College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
Headquarter, Inventage Lab, Inc., 12, Yanghyeon-ro 405beon-gil, Jungwon-gu, Seongnam-si, Gyeonggi-do 13438, Republic of Korea.
J Control Release. 2021 Dec 10;340:72-86. doi: 10.1016/j.jconrel.2021.10.022. Epub 2021 Oct 29.
Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.
基于可生物降解的聚（乳酸-共-乙醇酸）（PLGA）聚合物，开发了一种具有一个月作用持续时间的新型多奈哌齐（DNP）载药微球制剂，旨在降低给药频率和不良反应，提高患者的顺应性。通过 Inventage Lab 精密颗粒制备方法（IVL-PPFM®），基于微机电系统（MEMS）和微流控技术，精确制备出球形和单分散的 DNP 载药微球。研究了聚合物类型和端基、药物/聚合物比（DPR）以及 DNP 的给药途径，以确保有效浓度和所需的作用持续时间。采用激光光粒度分析和扫描电子显微镜对其进行了表征。此外，还使用比格犬非临床动物模型对 DNP 制剂进行了优化，并评估了其药代动力学特性。PK 结果表明，DPR 是决定 DNR 释放暴露水平和持续时间的关键因素。此外，取决于聚合物类型的丙交酯比例决定了疏水性相互作用，也是影响所需 DNP 释放的重要因素。由于 DNP 在狗和人类之间存在较大的种间差异，因此使用参考药物（即 Aricept®）和 DNP 载药微球的 PK 模型化和模拟进行制剂开发，以克服和解释这些差异。此外，使用估计的 PK 参数和已发表的 DNP 临床药理学数据，将开发的 PK 模型外推到人类。DNP 载药微球在人体内的预测 PK 谱表明，PLGA 7525A 和 DPR 为 1/9 的制剂可以维持一个月的药物浓度，并可以控制初始突释。从研究中获得的数据可作为未来制剂开发决策的科学依据。
