Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment.
Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment.
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在聚（乳酸-乙醇酸）微球中水性远程装载塞黑肽，用于长期肥胖治疗。
DOI：
10.1016/j.jconrel.2023.09.015
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Schwendeman,StevenP
中科院分区：
文献类型：
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作者：
Wang,Shuying;Downing,Griffin;Olsen,KarlF;Sawyer,TomiK;Cone,RogerD;Schwendeman,StevenP
Setmelanotide（Imcivree ™）被开发为每日可注射的治疗肽，用于治疗罕见形式的综合征性肥胖症，例如POMC缺乏症和瘦素受体缺乏症。聚乳酸-羟基乙酸共聚物（PLGA）控释微球的重要选择对于这类药物已经变得更有吸引力，因为发现净正电荷肽可以以高负载和包封效率从肽水溶液快速远程负载到空白微球中。在这里，我们试图远程加载塞替米拉诺肽的PLGA微球，并检查其长期控制释放和体重控制的潜力。PLGA微球的孔隙率的影响进行了研究，相对于形态，载药量，和在体外释放曲线。微球密度的增加抑制了双阳离子肽的包封进展。然后使用饮食诱导的肥胖鼠模型来确定药代动力学特征并评价最佳制剂的长期功效。远程加载的PLGA制剂包封的塞米拉诺肽高达1063%（106.3%w/w加载），并且在体外表现出缓慢和连续的肽释放超过106周，在很大程度上与微球孔隙率无关。从皮下注射微球后的药代动力学解卷积获得的体内释放模式与体外释放模式一致，但初始突释较低，总体释放速率略快。在单次注射远程加载的塞米拉诺肽后，分别在17天和30天内观察到对食物摄入和体重控制的连续长期抑制。与无药物微球溶媒给药对照组相比，体重控制的改善与观察到的PK特征相匹配。该研究提供了在饮食诱导的肥胖小鼠模型中用于塞替米拉诺肽的1个月控释和体重控制的长效释放制剂的第一份报告，并支持进一步开发用于肥胖患者的长效治疗选择。
Setmelanotide (Imcivree™) was developed as a daily injectable therapeutic peptide for the treatment of rare forms of syndromic obesity, such as POMC deficiency and leptin receptor deficiency. The important option of poly(lactic-co-glycolic acid) (PLGA) controlled release microspheres has become more attractive for this class of drugs upon the discovery that net positively charged peptides can be remote-loaded rapidly from aqueous peptide solution into blank microspheres at high loading and encapsulation efficiency. Here we sought to remote-load setmelanotide in PLGA microspheres and examine its potential for long-term controlled release and body weight control. The influence of PLGA microsphere porosity was investigated with respect to morphology, drug loading, andin vitrorelease profiles. Increased density of the microspheres inhibited the progress of encapsulation of the dicationic peptide. A diet-induced obese murine model was then used to determine the pharmacokinetic profile and to evaluate long-term efficacy of an optimal formulation. Remote loaded PLGA formulations encapsulated setmelanotide as high as ∼63% (∼6.3%w/w loading) and exhibited slow and continuous peptide release over ∼6 weeksin vitrolargely independent of microsphere porosity. The obtainedin vivorelease pattern from deconvolution of the pharmacokinetics after subcutaneous microsphere injection was consistent with thein vitrorelease profile but with a lower initial burst release and overall slightly faster release rate. After a single injection of remote-loaded setmelanotide, continuous long-term inhibition of food intake and body weight control was observed over 17 and 30 days, respectively. The improvement in body weight control over drug-free microsphere vehicle-treated control groups matched the observed PK profile. This study provides the first report of long-acting release formulation for 1-month controlled release of setmelanotide and body weight control in a diet induced obese murine model, and supports the further development of long-acting treatment options for obese patients.