In Vitro-In Vivo Correlation of Ocular Implants

根据FDA指南，仿制药产品必须证明药物等效性 以及与参考上市药物（RLD）的生物等效性，以获得FDA批准。用于通用眼科 定性（Q1）和定量（Q2）与RLD相同的溶液，生物等效性为 被认为是不言自明的，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具有额外的步骤;这些步骤共同 称为“药物释放”，表现出复杂的行为，并依赖于药物扩散， 聚合物降解药物等同植入物可能具有不同的物理化学性质， 由于其制造过程中引入的差异，这些理化性质 这些差异又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相同的眼用植入物，生物等效性必须 演示。目前尚无适用于仿制药的生物等效性方法， 包括玻璃体内植入物的复杂剂型。理解了 植入物的物理化学性质及其对眼部生物利用度的影响在设计中至关重要 生物等效的药物等效植入物。然而， 解释眼科植入物的物理化学性质差异如何影响眼 生物利用度此外，生物药剂学研究的一个关键障碍是开发一种完美的 各种药物制剂的体外药物释放信息与其体内药物释放信息之间的相关性 药物释放曲线;这需要开发稳健的体外释放研究设计以及 可靠的体内药物释放监测。关于体外预测的信息很少或没有 各种复杂眼科制剂（尤其是眼植入物）的体内相关性（IVIVC）。我们 假设植入物表面积、孔隙率、拉伸强度等关键物理化学性质 聚合物降解（由于从不同来源采购聚合物）可能不同， Q1/Q2植入物，导致药物释放和生物利用度的差异。对于这种不同的植入物， 在其理化性质，我们将开发合适的体外释放研究和预测 IVIVC。为了解决项目假设和目标，我们将改变制造方面， 制备几种Q1/Q2但物理化学性质不同的玻璃体内植入物。的 植入物将表征其物理化学性质和体外溶解/释放， 鉴定体内试验制剂。将进行体内药代动力学研究以评估药物 在几个时间点在眼组织和血浆中的分布。一项体外释放研究， 将确定/开发体内结果。通过与林业发展局的协作协商 该项目将确定关键的物理化学和物理化学性质， 改变眼部药物生物利用度的Q1和Q2植入剂型的机械性能， 开展适当的体外溶出度研究，以预测眼部植入物的体内药物释放 具有良好的准确性。该项目的研究结果将为制定指导方针奠定基础， 进行通用眼部植入物的生物等效性研究。

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.