摘要
处方工艺差别会导致缓释制剂具有截然不同的体内外释药性质。本研究以进口药品注册标准、《中华人民共和国药典》及相关指导原则为依据,对4种国内、外不同厂家生产的盐酸氨溴索缓释胶囊的体外释放曲线以及乙醇诱发的剂量倾泻行为进行了系统评价。在pH 1.2盐酸中,蜡质骨架型缓释胶囊Mucosolvan®Retard 24 h累积释放率仅为25.6%,而另外3种膜控包衣型缓释市售制剂4~6 h累积释放率均已超过85.0%。释药机制对药物释放的影响还体现在其他pH溶出介质及乙醇剂量倾泻的对比研究结果中。因此,该研究选择Mucosolvan®Retard和一种市售膜控缓释胶囊,对其生理相关释放介质中的释放曲线及犬口服药动学做了进一步研究。结果显示,在空腹状态模拟胃液(FaSSGF)中,Mucosolvan®Retard和所选膜控缓释胶囊2 h分别释放16.0%和67.2%,体现了释药机制差异对缓释胶囊生理环境溶出的影响。药动学结果表明,所选膜控缓释胶囊的cmax是Mucosolvan®Retard的1.41倍,推测与其在消化道上端酸性介质中释放更快有关。最后,综合BCS分类、本研究结果及已报道的人体药动学研究结果,对本品种的仿制药一致性开发要点进行了讨论。
The differences in formulations and manufacturing processes will lead to the distinct in vitro and in vivo release properties of sustained-release preparations.According to the standards of imported registered drugs,Chinese Pharmacopoeia and relevant guidelines,the in vitro release curves and ethanol-induced dose-dumping behaviors of ambroxol hydrochloride sustained-release capsules from four different domestic and foreign manufacturers were systematically evaluated.Because of the different drug release mechanisms,the 24 h cumulative release amount of the drug from wax-matrix sustained-release capsules(Mucosolvan®Retard)was only 25.6%,while the 4-6 h cumulative release amounts of the other three film-controlled sustained-release capsules were more than 85%.The differences of drug release were also found in other pH media and ethanol-induced dose-dumping studies.Therefore,Mucosolvan®Retard and one commercially available film-controlled sustained-release capsule were selected for further release studies in simulated gastrointestinal fluids and pharmacokinetics studies in beagle dogs.In the fasted state simulated gastric fluid(FaSSGF)medium,the release of Mucosolvan®Retard and the film-controlled sustained-release capsules at 2 h were 16.0%and 67.2%,respectively.The pharmacokinetic results showed that the cmax of film-controlled sustained-release capsules was 1.41 times higher than that of Mucosolvan®Retard.The reason for the different in vivo release results was speculated to be related to faster release of film-controlled sustained-release capsules in the acidic medium of upper digestive tract.Finally,based on the BCS classification of ambroxol hydrochloride,the results of this study and the reported human pharmacokinetics results,the key factors for the consistent development of this generic products were discussed.
作者
董俊
张悦
丁弋菲
柴旭煜
王健
DONG Jun;ZHANG Yue;DING Yifei;CHAI Xuyu;WANG Jian(National Advanced Medical Engineering Research Center,China State Institute of Pharmaceutical Industry,Shanghai 201203)
出处
《中国医药工业杂志》
EI
CAS
CSCD
2024年第7期987-993,共7页
Chinese Journal of Pharmaceuticals
关键词
盐酸氨溴索
缓释胶囊
一致性评价
体外释放
药动学
ambroxol hydrochloride
sustained-release capsule
consistency evaluation
in vitro release
pharmacokinetics
