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21CFR 314.94（a）（9）（iv）中列出的FDA指南，通用药品必须 证明了与参考列出的药物（RLD）的药物等效性和生物等效性 获得FDA批准。对于定性（Q1）和定量的通用眼科解决方案 （Q2）与RLD相同，生物等效性被认为是不言而喻的，是体内的豁免 可以要求进行研究。与解决方案不同，眼科悬浮液/乳液需要额外 从剂型吸收药物之前，“溶解或释放”的步骤。 等效的悬浮液或乳液可以具有不同的物理化学特性 制造或配方期间引入的差异反过来可能会影响重生 停留时间，药物释放和眼部生物利用度。因此，FDA指南建议 眼科剂型的悬浮液和乳液等Q1和Q2与 RLD，必须证明生物等效性。但是，有稀疏的文献解释了 眼科悬浮液/乳液的物理化学特性差异导致差异 在眼部生物利用度中。此外，缺乏研究通用的合适的生物等效方法 眼科悬浮液和乳液。对物理化学之间关系的研究 特性及其对眼睛生物利用度的影响对于制定悬浮液/乳液至关重要 都是药物等效的和生物等效的。我们假设这是关键的物理化学 诸如粒子/球尺寸，尺寸分布，粘度，pH和Zeta电位之类的特性可以 影响悬浮液或乳液的药物释放，停留时间和稳定性，因此 生物利用度。为了解决这一假设，我们将生产皮质类固醇悬浮液和 具有不同物理化学特性的乳液配方，并评估其药物释放， 稳定性和离体传递。基于这些研究，我们将确定稳定的配方和关键 物理化学特性，导致释放和/或离体局部眼有显着差异 送货。物理化学特性，显示药物释放和/或离体的最大差异 每个悬浮液/乳液配方的输送将被识别和评估体内 兔子的前胚居住和眼生物利用度。我们将采用一个统计模型 种群药代动力学分析以计算悬浮液和乳液的生物等效性。 通过与允许研究最佳设计的FDA的合作咨询，这 项目将确定Q1和Q2悬架/乳液剂型的关键物理化学特性 这改变了眼药的生物利用度。该项目的发现将为发展奠定基础 进行通用眼科悬浮液和乳液的生物等效性研究指南。