In Vitro-In Vivo Correlation of Ocular Implants

眼植入物的体外与体内相关性

• 批准号: 8669687
• 负责人: UDAY B KOMPELLA
• 金额: $ 56.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669687
• 关键词: Vitro; Vivo; Correlation; Ocular; Implants

According to FDA guidelines, 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 implants have additional steps before the drug is absorbed; these steps collectively referred to as "drug release", exhibit a complex behavior and depend on drug diffusion as well as polymer degradation. Pharmaceutically equivalent implants can have varying physicochemical properties due to the differences introduced during their manufacturing; these physicochemical differences in turn may affect drug release and ocular bioavailability. FDA guidelines recommend that for ophthalmic implants that are Q1 and Q2 the same as the RLD, bioequivalence must be demonstrated. Currently there are no suitable bioequivalence methods for generic products of complex dosage forms including intravitreal implants. An understanding of the relationship between physicochemical properties of implants and their effect on ocular bioavailability is crucial in designing pharmaceutically equivalent implants that are bioequivalent. However, there is sparse literature explaining how the differences in physicochemical properties of ophthalmic implants influence ocular bioavailability. Moreover, a key hurdle in biopharmaceutics research is development of a perfect correlation between in vitro drug release information of various drug formulations and their in vivo drug release profiles; this requires development of robust in vitro release study designs as well as reliable in vivo drug release monitoring. There is little or no information regarding predictive in vitro-in vivo correlation (IVIVC) for various complex ophthalmic formulations, especially ocular implants. We hypothesize that key physicochemical properties such as implant surface area, porosity, tensile strength, and polymer degradation (due to polymer procurement from different sources) can differ for Q1/Q2 implants, resulting in differences in drug release and bioavailability. For such implants differing in their physicochemical properties, we will develop suitable in vitro release studies and predictive IVIVC. To address the project hypothesis and objectives, we will vary manufacturing aspects to prepare several intravitreal implants that are Q1/Q2 but differ in physicochemical properties. The implants will be characterized for their physicochemical properties and in vitro dissolution/release to identify in vivo test formulations. An in vivo pharmacokinetic study will be conducted to assess drug distribution in eye tissues and plasma at several time points. An in vitro release study that correlates with in vivo outcomes will be identified/developed. Through collaborative consultations with FDA counterparts for optimal design of studies, this project will identify key physicochemical and mechanical properties of Q1 and Q2 implant dosage forms that alter ocular drug bioavailability and develop appropriate in vitro dissolution studies to predict in vivo drug release from ocular implants with good accuracy. The findings of this project would lay a foundation for developing guidelines for conducting bioequivalence studies for generic ocular implants.

根据FDA的指导方针，仿制药产品必须证明药物等效性 与参考上市药物(RLD)的生物等效性，以获得FDA的批准。适用于普通眼科 与RLD定性(Q1)和定量(Q2)相同的溶液，生物等效性为 被认为是不言而喻的，可以要求豁免体内研究。与解决方案不同， 眼科植入物在药物被吸收之前有额外的步骤；这些步骤统称为 称为“药物释放”，表现出复杂的行为，依赖于药物的扩散以及 聚合物降解。药物等效的植入物可以有不同的物理化学 由于在制造过程中引入的差异而产生的特性；这些物理化学 不同的药物反过来可能会影响药物释放和眼部生物利用度。FDA指南建议 对于Q1和Q2与RLD相同的眼科植入物，生物等效性必须为 演示了。目前还没有合适的仿制药生物等效性方法。 复杂的剂型，包括玻璃体内植入物。对两国关系的认识 植入物的物理化学性质及其对眼部生物利用度的影响是设计中的关键 具有生物等效性的药物等效植入物。然而，有稀少的文献 解释眼科植入物的物理化学性质的差异如何影响眼睛 生物利用度。此外，生物制药研究的一个关键障碍是开发一种完美的 不同剂型体外释药信息与体内释药信息的相关性 药物释放概况；这需要开发强有力的体外释放研究设计以及 可靠的体内药物释放监测。很少或根本没有关于体外培养的预测信息。 各种复杂眼科制剂，特别是眼科植入物的体内相关性(IVIVC)。我们 假设种植体表面积、孔隙率、抗拉强度等关键物理化学性质 强度和聚合物降解(由于从不同来源采购的聚合物)可能不同 Q1/Q2植入剂，导致药物释放和生物利用度的差异。对于不同类型的植入物 在它们的物理化学性质方面，我们将开发适合的体外释放研究和预测 IVIVC。为了解决项目假设和目标，我们将不同的制造方面 准备几个Q1/Q2但物理化学性质不同的玻璃体内植入物。这个 将对植入物的物理化学性质和体外溶出/释放进行表征 确定体内试验配方。将进行体内药代动力学研究以评估药物 在几个时间点的眼组织和血浆中的分布。一项体外释放研究表明， 体内结果将被确定/开发。通过与FDA的协作协商 对于研究的优化设计，该项目将确定关键的物理化学和 Q1和Q2植入剂型的机械性能改变眼部药物生物利用度和 发展合适的体外溶出度研究以预测眼内植入物的体内药物释放 精确度很高。该项目的发现将为制定指导方针奠定基础 开展非专利眼科植入物的生物等效性研究。