TY - JOUR
T1 - Amphotericin B and monoacyl-phosphatidylcholine form a stable amorphous complex
AU - Liu, Xiaona
AU - Berthelsen, Ragna
AU - Bar-Shalom, Daniel
AU - Kjellerup Lind, Tania
AU - Doutch, James
AU - Müllertz, Anette
N1 - Funding Information:
Support from the University of Copenhagen and the grant from China Scholarship Council (Fund No. 201706010335) for the research are kindly acknowledged. SANS analysis was benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. SasView also contains code developed with funding from the EU Horizon 2020 programme under the SINE2020 project Grant No 654000. We thank the STFC ISIS Facility for the beamtime granted, with experiment number RB2010360 (DOI: 10.5286/ISIS.E.RB2010360).
Funding Information:
Support from the University of Copenhagen and the grant from China Scholarship Council (Fund No. 201706010335) for the research are kindly acknowledged. SANS analysis was benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. SasView also contains code developed with funding from the EU Horizon 2020 programme under the SINE2020 project Grant No 654000. We thank the STFC ISIS Facility for the beamtime granted, with experiment number RB2010360 (DOI: 10.5286/ISIS.E.RB2010360).
PY - 2023
Y1 - 2023
N2 - Amphotericin B (AmB) is a “life-saving” medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, “rod-like” and “worm-like” micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.
AB - Amphotericin B (AmB) is a “life-saving” medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, “rod-like” and “worm-like” micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.
KW - Amorphous
KW - Amphotericin B
KW - Dissolution
KW - Drug-phospholipid complexes
KW - Monoacyl phosphatidylcholine
KW - Oral drug delivery
U2 - 10.1016/j.ijpharm.2023.122601
DO - 10.1016/j.ijpharm.2023.122601
M3 - Journal article
C2 - 36632922
AN - SCOPUS:85146587364
VL - 633
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
M1 - 122601
ER -