In Situ Liposomal Preparation Containing Amphotericin B: Related Toxicity and Tissue Disposition Studies

Abstract

The purpose of this research was to develop a novel hydroalcoholic method for the preparation of liposome entrapping inclusion complex of amphotericin B (AmB) with a view to obtaining reduced toxicity and superior tissue distribution of AmB in vivo. The method involves initial preparation of AmB-hydroxypropyl-beta-cyclodextrin (AmB-HPBCD) intercalated proliposome which is subsequently converted into a liposome dispersion by single dilution method. The AmB-liposome (L-AmB) derived from proliposome exhibited a superior entrapment efficiency (94.8 +/- 0.7%) compared to liposomes prepared by employing a conventional solvent-based technique (89.7 +/- 2.9%). The dose that was lethal to 50% of subjects (LD50) (mg/kg) value of AmB contained in stabilized proliposome-based liposomes was 18.6 +/- 0.25, whereas that in conventional solvent-based liposomes was 7.8 +/- 0.25. Incorporation of AmB-HPBCD into hydroalcoholic liposomes enhanced antifungal activity in experimental aspergillosis in Balb/c mice in vivo: 80% survival was recorded after 7 days of therapy and the fungal load in lung was reduced. The results clearly demonstrate that preferential uptake of L-AmB entrapped inclusion complex (AmB-HPBCD) by the reticulo endothelial system correlated with diminished levels of AmB in infected (p > 0.05) and noninfected (p > 0.001) kidney after 24 hr compared to that observed with conventional solvent-based L-AmB. Therefore, proliposome-based liposome entrapping inclusion complex of AmB with HPBCD offered an improved therapeutic efficacy by lowering toxicity as well as by altering the tissue distribution pattern.

ESCMID guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT)

“…The experience of treatment is currently only anecdotal. Lipid formulations of amphotericin B might be a good choice because of potential accumulation in the reticulo‐endothelial system [127]. Frequently, sequential approaches are employed empirically, for example liposomal amphotericin B followed by prolonged treatment of fluconazole.…”

PHARMACOKINETIC STUDIES OF IN-SITU LIPOSOMAL PREPARATION CONTAINING AMPHOTERICIN B COMPLEXED WITH DIFFERENT CHEMICALLY MODIFIED Β-Cyclodextrins

“…Cyclodextrin possessing a hydrophilic exterior surface and nonpolar cavity can interact with appropriate sized moles to form noncovalent inclusion complexes and its chemical modification results an increase in drug complexation and interaction (19). The proliposome approach, which is described in this communication, circumvented, successfully AmB leakage problem associated with inclusion complex (AmB-βCD) free liposomes (liposome prepared with conventional method) as discussed in previous publication (10). Hydroxypropyl β-CD and Sulfobutyl ether β-CD have been reported to elicit a very low toxicity and, therefore widely as solubilizing and stabilizing agent in parenteral pharmaceutical formulations (20,21).…”

“…The proliposome mixture was finally converted into a multilamellar liposome (MLV) suspension by drop wise addition of PBS (pH 7.4) containing amphotericin-B complexed with different chemically modified β-Cyclodextrin in the ratio of 1 : 10 w/w to a final volume of 10 ml. The suspension was vortex mixed throughout this last stage (10).…”

“…Previous work (10) has already established optimal conditions (in terms of structural organization of proliposome mixtures) for the entrapment of inclusion complexes (AmB-BCD) into vesicles and its stabilization in-vitro.…”

Cyclodextrin-Mediated Recruitment and Delivery of Amphotericin B

“…The discovery of new biologically active derivatives that can be exploited therapeutically to treat disease has, however, stalled, with fewer drugs entering the market every year. In contrast, cyclodextrin (CD)-based DDSs, such as CDs, CD-based copolymers, and lipid formulations, − have proven to be a versatile and multifaceted platform for the delivery of AmB. From this point, it is necessary to understand how CDs and AmB recognize and associate.…”