Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method

Josep Merlo-Mas, Judit Tomsen-Melero, José Luis Corchero, Elisabet González-Mira, Albert Font, Jannik N. Pedersen, Natalia García-Aranda, Edgar Cristóbal-Lecina, Marta Alcaina-Hernando, Rosa Mendoza, Elena Garcia-Fruitós, Teresa Lizarraga, Susanne Resch, Christa Schimpel, Andreas Falk, Daniel Pulido, Miriam Royo, Simó Schwartz, Ibane Abasolo, Jan Skov PedersenDganit Danino, Andreu Soldevila, Jaume Veciana, Santi Sala, Nora Ventosa*, Alba Córdoba

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Article number105204
JournalJournal of Supercritical Fluids
Volume173
DOIs
StatePublished - Jul 2021
Externally publishedYes

Keywords

  • DELOS
  • Fabry disease
  • Protein-loaded liposomes
  • Quality by Design
  • Scale-up
  • α-galactosidase

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