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: 10599677
• 负责人: Jie Shen
• 金额: $ 25万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 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/10599677
• 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.

摘要 局部作用的直肠和阴道半固体产品已广泛用于治疗疾病， 直肠和阴道（和/或子宫颈）的疾病。尽管其盛行， 这些药物产品的非专利版本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 各种半固体剂型（如含/不含明胶的栓剂）的质量属性（CQA 包衣和乳膏），通常用于直肠和阴道给药; 2）开发体外性能测试 这些直肠和阴道产品特有的方法和方法验证策略;以及3）阐明 药物通过直肠和阴道粘膜的渗透机制。拟议的研究建立 根据我们之前对比较产品表征和方法开发与验证的研究， 直肠给药的体外性能试验（如体外释放试验（IVRT）和体外渗透试验（IVPT）） 栓剂和阴道乳膏。市售硝酸咪康唑，有多种阴道剂量 形式（即，具有/不具有明胶包衣的栓剂、乳膏）和美沙拉嗪将用作模型药物。 各种半固态材料的相关理化和结构性能的综合表征 将采用直肠和阴道给药的常用剂型。设计质量（QbD） 原则将被实施，以确定CQA以及关键材料和工艺参数， 影响各种局部直肠和阴道半固体剂量的CQA和体外产品性能 forms.各种局部半固体剂型和药物（例如，亲水 vs.疏水性）将使用动物和人体组织进行研究，以阐明药物渗透 穿过粘膜的机制。最后，一项关于扩大基于生理的 药代动力学（PBPK）建模，以支持局部作用直肠和阴道药物产品的BE评估 将进行。希望全面了解CQA及其与 将为各种局部半固体剂型提供材料和加工差异。此外，委员会认为， 稳健和灵敏的体外性能检测方法和方法验证策略， 并将开发阴道产品。拟议的研究将支持建立体外 基于比较产品特征的BE方法，适用于局部作用的直肠和阴道 半固体药物产品，从而促进这些药物产品的仿制药的开发， 推进创新药和仿制药的监管审查和批准程序。这将 最终增加公众获得高质量和负担得起的局部直肠和阴道药物的机会。