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Synthesis and evaluation of styrene-maleic acid copolymer conjugated amphotericin B.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2019 Dec 15; Vol. 572, pp. 118719. Date of Electronic Publication: 2019 Oct 22. - Publication Year :
- 2019
-
Abstract
- Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because it's sparingly soluble in water and organic solvents. We previously prepared AmB-loaded micelles using styrene-maleic acid copolymer (SMA). Although solubilization was achieved by this formulation, stability in the blood circulation was as insufficient as that of Fungizone®, which is a conventional formulation of AmB. Meanwhile, it is well known that polymer-drug conjugates are more stable in circulation than drug-loaded micelles. Therefore, in this study, we developed covalently conjugated SMA-AmB (SMA-AmB conjugate). The SMA-AmB conjugate was found to be soluble and present as micelles in aqueous solution. Furthermore, it was revealed that this micelle behaves as a larger molecule by forming a complex with albumin. The circulation in the blood increased significantly compared to that of Fungizone®, which was suggested to be due to this complex-forming ability. Although in vitro and in vivo antifungal activity of the SMA-AmB conjugate against Saccharomyces cerevisiae was reduced by 1/3 compared to that of Fungizone®, hemolysis decreased to 1/40 or less, and the LD <subscript>50</subscript> decreased to 1/10. In conclusion, it is expected that the SMA-AmB conjugate can be a polymer-therapeutic agent with high antifungal selectivity.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Drug Liberation
Erythrocytes drug effects
Hemolysis drug effects
Lethal Dose 50
Male
Mice
Micelles
Saccharomyces cerevisiae drug effects
Saccharomyces cerevisiae growth & development
Solubility
Amphotericin B administration & dosage
Amphotericin B blood
Amphotericin B chemistry
Amphotericin B pharmacokinetics
Antifungal Agents administration & dosage
Antifungal Agents blood
Antifungal Agents chemistry
Antifungal Agents pharmacokinetics
Maleates administration & dosage
Maleates blood
Maleates chemistry
Maleates pharmacokinetics
Styrene administration & dosage
Styrene blood
Styrene chemistry
Styrene pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3476
- Volume :
- 572
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31654700
- Full Text :
- https://doi.org/10.1016/j.ijpharm.2019.118719