丸剂表面出现可见裂缝，而暴露于 40°C/高湿度条件下的肠溶性丸剂则融合成团聚体。在非破坏性时间推移研究中，X 射线 CT 显示在 5°C/98%RH 储存条件下，微晶纤维素核在数天内发生肿胀、裂纹起始和通过 API 层传播，最终通过肠溶性涂层断裂。DMA 数据显示，肠溶性涂层材料在暴露于湿度后 T 值明显降低。在 5°C/高湿度条件下，吸湿的微晶纤维素核吸收水分导致核肿胀，进而导致脆性 API 和肠溶性层断裂。在高于肠溶性聚合物 T 的 40°C（高湿度）下，肠溶性包衣丸剂由于肠溶性涂层的熔融流动而聚集在一起。我们相信这是第一个关于肠溶性包衣剂型两种不同失效模式的报告。
