In Vitro Based Approaches to Evaluate the Bioequivalence of Locally-Acting Rectal and Vaginal Semi-Solid Drug Products

评估局部作用直肠和阴道半固体药品生物等效性的体外方法

• 批准号: 10937020
• 负责人: Jie Shen
• 金额: $ 23.14万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10937020
• 关键词: Vitro; Based; Approaches; Evaluate; Bioequivalence

ABSTRACT Locally-acting rectal and vaginal semi-solid products have been widely used for the treatment of diseases and disorders in the rectum and vagina (and/or cervix) over the past few decades. Despite their prevalence, the development and approval of generic versions of these drug products have remained difficult due to the complexity of these products as well as the challenges of conducting bioequivalence (BE) studies with clinical pharmacodynamic (or pharmacokinetic) endpoints. The main objectives of the project are to: 1) identify critical quality attributes (CQA’s) of a variety of semi-solid dosage forms (such as suppositories with/without a gelatin coating and creams) that are common for rectal and vaginal administration; 2) develop in vitro performance test methods and method validation strategies that are unique for these rectal and vaginal products; and 3) elucidate drug permeation mechanisms across the rectal and vaginal mucosal membranes. The proposed research builds upon our previous research on the comparative product characterization and method development and validation of in vitro performance tests (such as in vitro release test (IVRT) and in vitro permeation test (IVPT)) for rectal suppositories and vaginal creams. Miconazole nitrate that is commercially available in a variety of vaginal dosage forms (i.e., suppository with/without a gelatin coating, cream) and mesalamine will be used as the model drugs. Comprehensive characterization of relevant physicochemical and structural properties of a variety of semi-solid dosage forms prevalent for rectal and vaginal administration will be conducted. The quality-by-design (QbD) principles will be implemented to identify CQA’s as well as the key material and processing parameters that can affect the CQA’s and in vitro product performance for a variety of topical rectal and vaginal semi-solid dosage forms. In vitro permeation behavior of a variety of topical semi-solid dosage forms and drugs (e.g., hydrophilic vs. hydrophobic) will be investigated using both animal and human tissues to elucidate drug permeation mechanisms across the mucosal membranes. Lastly, a pilot study on expanding physiologically based pharmacokinetic (PBPK) modeling to support BE assessment of locally-acting rectal and vaginal drug products will be conducted. It is expected that a comprehensive understanding of the CQA’s and their relationship to material and processing differences will be provided for a variety of topical semi-solid dosage forms. Moreover, robust and sensitive in vitro performance test methods and method validation strategies that are unique for rectal and vaginal products will be developed. The proposed research will support the establishment of in vitro comparative product characterization-based BE approaches that are suitable for locally-acting rectal and vaginal semi-solid drug products, thus facilitating the development of generic versions of these drug products and helping advance the regulatory review and approval processes for both innovator and generic drug products. This will ultimately increase the public access to high quality and affordable topical rectal and vaginal medication.

抽象的 局部作用的直肠和阴道半固体产品已广泛用于治疗疾病和 过去几十年来，直肠和阴道（和/或子宫颈）疾病尽管普遍存在，但 由于以下原因，这些药品的仿制药的开发和批准仍然很困难 这些产品的复杂性以及进行临床生物等效性 (BE) 研究的挑战 药效学（或药代动力学）终点 该项目的主要目标是： 1) 确定关键点。 各种半固体剂型（例如含/不含明胶的栓剂）的质量属性 (CQA) 2) 开展体外性能测试 这些直肠和阴道产品独特的方法和方法验证策略；3) 阐明； 拟议的研究建立了直肠和阴道粘膜的药物渗透机制。 根据我们之前对比较产品表征以及方法开发和验证的研究 直肠体外性能测试（如体外释放测试（IVRT）和体外渗透测试（IVPT）） 市售的各种阴道剂量的栓剂和阴道霜。 剂型（即带/不带明胶包衣的栓剂、乳膏）和美沙拉嗪将用作模型药物。 多种半固体相关物理化学和结构特性的综合表征 将采用直肠和阴道给药常用的形式 质量源于设计 (QbD)。 将实施原则来确定 CQA 以及关键材料和加工参数 影响各种直肠和阴道外用半固体制剂的 CQA 和体外产品性能 各种外用半固体剂型和药物（例如亲水剂）的体外渗透行为。 将使用动物和人体组织进行研究，以阐明药物渗透 最后，基于生理学的扩展的初步研究。 药代动力学 (PBPK) 模型支持局部作用直肠和阴道药物产品的 BE 评估 预计将全面了解 CQA 及其与 CQA 的关系。 将为各种局部半固体剂型提供材料和加工差异。 直肠独有的稳健且灵敏的体外性能测试方法和方法验证策略 拟议的研究将支持体外试验的建立。 基于比较产品表征的 BE 方法，适用于局部作用的直肠和阴道 半固体药品，从而促进这些药品仿制药的开发，并帮助 推进创新药和仿制药产品的监管审查和审批流程。 最终增加公众获得高质量且负担得起的直肠和阴道外用药物的机会。