Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation
In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmissi...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8756 |
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| author | Francesca Ferrara Mascia Benedusi Franco Cervellati Maddalena Sguizzato Leda Montesi Agnese Bondi Markus Drechsler Walter Pula Giuseppe Valacchi Elisabetta Esposito |
| author_facet | Francesca Ferrara Mascia Benedusi Franco Cervellati Maddalena Sguizzato Leda Montesi Agnese Bondi Markus Drechsler Walter Pula Giuseppe Valacchi Elisabetta Esposito |
| author_sort | Francesca Ferrara |
| collection | DOAJ |
| description | In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmission electron microscopy, photon correlation spectroscopy, and HPLC. The stability of vesicles was evaluated, both for size increase and capability to control the drug degradation. Drug release kinetics and permeability profiles were evaluated in vitro using Franz cells, associated with different synthetic membranes. The in vitro viability, as well as the capacity to improve wound healing, were evaluated in human keratinocytes. Transmission electron microscopy enabled the evaluation of transethosome uptake and intracellular fate. Based on the obtained results, a transethosome gel was further formulated for the cutaneous application of dimethyl fumarate, the safety of which was evaluated in vivo with a patch test. It was found that the phosphatidylcholine concentration affected vesicle size and lamellarity, influencing the capacity to control dimethyl fumarate’s chemical stability and release kinetics. Indeed, phosphatidylcholine 2.7% <i>w</i>/<i>w</i> led to multivesicular vesicles with 344 nm mean size, controlling the drug’s chemical stability for at least 90 days. Conversely, phosphatidylcholine 0.9% <i>w</i>/<i>w</i> resulted in 130 nm sized unilamellar vesicles, which maintained 55% of the drug over 3 months. These latest kinds of transethosomes were able to improve wound healing in vitro and were easily internalised by keratinocytes. The selected transethosome gel, loading 25 mg/mL dimethyl fumarate, was not irritant after cutaneous application under occlusion, suggesting its possible suitability in the treatment of wounds caused by diabetes mellitus or peripheral vascular diseases. |
| first_indexed | 2024-03-09T05:20:02Z |
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| id | doaj.art-42fce109bd7846c8a8fe772fa00d5a96 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:20:02Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-42fce109bd7846c8a8fe772fa00d5a962023-12-03T12:41:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012315875610.3390/ijms23158756Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo EvaluationFrancesca Ferrara0Mascia Benedusi1Franco Cervellati2Maddalena Sguizzato3Leda Montesi4Agnese Bondi5Markus Drechsler6Walter Pula7Giuseppe Valacchi8Elisabetta Esposito9Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, ItalyDepartment of Neurosciences and Rehabilitation, University of Ferrara, I-44121 Ferrara, ItalyDepartment of Neurosciences and Rehabilitation, University of Ferrara, I-44121 Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, ItalyDepartment of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, ItalyBavarian Polymer Institute (BPI) Keylab “Electron and Optical Microscopy”, University of Bayreuth, D-95440 Bayreuth, GermanyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, ItalyAnimal Science Department, Plants for Human Health Institute, NC Research Campus, NC State University, Kannapolis, NC 28081, USADepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, ItalyIn this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmission electron microscopy, photon correlation spectroscopy, and HPLC. The stability of vesicles was evaluated, both for size increase and capability to control the drug degradation. Drug release kinetics and permeability profiles were evaluated in vitro using Franz cells, associated with different synthetic membranes. The in vitro viability, as well as the capacity to improve wound healing, were evaluated in human keratinocytes. Transmission electron microscopy enabled the evaluation of transethosome uptake and intracellular fate. Based on the obtained results, a transethosome gel was further formulated for the cutaneous application of dimethyl fumarate, the safety of which was evaluated in vivo with a patch test. It was found that the phosphatidylcholine concentration affected vesicle size and lamellarity, influencing the capacity to control dimethyl fumarate’s chemical stability and release kinetics. Indeed, phosphatidylcholine 2.7% <i>w</i>/<i>w</i> led to multivesicular vesicles with 344 nm mean size, controlling the drug’s chemical stability for at least 90 days. Conversely, phosphatidylcholine 0.9% <i>w</i>/<i>w</i> resulted in 130 nm sized unilamellar vesicles, which maintained 55% of the drug over 3 months. These latest kinds of transethosomes were able to improve wound healing in vitro and were easily internalised by keratinocytes. The selected transethosome gel, loading 25 mg/mL dimethyl fumarate, was not irritant after cutaneous application under occlusion, suggesting its possible suitability in the treatment of wounds caused by diabetes mellitus or peripheral vascular diseases.https://www.mdpi.com/1422-0067/23/15/8756dimethyl fumaratecryogenic transmission electron microscopywound healingtransethosomestransdermal delivery |
| spellingShingle | Francesca Ferrara Mascia Benedusi Franco Cervellati Maddalena Sguizzato Leda Montesi Agnese Bondi Markus Drechsler Walter Pula Giuseppe Valacchi Elisabetta Esposito Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation International Journal of Molecular Sciences dimethyl fumarate cryogenic transmission electron microscopy wound healing transethosomes transdermal delivery |
| title | Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation |
| title_full | Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation |
| title_fullStr | Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation |
| title_full_unstemmed | Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation |
| title_short | Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation |
| title_sort | dimethyl fumarate loaded transethosomes a formulative study and preliminary ex vivo and in vivo evaluation |
| topic | dimethyl fumarate cryogenic transmission electron microscopy wound healing transethosomes transdermal delivery |
| url | https://www.mdpi.com/1422-0067/23/15/8756 |
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