Wang Xiaoyi, Bao Quanying, Wang Ruifeng, Kwok Owen, Maurus Kellen, Wang Yan, Qin Bin, Burgess Diane J
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
J Control Release. 2023 Sep;361:777-791. doi: 10.1016/j.jconrel.2023.08.029. Epub 2023 Aug 22.
Despite the unique advantages of injectable, long-acting in situ forming implant formulations based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone (NMP), only six products are commercially available. A better understanding of PLGA will aid in the development of more in situ forming implant innovator and generic products. This article investigates the impact of slight changes in PLGA attributes, i.e., molecular weight (MW), lactide:glycolide (L/G) ratio, blockiness, and end group, on the in vitro and in vivo performance of PLGA-based in situ forming implant formulations. Perseris (risperidone) for extended-release injectable suspension was selected as the reference listed drug (RLD). A previously developed adapter-based USP 2 method was used for the in vitro release testing of various risperidone implant formulations. A rabbit model was used to determine the in vivo pharmacokinetic profiles of the formulations (subcutaneous administration) and deconvolution (Loo-Riegelman method) was conducted to obtain the in vivo release profiles. The results showed that a 5 KDa difference in the MW (19.2, 24.2, 29.2 KDa), a 5% variation in the L/G ratio (85/15, 80/20, 75/25) and the end-cap (acid vs ester) all significantly impacted the formulation behavior both in vitro and in vivo. Higher MW, higher L/G ratio and ester end-cap PLGA all resulted in longer release durations. The formulations prepared with polymers with different blockiness values (within the blockiness range tested) did not show differences in in vitro and in vivo release. An in vitro-in vivo correlation (IVIVC) was not developed due to the different in vitro and in vivo phase separation rates, swelling tendencies and consequent significantly different release profiles. This is the first report evaluating the impact of PLGA property variation (over a narrow range) on the performance of in situ forming implants. The knowledge gained will provide a better understanding of the mechanisms underlying risperidone in situ forming implant performance and will aid the development of future products.
尽管基于聚（丙交酯-共-乙交酯）（PLGA）和N-甲基-2-吡咯烷酮（NMP）的可注射长效原位形成植入剂配方具有独特优势，但市面上仅有六种产品可供商业使用。对PLGA有更深入的了解将有助于开发更多的原位形成植入剂创新产品和仿制药。本文研究了PLGA属性的微小变化，即分子量（MW）、丙交酯：乙交酯（L/G）比例、嵌段性和端基，对基于PLGA的原位形成植入剂配方的体外和体内性能的影响。长效注射用利培酮混悬液Perseris被选为参比上市药品（RLD）。使用先前开发的基于适配器的美国药典2方法对各种利培酮植入剂配方进行体外释放测试。使用兔模型确定配方的体内药代动力学概况（皮下给药），并进行反卷积（Loo-Riegelman方法）以获得体内释放概况。结果表明，分子量相差5 KDa（19.2、24.2、29.2 KDa）、L/G比例相差5%（85/15、80/20、75/25）以及端基封端（酸封端与酯封端）均对配方的体外和体内行为产生显著影响。较高的分子量、较高的L/G比例和酯封端的PLGA均导致更长的释放持续时间。用具有不同嵌段性值（在所测试的嵌段性范围内）的聚合物制备的配方在体外和体内释放方面未显示出差异。由于体外和体内相分离速率、溶胀趋势以及由此导致的显著不同的释放概况，未建立体外-体内相关性（IVIVC）。这是第一份评估PLGA属性变化（在狭窄范围内）对原位形成植入剂性能影响的报告。所获得的知识将有助于更好地理解利培酮原位形成植入剂性能的潜在机制，并有助于未来产品的开发。
