title: Synthesis and evaluation of sodium deoxycholate sulfate as a lipid drug carrier to enhance the solubility, stability and safety of an amphotericin B inhalation formulation.
abstract: Amphotericin B (AmB) is still used as the gold standard for therapy against invasive fungal diseases. However, the use of AmB through oral administration is restricted due to its low solubility and stability in aqueous solution, which is the cause for its poor bioavailability and highly varying absorption. Therefore, an attempt has been made to enhance the solubility and stability of AmB to evaluate its bioactivity and safety for use as an inhaler by using a new excipient sodium deoxycholate sulfate (SDS) with aim of using it as a drug carrier for AmB. Therefore, SDS was formulated together with AmB as a dry powder by lyophilization. The dry powder was reconstituted in distilled water and evaluated its physicochemical properties such as zeta potential, particle size and pH to compare its solubility and stability of the formulations with a SDC-AmB (i.e., known as Fungizone(®)). In vitro toxicity studies were carried out with red blood cells (RBC) and respiratory cell lines. Bioactivity was determined by a micro-dilution method against Candidaalbicans and Cryptococcusneoformans. We found that SDS-AmB had a zeta potential (-45.53 mV), which was higher than of Fungizone(®); and produced a stable particle size in solution (73.8 nm). The particle size distributions of both formulations were expressed as their mass median aerodynamic diameters (MMAD; 1.70 and 1.74 μm), their fine particle fractions (FPF; 70 and 80%) and geometric standard deviations (GSD; 2.3 and 2.0), respectively. These values indicated that the sizes were appropriate for use in an inhaler. Pure AmB was found to hemolyse RBC and was very toxic to alveolar macrophage cells, as their viability rapidly declined from 93 to 56% when the AmB concentration increased from 1 to 8 μg/mL. The SDS-AmB formulation had a significantly reduced toxicity compared to AmB. The results clearly indicated that the SDS-lipid based nanoparticles had the potential to be used as an alternative option to Fungizone(®) for an AmB formulation for inhalation.
authors.affiliation: Institute of Chemical and Biological Technology, New University of Lisbon, Portugal.
authors.forename: Katkam N
authors.initials: KN
authors.lastname: Gangadhar
authors.affiliation: Drug Delivery System Excellence Center, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
authors.forename: Kajiram
authors.initials: K
authors.lastname: Adhikari
authors.affiliation: Drug Delivery System Excellence Center, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand; Nanotec-PSU Excellence Center on Drug Delivery System, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand. Electronic address: teerapol.s@psu.ac.th.
authors.forename: Teerapol
authors.initials: T
authors.lastname: Srichana
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development; D003840:Deoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D016676:Macrophages, Alveolar / Q000187:drug effects; D010316:Particle Size; D012995:Solubility; D013499:Surface Properties
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D008055:Lipids; D003840:Deoxycholic Acid; D000666:Amphotericin B
keywords: Aerosol; Amphotericin B; Fungizone(®); SDS–AmB; Toxicities; Zeta potential