Ofner C M, Zhang Y E, Jobeck V C, Bowman B J
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, Pennsylvania 19104, USA.
J Pharm Sci. 2001 Jan;90(1):79-88. doi: 10.1002/1520-6017(200101)90:1<79::aid-jps9>3.0.co;2-l.
Incomplete in vitro capsule shell dissolution and subsequent drug release problems have recently received attention. A modified USP dissolution method was used to follow capsule shell dissolution, and a 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay was used to follow loss of epsilon-amino groups to study this shell dissolution problem postulated to be due to gelatin crosslinking. The dissolution problems were simulated using hard gelatin capsule (HGC) shells previously treated with formaldehyde to crosslink the gelatin. These methods were also used to study the effect of uncrosslinked HGC stored under stressed conditions (37 degrees C and 81% RH) with or without the presence of soft gelatin capsule shells (SGC). A 120 ppm formaldehyde treatment reduced gelatin shell dissolution to 8% within 45 min in water at 37 degrees C. A 200 ppm treatment reduced gelatin epsilon-amino groups to 83% of the original uncrosslinked value. The results also support earlier reports of non-amino group crosslinking by formaldehyde in gelatin. Under stressed conditions, HGC stored alone showed little change over 21 weeks. However, by 12 to 14 weeks, the HGC exposed to SGC showed a 23% decrease in shell dissolution and an 8% decrease in the number of epsilon-amino groups. These effects on the stressed HGC are ascribed to a volatile agent from SGC shells, most likely formaldehyde, that crosslinked nearby HGC shells. This report also includes a summary of the literature on agents that reduce gelatin and capsule shell dissolution and the possible mechanisms of this not-so-simple problem.
体外胶囊壳不完全溶解及随后的药物释放问题近来受到关注。采用改良的美国药典溶出度方法跟踪胶囊壳溶解情况，并使用2,4,6-三硝基苯磺酸（TNBS）测定法跟踪ε-氨基的损失，以研究推测因明胶交联导致的这种壳溶解问题。使用先前用甲醛处理以交联明胶的硬明胶胶囊（HGC）壳模拟溶解问题。这些方法还用于研究在有或没有软明胶胶囊壳（SGC）存在的情况下，在加速条件（37℃和81%相对湿度）下储存的未交联HGC的影响。120 ppm的甲醛处理在37℃水中45分钟内将明胶壳溶解率降低至8%。200 ppm的处理将明胶ε-氨基降低至原始未交联值的83%。结果还支持了先前关于甲醛在明胶中进行非氨基交联的报道。在加速条件下，单独储存的HGC在21周内变化不大。然而，到12至14周时，暴露于SGC的HGC壳溶解率下降了23%，ε-氨基数量下降了8%。对加速条件下HGC的这些影响归因于来自SGC壳的挥发性物质，很可能是甲醛，它交联了附近的HGC壳。本报告还总结了关于降低明胶和胶囊壳溶解的试剂的文献以及这个并非简单问题的可能机制。
