Merlo-Mas Josep, Tomsen-Melero Judit, Corchero José-Luis, González-Mira Elisabet, Font Albert, Pedersen Jannik N, García-Aranda Natalia, Cristóbal-Lecina Edgar, Alcaina-Hernando Marta, Mendoza Rosa, Garcia-Fruitós Elena, Lizarraga Teresa, Resch Susanne, Schimpel Christa, Falk Andreas, Pulido Daniel, Royo Miriam, Schwartz Simó, Abasolo Ibane, Pedersen Jan Skov, Danino Dganit, Soldevila Andreu, Veciana Jaume, Sala Santi, Ventosa Nora, Córdoba Alba
Nanomol Technologies S.L., 08193 Cerdanyola del Vallès, Spain.
Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, 08193 Bellaterra, Spain.
J Supercrit Fluids. 2021 Jul;173:105204. doi: 10.1016/j.supflu.2021.105204.
Fabry disease is a lysosomal storage disease arising from a deficiency of the enzyme α-galactosidase A (GLA). The enzyme deficiency results in an accumulation of glycolipids, which over time, leads to cardiovascular, cerebrovascular, and renal disease, ultimately leading to death in the fourth or fifth decade of life. Currently, lysosomal storage disorders are treated by enzyme replacement therapy (ERT) through the direct administration of the missing enzyme to the patients. In view of their advantages as drug delivery systems, liposomes are increasingly being researched and utilized in the pharmaceutical, food and cosmetic industries, but one of the main barriers to market is their scalability. Depressurization of an Expanded Liquid Organic Solution into aqueous solution (DELOS-susp) is a compressed fluid-based method that allows the reproducible and scalable production of nanovesicular systems with remarkable physicochemical characteristics, in terms of homogeneity, morphology, and particle size. The objective of this work was to optimize and reach a suitable formulation for in vivo preclinical studies by implementing a Quality by Design (QbD) approach, a methodology recommended by the FDA and the EMA to develop robust drug manufacturing and control methods, to the preparation of α-galactosidase-loaded nanoliposomes (nanoGLA) for the treatment of Fabry disease. Through a risk analysis and a Design of Experiments (DoE), we obtained the Design Space in which GLA concentration and lipid concentration were found as critical parameters for achieving a stable nanoformulation. This Design Space allowed the optimization of the process to produce a nanoformulation suitable for in vivo preclinical testing.
法布里病是一种溶酶体贮积病，由α -半乳糖苷酶A（GLA）缺乏引起。酶缺乏导致糖脂蓄积，随着时间的推移，会引发心血管、脑血管和肾脏疾病，最终在患者四五十岁时导致死亡。目前，溶酶体贮积症通过酶替代疗法（ERT）进行治疗，即直接向患者施用缺失的酶。鉴于脂质体作为药物递送系统的优势，其在制药、食品和化妆品行业正得到越来越多的研究和应用，但市场的主要障碍之一是其可扩展性。将膨胀的液体有机溶液减压至水溶液（DELOS - susp）是一种基于压缩流体的方法，能够以可重复且可扩展的方式生产具有显著物理化学特性（在均一性、形态和粒径方面）的纳米囊泡系统。本研究的目的是通过实施质量源于设计（QbD）方法来优化并获得适合体内临床前研究的制剂，QbD是美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）推荐的一种用于开发稳健的药物制造和控制方法的策略，应用于制备用于治疗法布里病的载α -半乳糖苷酶纳米脂质体（nanoGLA）。通过风险分析和实验设计（DoE），我们获得了设计空间，其中发现GLA浓度和脂质浓度是实现稳定纳米制剂的关键参数。该设计空间有助于优化制备适合体内临床前测试的纳米制剂的工艺。
