Effect of Physicochemical Properties of Ophthalmic Formulations on Ocular Bioavai

眼科制剂的理化性质对眼部生物利用度的影响

• 批准号: 8496268
• 负责人: UDAY B KOMPELLA
• 金额: $ 44.43万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496268
• 关键词: Effect; Physicochemical; Properties; Ophthalmic; Formulations

According to FDA guidelines as listed in 21CFR 314.94 (a)(9)(iv), generic drug products must demonstrate pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD) to gain FDA approval. For generic ophthalmic solutions that are qualitatively (Q1) and quantitatively (Q2) the same as the RLD, bioequivalence is considered to be self-evident and a waiver for in vivo studies can be requested. Unlike solutions, ophthalmic suspensions/emulsions require an additional step of "dissolution or "release" before the drug is absorbed from the dosage form. Pharmaceutically equivalent suspensions or emulsions can have varying physicochemical properties either because of the differences introduced during manufacturing or formulation, which in turn may affect precorneal residence time, drug release, and ocular bioavailability. Therefore, FDA guidelines recommend that ophthalmic dosage forms such as suspensions and emulsions that are Q1 and Q2 the same as the RLD, bioequivalence must be demonstrated. However, there is sparse literature explaining how the differences in physicochemical properties of ophthalmic suspensions/emulsions result in differences in ocular bioavailability. Moreover, suitable bioequivalence methods are lacking for studying generic ophthalmic suspensions and emulsions. An investigation of the relationship between physicochemical properties and their effect on ocular bioavailability is crucial to formulate suspensions/emulsions that are both pharmaceutically equivalent and bioequivalent. We hypothesize that key physicochemical properties such as particle/globule size, size distribution, viscosity, pH, and zeta potential can influence drug release, residence time, and stability of the suspensions or emulsions, and hence, bioavailability. To address this hypothesis, we will manufacture corticosteroid suspension and emulsion formulations with different physicochemical properties and assess their drug release, stability, and ex vivo delivery. Based on these studies, we will identify stable formulations and key physicochemical properties that result in significant differences in release and/or ex vivo topical ocular delivery. A physicochemical property that shows maximum differences in drug release and/or ex vivo delivery for each the suspension/emulsion formulations will be identified and assessed for in vivo precorneal residence and ocular bioavailability in rabbits. We will employ a statistical model for population pharmacokinetic analyses to calculate the bioequivalence of suspensions and emulsions. Through collaborative consultations with FDA counterparts that allow optimal design of studies, this project will identify key physicochemical properties of Q1 and Q2 suspension/emulsion dosage forms that alter ocular drug bioavailability. The findings of this project would lay a foundation for developing guidelines for conducting bioequivalence studies for generic ophthalmic suspensions and emulsions.

根据21 CFR 314.94（a）（9）（iv）中列出的FDA指南，仿制药产品必须 证明与参比上市药物（RLD）的药物等效性和生物等效性， 获得FDA批准。对于定性（Q1）和定量 (Q2)与RLD相同，生物等效性被认为是不言而喻的，并且豁免了体内试验 可以要求研究。与溶液不同，眼用混悬剂/乳剂需要额外的 在药物从剂型中吸收之前的“溶解”或“释放”步骤。药学 等效的悬浮液或乳液可以具有不同的物理化学性质， 在制造或配制过程中引入的差异，这反过来可能会影响角膜前区 停留时间、药物释放和眼部生物利用度。因此，FDA指南建议， 眼用剂型，如混悬剂和乳剂，其Q1和Q2与 必须证明RLD、生物等效性。然而，很少有文献解释了 眼用混悬剂/乳剂的理化性质的差异导致 眼部生物利用度。此外，缺乏合适的生物等效性研究方法， 眼用混悬剂和乳剂。物理化学与生物化学之间关系的探讨 性质及其对眼部生物利用度的影响对于配制 是药学上和生物学上等价的。我们假设关键的物理化学 诸如颗粒/小球尺寸、尺寸分布、粘度、pH和zeta电位的性质可 影响药物释放、停留时间和悬浮液或乳液的稳定性，因此， 生物利用度为了解决这一假设，我们将制造皮质类固醇混悬液， 具有不同物理化学性质的乳剂制剂并评估它们的药物释放， 稳定性和离体递送。基于这些研究，我们将确定稳定的制剂和关键的 这些物理化学性质导致在释放和/或离体局部眼用方面的显著差异 交付.在药物释放和/或离体释放中显示最大差异的物理化学性质 每种悬浮液/乳剂制剂的递送将被鉴定并评估用于体内 兔角膜前滞留和眼部生物利用度。我们将使用一个统计模型， 群体药代动力学分析，以计算混悬剂和乳剂的生物等效性。 通过与FDA同行的合作协商，允许优化研究设计， 项目将确定Q1和Q2混悬液/乳剂剂型的关键理化性质 改变眼部药物生物利用度。该项目的研究结果将为开发 通用眼用混悬剂和乳剂生物等效性研究指南。