BIOEQUIVALENCE CONSIDERATIONS OF TOPICAL RECTAL AND VAGINAL SUPPOSITORIES

摘要 局部直肠和阴道栓剂已广泛用于局部治疗 直肠或阴道疾病和紊乱在过去几十年。尽管其盛行， 开发和批准的通用局部直肠和阴道药物产品 由于这些产品的复杂性以及缺乏关于比较的监管指导， 基于产品特征的生物等效性（BE）评估方法。的主要目标 该项目旨在制定一个合理的框架，以减轻BE潜在故障模式的风险 研究，用于局部直肠和阴道栓剂。这项研究建立在我们以前的研究基础上。 研究开发适当的体外性能测试方法以及体外 复杂剂型的体内相关性（IVIVC）/相关性（IVIVR），包括胃肠外聚合物 微球和眼用软膏。基于质量保证（QbD）原则， 局部栓剂的目标产品特征（QTPP）和关键质量属性（CQA）将 定义了然后将进行风险评估，以确定推定的配方和生产 可能影响目标产品CQA的可能性较高的属性。CANASA®（美沙拉嗪） 和特康唑（Terconazole）栓剂分别作为直肠和阴道模型 栓剂。美沙拉嗪和特康唑栓剂的生产和 将制备材料差异并进行全面表征， 将进行性能测试。市售的美沙拉嗪和特康唑 将栓剂产品作为对照进行研究。根据这些研究的结果，关键 将确定可能影响产品CQA的制造和材料参数。预计 全面了解CQA及其与制造和材料的关系 将提供局部直肠栓剂和阴道栓剂的差异。此外，鲁棒， 将确定和/或开发适当的体外和离体性能测试方法。 这些将导致基于比较产品特性的BE方法的发展 其适用于局部直肠和阴道栓剂药物产品。拟议的研究将 促进体外BE检测方法的建立，从而帮助推进监管审查 以及局部直肠和阴道栓剂产品的批准程序。这将反过来帮助 减少对人体研究的需求，并为公众提供高质量，负担得起的通用主题 及时用药。

ABSTRACT Topical rectal and vaginal suppositories have been widely used for the localized treatment of rectum or vagina diseases and disorders over the past few decades. Despite their prevalence, the development and approval of generic topical rectal and vaginal drug products have remained challenging due to the complexity of these products and a lack of regulatory guidance on comparative product characterization-based bioequivalence (BE) assessment approaches. The main objective of the project is to develop a rational framework to mitigate the risk of potential failure modes of BE studies, for topical rectal and vaginal suppositories. The proposed research, builds upon our previous research in the development of appropriate in vitro performance testing methods as well as in vitro-in vivo correlation (IVIVC)/relationship (IVIVR) for complex dosage forms, including parenteral polymeric microspheres and ophthalmic ointments. Based on the quality-by-besign (QbD) principles, quality target product profile (QTPP) and critical quality attributes (CQA) of the topical suppositories will be defined. A risk assessment will then be conducted to identify putative formulation and manufacturing attributes that may have high likelihood to affect CQA of the target product. CANASA® (mesalamine) and Terconazole (terconazole) suppositories have been selected as model rectal and vaginal suppositories, respectively. Mesalamine and terconazole suppositories with manufacturing and material differences will be prepared and thoroughly characterized, and in vitro and ex vivo performance testing will be conducted. The commercially available mesalamine and terconazole suppository products will be studied as controls. Based upon the outcomes of these studies, the key manufacturing and material parameters that can impact product CQA will be identified. It is expected that a comprehensive understanding of CQA and their relationship to manufacturing and material differences will be provided for topical rectal and vaginal suppositories. In addition, robust, appropriate in vitro and ex vivo performance testing methods will be identified and/or developed. These will lead to the development of comparative product characterization-based BE approaches that are suitable for topical rectal and vaginal suppository drug products. The proposed research will facilitate the establishment of in vitro BE testing methods, thus helping advance the regulatory review and approval processes for topical rectal and vaginal suppository products. This will in turn help reduce the need for human studies and provide the public with high quality, affordable generic topical medications in a timely fashion.