乙醇控制对环孢素软胶囊质量影响研究

摘 要

环孢素为窄治疗窗药物，环孢素软胶囊的生物利用度具有高变异性，因此其在临床应用中为高风险药物。环孢素软胶囊的这种高变异性与产品配方和工艺存在关联，本论文目的是找到影响环孢素软胶囊关键质量属性的关键因素及其影响机理，提出控制策略并加以控制，从而降低配方和工艺因素引起的变异性，以降低环孢素软胶囊临床应用风险。

论文主要通过文献上市产品质量差异的比较；自乳化释药系统对配方的要求及关键物料属性对产品配方的质量影响风险分析，对比分析同一产品不同乙醇含量乙醇与溶出度等关键质量属性的关系，上市产品乙醇含量与溶出行为对比，证明乙醇与环孢素软胶囊关键质量属性溶出度之间存在关联，通过乙醇在产品生产和贮存过程中和的变化及这种变化对产品质量的影响及目前环孢素软胶囊质量控制现状，证明通常工艺和目前质量标准在控制环孢素软胶囊的质量方面存在欠缺。

研究结果证明乙醇是环孢素软胶囊中的关键辅料，且其在生产过程中容易损失，改变配方体系，从而引起溶出迟缓，有必要通过合理质量标准，提高工艺，加强过程中控制，将乙醇在产品中的含量控制在目标范围内。

关键词：环孢素软胶囊；乙醇；溶出度；控制

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Study of ethanol control impact quality of cyclosporine softgel

For Cyclosporine is a drug with narrow therapeutic window and Highly bioavailability Variable, so cyclosporine is a high risk drug In the clinical. The high bioavailability which has a certain relationship with the formulation and manufacture processes for cyclosporine softgel. This objective of this article is to find out the critical factor which impact the critical quality attribute and how it impact critical quality attribute. Then propose a control strategy to control it, to decrease the bioavailability variable which caused by formulation and processes.

According to compare the quality of cyclosporine product in market, and the self-micro emulsifying drug delivery system (SMEDDS) formulation requirement and critical material impact formulation quality risk evaluation, and compare the dissolution profile of same product with different content of ethanol, and compare dissolution profile and ethanol content for product form market with different manufacture, prove that ethanol content has a relationship with dissolution profile of cyclosporine softgel. By studying the ethanol content variation in the manufacture process and store, and the impact of variation related to the dissolution, and the status of cyclosporine softgel quality control, to prove that normal process control and the current specification need to improve. The study prove that the ethanol is the critical excipient in cyclosporine softgel. The ethanol could easily decrease in the manufacture process and store, change the formulation system，and cause dissolve slowly. It is necessary to improve the specification and process, to control the ethanol content control in target range.

Keywords: Cyclosporine softgel, Quality, Dissolution, Control

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目 录

第1章引言............................................................................................................................................... 1 1.1研究背景 ......................................................................................................................................... 1 1.1.1 环孢素及环孢素软胶囊简介 ................................................................................................. 1 1.1.2 环孢素软胶囊在我国的上市情况 ......................................................................................... 1 1.1.3 环孢素软胶囊的吸收代谢及临床应用 ................................................................................. 2 1.1.4环孢素的不良反应 .................................................................................................................. 3 1.1.5 环孢素制剂的监管 ................................................................................................................. 3 1.2 研究的目的与意义 ........................................................................................................................ 4 1.2.1 研究的目的 ............................................................................................................................. 4 1.2.2 研究的意义 ............................................................................................................................. 4 第2章研究设计 ....................................................................................................................................... 5 2.1 数据来源 ........................................................................................................................................ 5 2.2 研究方法 ........................................................................................................................................ 5 第3章研究结果 ....................................................................................................................................... 6 3.1 软胶囊的应用、配方、生产及质量控制 .................................................................................... 6 3.1.1 软胶囊的应用 ......................................................................................................................... 6 3.1.1.1脂溶性药物 ....................................................................................................................... 6 3.1.1.2低溶解性/低渗透性药物 .................................................................................................. 6 3.1.2 软胶囊的优势和劣势 ............................................................................................................. 6 3.1.2.1 软胶囊的优势 .................................................................................................................. 6 3.1.2.2软胶囊的缺点 ................................................................................................................... 7 3.1.3 软胶囊的配方 ......................................................................................................................... 8 3.1.3.1 囊壳的组成 ...................................................................................................................... 8 3.1.4 软胶囊的生产及中间控制 ................................................................................................... 9 3.1.4.1 溶胶工艺与控制 ............................................................................................................ 9 3.1.4.2 配液工艺与控制 ............................................................................................................ 10 3.1.4.3 灌装工艺与控制 ............................................................................................................ 11 3.1.4.4干燥和中间控制 ............................................................................................................. 12 3.1.4.5 包装 ................................................................................................................................ 13 3.1.5 软胶囊的溶出特点及影响因素 ........................................................................................... 13 3.1.5.1 囊壳的组成 .................................................................................................................... 13 3.1.5.2内容物组成 ..................................................................................................................... 13 3.1.5.3其它因素 ......................................................................................................................... 13

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3.2 自微乳药物传递系统在软胶囊中的应用 .................................................................................. 14 3.2.1油脂配方分类系统 ................................................................................................................ 14 3.2.3 自乳化释药体系配方组成及配方要求 ............................................................................... 15 3.2.4 乙醇在自乳化体系中的作用与应用 ................................................................................... 15 3.3 制剂配方对环孢素软胶囊生物等效性的影响 .......................................................................... 16 3.3.1 环孢素软胶囊配方 ............................................................................................................... 16 3.3.2环孢素软胶囊配方与生物利用度相关性 ............................................................................ 16 3.3.3 仿制药一致性对环孢素软胶囊的要求 ............................................................................... 18 3.4 环孢素软胶囊的关键质量属性鉴别 .......................................................................................... 18 3.4.1环孢素软胶囊的关键质量属性 ............................................................................................ 18 3.4.2环孢素软胶囊质量属性关键性评估 .................................................................................... 20 3.5 关键辅料的鉴别 .......................................................................................................................... 22 3.6 乙醇与环孢素软胶囊质量属性的关系研究 .............................................................................. 24 3.6.1 市售环孢素软胶囊乙醇含量差异及质量差异 ................................................................... 24 3.6.2 同一产品乙醇含量对产品质量的影响 ............................................................................... 25 3.6.3 环孢素软胶囊对乙醇含量的要求 ....................................................................................... 27 3.7 配方及生产工艺、包装对乙醇含量的影响研究 ...................................................................... 28 3.7.1 配方对乙醇含量的影响 ....................................................................................................... 28 3.7.2 生产工艺对乙醇含量的影响 ............................................................................................... 30 3.8 对策与建议 ...................................................................................................................................... 31 3.8.1 提高质量标准 ........................................................................................................................... 31 3.8.2 改进配方 ................................................................................................................................... 32 3.8.3 改进工艺 ................................................................................................................................... 34 3.8.4 加强过程中的控制 ................................................................................................................... 34 第4章结论与讨论 ................................................................................................................................. 35 4.1 结论.............................................................................................................................................. 35 4.2 讨论.............................................................................................................................................. 35

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