학술논문
Rapid optimization of liposome characteristics using a combined microfluidics and design-of-experiment approach.
Document Type
Academic Journal
Author
Sedighi M; Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.; Sieber S; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.; Rahimi F; Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran. rahimi.f@ut.ac.ir.; Shahbazi MA; Department of Micro- and Nanotechnology, Technical University of Denmark, Ørsteds Plads, DK-2800, Kongens Lyngby, Denmark.; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.; Rezayan AH; Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.; Huwyler J; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland. joerg.huwyler@unibas.ch.; Witzigmann D; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.; Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada.
Source
Publisher: Springer Country of Publication: United States NLM ID: 101540061 Publication Model: Print Cited Medium: Internet ISSN: 2190-3948 (Electronic) Linking ISSN: 2190393X NLM ISO Abbreviation: Drug Deliv Transl Res Subsets: MEDLINE
Subject
Language
English
Abstract
Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposome formulations, i.e., up to 30 liposome formulations in 1 day. Five representative liposome formulations based on clinically approved lipid compositions were formulated using systematic variations in microfluidics flow rate settings, i.e., flow rate ratio (FRR) and total flow rate (TFR). Interestingly, flow rate-dependent DoE models for the prediction of liposome characteristics could be grouped according to lipid-phase transition temperature and surface characteristics. For all formulations, the FRR had a significant impact (p < 0.001) on hydrodynamic diameter and size distribution of liposomes, while the TFR mainly affected the production rate. Liposome characteristics remained constant for TFRs above 8 mL/min. The stability study revealed an influence of lipid:cholesterol ratio (1:1 and 2:1 ratio) and presence of PEG on liposome characteristics during storage. To validate our DoE models, we formulated liposomes incorporating hydrophobic dodecanethiol-coated gold nanoparticles. This proof-of-concept step showed that flow rate settings predicted by DoE models successfully determined the size of resulting empty liposomes (109.3 ± 15.3 nm) or nanocomposites (111 ± 17.3 nm). This study indicates that a microfluidics-based formulation approach combined with DoE is suitable for the routine development of monodisperse and size-specific liposomes in a reproducible and rapid manner.