Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.
Production Engineering Department, Chugai Pharmaceutical Co., Ltd., 5-5-1, Ukima, Kita-ku, Tokyo, 115-8543, Japan.
AAPS J. 2018 Oct 2;20(6):105. doi: 10.1208/s12248-018-0253-2.
The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Specific attributes analyzed for microspheres were as follows: leuprolide content by three methods; gelatin content, type, and molecular weight distribution; PLGA content, lactic acid/glycolic acid ratio, and molecular weight distribution; mannitol content; in vitro drug release; residual solvent and moisture content; particle size distribution and morphology; and glass transition temperature. For the diluent, composition, viscosity, and specific gravity were analyzed. Analyzed contents of the formulation and the determined PLGA characteristics matched well with the official numbers stated in the package insert and those found in literature, respectively. The gelatin was identified as type B consistent with ~ 300 bloom. The 11-μm volume-median microspheres in the LD slowly released the drug in vitro in a zero-order manner after ~ 23% initial burst release. Very low content of residual moisture (< 0.5%) and methylene chloride (< 1 ppm) in the product indicates in-water drying is capable of removing solvents to extremely low levels during manufacturing. The rigorous approach of reverse engineering described here may be useful for development of generic leuprolide-PLGA microspheres as well as other new and generic PLGA microsphere formulations.
1 个月的亮丙瑞林 Depot®（LD）将水溶性亮丙瑞林包封在聚（乳酸-共-乙醇酸）（PLGA）微球中，是现代长效释放产品经常比较的基准产品。尽管专利保护期已过，但美国尚未批准 LD 的仿制药，可能是由于产品涉及的成分和制造工艺复杂。在这里，我们描述了 LD 成分和重要产品属性的反向工程。对微球分析的特定属性如下：三种方法测定的亮丙瑞林含量；明胶含量、类型和分子量分布；PLGA 含量、乳酸/乙醇酸比和分子量分布；甘露醇含量；体外药物释放；残留溶剂和水分含量；粒径分布和形态；以及玻璃化转变温度。对于稀释剂，分析了组成、粘度和比重。分析的配方含量和确定的 PLGA 特性与包装插页中所述的官方数字以及文献中发现的数字分别非常吻合。明胶被鉴定为与~300 布卢姆相当的 B 型。LD 中的 11μm 体积中值微球在初始突释后约 23%，以零级方式缓慢释放体外药物。产品中残留水分（<0.5%）和二氯甲烷（<1ppm）含量非常低，表明在制造过程中，水干燥能够将溶剂去除到极低水平。这里描述的逆向工程的严格方法可能对开发通用亮丙瑞林-PLGA 微球以及其他新的和通用的 PLGA 微球制剂有用。
