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指南，通用药品必须证明药物等效性 与参考药物（RLD）获得FDA批准的生物等效性。用于通用眼科 定性（Q1）和定量（Q2）的解决方案与RLD相同，生物等效性为 可以要求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， 眼科植入物在吸收该药物之前有其他步骤。这些步骤集体 称为“药物释放”，表现出复杂的行为，依赖于药物扩散以及 聚合物降解。药物等效植入物可以具有不同的物理化学化学 由于其制造过程中引入的差异而引起的属性；这些物理化学 差异又可能影响药物释放和眼生物利用度。 FDA指南建议 对于Q1和Q2的眼科植入物与RLD相同，生物等效性必须为 证明。目前没有适当的生物等效方法用于 复杂剂型包括玻璃体内植入物。对关系的理解 植入物的物理化学特性及其对眼睛生物利用度的影响对于设计至关重要 具有生物等效性的药物等效植入物。但是，有稀疏的文学作品 解释眼科植入物的物理化学特性差异如何影响眼 生物利用度。此外，生物制药研究的关键障碍是发展完美 各种药物配方的体外药物释放信息与其体内的相关性 药物释放曲线；这需要开发强大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信息 用于各种复杂的眼科制剂，尤其是眼植入物的体内相关性（IVIVC）。我们 假设关键的物理化学特性，例如植入物表面积，孔隙率，拉伸 强度和聚合物降解（由于来自不同来源的聚合物采购）可能会有所不同 Q1/Q2植入物，导致药物释放和生物利用度差异。对于此类植入物不同 在其理化特性中，我们将开发合适的体外释放研究和预测性 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的玻璃体内植入物，但在理化特性方面有所不同。这 植入物以其物理化学特性和体外溶解/释放为特征 识别体内测试配方。将进行一项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分布。一项相关的体外释放研究 将确定/开发体内结果。通过与FDA的合作咨询 该项目的最佳研究设计将确定关键的物理化学和 Q1和Q2植入剂量的机械性能改变了眼药的生物利用度和 开发适当的体外溶解研究以预测体内药物从眼植入物中释放 良好的准确性。该项目的发现将为制定指导方针的基础 为通用眼植入物进行生物等效研究。