Schwendeman Steven P, Shah Ronak B, Bailey Brittany A, Schwendeman Anna S
Department of Pharmaceutical Sciences, The Biointerfaces Institute, North Campus Research Complex, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, The Biointerfaces Institute, North Campus Research Complex, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
Department of Pharmaceutical Sciences, The Biointerfaces Institute, North Campus Research Complex, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
J Control Release. 2014 Sep 28;190:240-53. doi: 10.1016/j.jconrel.2014.05.057. Epub 2014 Jun 12.
Biodegradable, injectable depot formulations for long-term controlled drug release have improved therapy for a number of drug molecules and led to over a dozen highly successful pharmaceutical products. Until now, success has been limited to several small molecules and peptides, although remarkable improvements have been accomplished in some of these cases. For example, twice-a-year depot injections with leuprolide are available compared to the once-a-day injection of the solution dosage form. Injectable depots are typically prepared by encapsulation of the drug in poly(lactic-co-glycolic acid) (PLGA), a polymer that is used in children every day as a resorbable suture material, and therefore, highly biocompatible. PLGAs remain today as one of the few "real world" biodegradable synthetic biomaterials used in US FDA-approved parenteral long-acting-release (LAR) products. Despite their success, there remain critical barriers to the more widespread use of PLGA LARproducts, particularly for delivery of more peptides and other large molecular drugs, namely proteins. In this review, we describe key concepts in the development of injectable PLGA controlled-release depots for peptides and proteins, and then use this information to identify key issues impeding greater widespread use of PLGA depots for this class of drugs. Finally, we examine important approaches, particularly those developed in our research laboratory, toward overcoming these barriers to advance commercial LAR development.
用于长期控释药物的可生物降解注射用长效制剂已改善了多种药物分子的治疗效果，并催生了十多种非常成功的药品。到目前为止，成功仅限于几种小分子和肽类药物，尽管在其中一些案例中已取得了显著进展。例如，亮丙瑞林的长效注射剂每半年注射一次，而溶液剂型则需每日注射一次。注射用长效制剂通常是通过将药物封装在聚乳酸-羟基乙酸共聚物（PLGA）中来制备的，这种聚合物每天都用于儿童体内作为可吸收的缝合材料，因此具有高度的生物相容性。PLGA至今仍是美国食品药品监督管理局（FDA）批准的肠胃外长效释放（LAR）产品中使用的少数几种“实际应用”的可生物降解合成生物材料之一。尽管取得了成功，但PLGA长效制剂更广泛应用仍存在关键障碍，尤其是对于更多肽类和其他大分子药物（即蛋白质）的递送。在本综述中，我们描述了用于肽类和蛋白质的可注射PLGA控释长效制剂开发中的关键概念，然后利用这些信息来确定阻碍PLGA长效制剂更广泛用于此类药物的关键问题。最后，我们研究了重要的方法，特别是我们研究实验室开发的方法，以克服这些障碍，推动商业长效制剂的开发。
