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.

抽象的 口服改性释放（MR）药物具有调节药物释放特性（例如，速率，持续时间和 药物释放部位已被广泛用于实现所需的治疗作用，减少了不良反应 与常规口服固体剂型形式相比，/或改善患者合规性。超过一半的FDA 批准的口服MR药品是具有多种优势的扩展释放（ER）片剂。到目前为止， 对于口服MR片剂的额外优势，尚未确定缩放公式的适当因素。 此外，影响不同MR的药物释放机制和公式设计空间的关键变量 技术尚未被充分理解和确定。该项目的主要目标是：1） 确定配方变量（例如药物特性和赋形剂）对药物释放的影响 内部机制基于质量设计（QBD）原理制造的ER片剂； 2）发展机械 使用综合溶解测试技术获得的溶出数据参数化的模型 比较跨多种强度的ER片剂和相应的参考药品以建立 解散安全空间并确定关键质量属性（CQA）； 3）构建“概念验证” 利用复杂口服MR药物产品数据库的机器学习模型来识别关键变量 影响不同配方设计策略的药物释放机制。拟议的研究基于 我们对公式开发，比较产品表征，体外溶解的广泛研究 复杂口服MR固体剂型的测试以及生物等效性评估和机械模型。 生物制药分类系统（BCS）I类和II类化合物盐酸ropinirole and盐酸盐和 硝苯地平将分别研究为模型药物。 ER片剂跨越了配方和配方的多种优势 将产生过程变量，并使用相应的参考药物进行相对表征 产品作为控件。 ER片剂的药物释放机制和体外溶解轮廓 在不同的测试条件下将表征多种优势 模拟胃肠道运动。此外，机械模型（例如，基于物理的药代动力学 （PBPK），基于物理的生物药物模型（PBBM）-PBPK）用体外数据进行了参数 将开发获得的以确定适当的因素，以扩展该公式的额外优势 MR平板电脑。最后，将建立批准的口服MR药品的全面数据库，并 将聘请ML技术来确定影响药物释放机制的关键变量。提议 研究将有助于推进口服MR片剂产品的监管审查和批准过程，并支持 批准此类药品的其他优势。促进复杂通用口头的发展 MR药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。