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

评估口服缓释片以支持其他规格的批准

• 批准号: 10937015
• 负责人: Jie Shen
• 金额: $ 20万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10937015
• 关键词: Evaluation; Oral; Modified; Release; Tablets

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.

摘要 具有调节药物释放特性的口服调释（MR）药物产品（例如，速率、持续时间和 药物释放位点）已被广泛用于实现所需治疗效果、减少副作用 和/或改善的患者依从性。超过一半的FDA 批准的口服MR药物产品是具有多种规格的缓释（ER）片剂产品。到现在为止， 用于口服MR片剂的其他规格的适当因素尚未确定。 此外，对影响不同MR的药物释放机制和处方设计空间的关键变量进行了研究。 技术尚未得到充分理解和确认。该项目的主要目标是：1） 确定配方变量的影响（例如，药物性质和赋形剂）对药物释放的影响 基于质量设计（QbD）原则的内部制造ER片剂的机制; 2）开发 使用综合溶出测试技术获得的溶出数据参数化的模型， 比较多种规格的ER片剂和相应的参比制剂，以确定 溶解安全空间，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口服MR药物产品的数据库来识别关键变量， 影响不同制剂设计策略的药物释放机制。拟议的研究建立在 我们对处方开发、比较产品表征、体外溶出度 测试以及生物等效性评估和复杂口服MR固体剂型的机理建模。 生物药剂学分类系统（BCS）I类和II类化合物盐酸罗匹尼罗和 分别以硝苯地平为模型药物进行研究。多种规格的ER片剂， 将产生过程变量，并使用相应的参比药物进行比较表征 产品作为对照。研究了缓释片的释药机制和体外溶出曲线， 多种规格将在不同的测试条件下进行表征，包括禁食和进食条件， 模拟胃肠蠕动。此外，机械模型（例如，生理药代动力学 （PBPK），基于生理学的生物药剂学模型（PBBM）-PBPK），用体外数据参数化 将开发所获得的数据，以确定适当的因素，以扩展制剂的其他规格，用于口服给药 磁共振药片。最后，将建立已批准口服MR制剂的综合数据库， ML技术将用于识别影响药物释放机制的关键变量。拟议 研究将有助于推进口服MR片剂产品的监管审查和批准流程，并支持 批准此类药品的其他规格。促进复杂通用口腔的发展 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。