Ghaffari Alireza Allen, Matter Brock A, Hartman Rachel R, Bourne David W A, Wang Yan, Choi Stephanie, Kompella Uday B
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
NextHerbal Labs, LLC, Aurora, CO 80045, USA.
Pharmaceutics. 2024 Jul 4;16(7):895. doi: 10.3390/pharmaceutics16070895.
Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% / of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products.
开发复杂剂型的生物等效（BE）仿制药，如基于可生物降解的聚（丙交酯-共-乙交酯）（PLGA）聚合物、采用热熔挤出（HME）制备的地塞米松等皮质类固醇的玻璃体内植入物（IVIs），可能具有挑战性。更好地理解IVIs的物理化学和物理机械性质之间的关系及其对药物释放和眼部生物利用度的影响，对于开发新的BE方法至关重要。IVIs的关键物理化学和物理机械性质，如药物性质、植入物表面粗糙度、机械强度和韧性以及植入物侵蚀，可能因不同的组成而有所不同，从而导致药物释放的变化。因此，本研究调查了以下假设：使用单程热熔挤出（HME）制备的含20%药物和80%PLGA聚合物的可生物降解的载地塞米松眼科植入物，其物理化学和/或物理机械性质以及药物释放因PLGA聚合物组成而异。将酸封端的PLGA与酯封端的PLGA混合，制成三种制剂：HME-1、HME-2和HME-3，分别含有100%、80%和60%的酸封端PLGA。此外，本研究比较了各组成独立批次之间药物释放情况。体外释放试验（IVRTs）表明，HME-1植入物可通过其释放曲线与HME-2和HME-3轻易区分，而HME-2和HME-3的释放情况相似。在早期阶段，药物释放通常与聚合物组成和植入物性质密切相关，释放量随PLGA酸含量增加（第1天释放，R = 0.80）和/或表面粗糙度增加（第1天和第14天释放，R≥0.82）而增加。此外，植入物的机械强度和韧性与PLGA酸含量和第1天药物释放呈负相关。各组成独立批次的药物释放情况相似。该项目的研究结果可能有助于开发基于PLGA聚合物的通用眼科植入产品。
