BIOEQUIVALENCE CONSIDERATIONS OF TOPICAL RECTAL AND VAGINAL SUPPOSITORIES

摘要 外用直肠和阴道栓剂已被广泛用于局部治疗 直肠或阴道疾病和疾病在过去的几十年。尽管它们很普遍，但 直肠和阴道外用仿制药产品的开发和批准仍然存在 由于这些产品的复杂性以及缺乏对比较产品的监管指导而具有挑战性 基于产品特性的生物等效性评价方法。的主要目标是 该项目旨在开发一个合理的框架，以降低BE潜在故障模式的风险 研究，用于外用直肠和阴道栓剂。这项拟议的研究建立在我们之前的基础上 开发合适的体外性能测试方法以及体外测试方法的研究 复杂剂型的体内相关性(IVIVC)/关系(IVR)，包括非肠道聚合物 微球和眼膏。基于QBD(Quality-by-Besign)原则，质量 外用栓剂的目标产品简介(QTPP)和关键质量属性(CQA)将为 已定义。然后将进行风险评估，以确定推定的配方和制造 极有可能影响目标产品CQA的属性。Canasa®(美沙拉明) 和特康唑(特康唑)栓剂被选为直肠和阴道模型 分别是栓剂。美沙拉明特康唑栓的研制及应用 材料差异将制备和彻底表征，并在体外和体外 将进行性能测试。市售美沙拉明和特康唑 栓剂产品将作为对照进行研究。根据这些研究的结果，关键是 将确定可能影响产品CQA的制造和材料参数。这是意料之中的 全面了解CQA及其与制造和材料的关系 将提供不同的局部直肠和阴道栓剂。此外，健壮， 将确定和/或开发合适的体外和体外性能测试方法。 这些都将导致基于比较产品表征的BE方法的发展 适用于外用直肠和阴道栓类药物产品。拟议的研究将 促进体外BE检测方法的建立，从而有助于推进监管审查 以及外用直肠和阴道栓剂产品的审批程序。这反过来又会有所帮助 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.