Evaluation of Oral Modified-Release Tablets to Support the Approval of Additional Strengths

摘要 具有调制药物释放特性的口服修饰释放(MR)药物产品(例如，速率、持续时间和 药物释放部位)已被广泛使用以达到预期的治疗效果，减少不良反应 和/或比传统的口服固体剂型更能改善患者的依从性。超过一半的FDA 批准的口服MR药物产品是具有多种强度的缓释(ER)片剂产品。到目前为止， 适当的因素，以扩大配方，以增加剂量的口服MR片尚未确定。 此外，影响药物释放机制的关键变量和不同MR的处方设计空间 技术还没有完全被理解和确定。本项目的主要目标是：1) 确定配方变量(例如，药物性质和辅料)对药物释放的影响 基于QBD(Quality-by-Design，质量设计)原则的自制ER片剂机构；2)开发机构 使用综合溶出度测试技术获得的溶出度数据进行参数化的模型 比较ER片剂和相应的参考药物产品的多个强度，以建立 解散安全空间并确定关键质量属性(CQA)；以及3)构建“概念验证” 机器学习模型利用复杂的口服MR药物产品的数据库来识别关键变量， 针对不同的处方设计策略影响药物释放机制。拟议的研究建立在 我们在处方开发、比较产品表征、体外释放等方面进行了广泛的研究 复杂口服MR固体剂型的测试、生物等效性评估和机理建模。 生物制药分类系统(BCS)I类和II类化合物盐酸罗匹尼罗和 硝苯地平将分别作为模型药物进行研究。多种强度的ER片剂，配方和 将产生过程变量，并使用相应的参考药物进行对比表征 产品作为对照。ER片的释药机制及体外溶出度 多种强度将在不同的测试条件下进行表征，包括禁食和进食条件 模拟胃肠运动。此外，机制模型(例如，基于生理学的药代动力学 (PBPK)，基于生理的生物制药模型(PBBM)-PBPK)用体外数据参数化 获得的结果将被开发以确定适当的因素，以衡量口腔额外强度的配方 MR平板电脑。最后，将建立一个经批准的口服MR药物产品的全面数据库，并 将使用ML技术来确定影响药物释放机制的关键变量。建议数 研究将有助于推进口服MR平板电脑产品的监管审查和审批流程，并支持 批准这类药物产品的额外强度。促进复杂的普通口腔的发展 MR药物产品最终将有助于增加公众获得高质量和负担得起的口服药物的机会。

ABSTRACT Oral modified-release (MR) drug products with modulated drug release characteristics (e.g., rate, duration, and the site of drug release) have been widely used to achieve desired therapeutic effects, reduced adverse effects and/or improved patient compliance than conventional oral solid dosage forms. More than half of the FDA approved oral MR drug products are extended-release (ER) tablet products with multiple strengths. Until now, appropriate factors to scale the formulation for additional strengths for oral MR tablets have yet to be determined. Moreover, the key variables affecting drug release mechanism and formulation design spaces for different MR technologies have not been fully understood and identified. The main objectives of this project are to: 1) determine the impact of formulation variables (e.g., drug properties and excipients) on the drug release mechanism of in-house made ER tablets based on quality-by-design (QbD) principles; 2) develop mechanistic models parameterized with dissolution data obtained using comprehensive dissolution testing technologies to compare the ER tablets and the corresponding reference drug products across multiple strengths to establish dissolution safe spaces and to identify critical quality attributes (CQA’s); and 3) construct a “proof-of-concept” machine learning model leveraging the database of complex oral MR drug products to identify key variables that affect drug release mechanisms for different formulation design strategies. The proposed research builds upon our extensive research on the formulation development, comparative product characterization, in vitro dissolution testing as well as bioequivalence assessment and mechanistic modeling of complex oral MR solid dosage forms. Biopharmaceutics classification system (BCS) Class I and Class II compounds ropinirole hydrochloride and nifedipine will be studied as model drugs, respectively. ER tablets across multiple strengths with formulation and process variables will be produced and comparatively characterized using the corresponding reference drug products as controls. The drug release mechanism and in vitro dissolution profiles of the ER tablets across multiple strengths will be characterized under different testing conditions including fasted and fed conditions with simulated gastrointestinal motility. Moreover, mechanistic models (e.g., physiologically based pharmacokinetic (PBPK), physiologically based biopharmaceutics models (PBBM)-PBPK) parameterized with the in vitro data obtained will be developed to identify appropriate factors to scale the formulation for additional strengths for oral MR tablets. Lastly, a comprehensive database of the approved oral MR drug products will be established, and ML techniques will be employed to identify the key variables that impact drug release mechanism. The proposed research will help advance the regulatory review and approval processes of oral MR tablet products, and support the approval of additional strengths for such drug products. Facilitating the development of complex generic oral MR drug products will ultimately help increase the public access to high quality and affordable oral medications.