Gangadhar Katkam N, Adhikari Kajiram, Srichana Teerapol
Institute of Chemical and Biological Technology, New University of Lisbon, Portugal.
Drug Delivery System Excellence Center, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
Int J Pharm. 2014 Aug 25;471(1-2):430-8. doi: 10.1016/j.ijpharm.2014.05.066. Epub 2014 Jun 4.
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.
两性霉素B（AmB）仍然是治疗侵袭性真菌疾病的金标准。然而，由于其在水溶液中的低溶解度和稳定性，口服AmB的应用受到限制，这导致其生物利用度差且吸收差异很大。因此，人们尝试通过使用新型辅料脱氧胆酸钠硫酸盐（SDS）来提高AmB的溶解度和稳定性，以评估其作为吸入剂的生物活性和安全性，目的是将其用作AmB的药物载体。因此，通过冻干将SDS与AmB一起制成干粉。将干粉在蒸馏水中复溶，并评估其物理化学性质，如zeta电位、粒径和pH值，以比较其制剂与SDC-AmB（即商品名为Fungizone®）的溶解度和稳定性。用红细胞（RBC）和呼吸道细胞系进行体外毒性研究。通过微量稀释法测定对白色念珠菌和新型隐球菌的生物活性。我们发现SDS-AmB的zeta电位为（-45.53 mV），高于Fungizone®；并且在溶液中产生稳定的粒径（73.8 nm）。两种制剂的粒径分布分别表示为它们的质量中值空气动力学直径（MMAD；1.70和1.74μm）、细颗粒分数（FPF；70%和80%）以及几何标准差（GSD；2.3和2.0）。这些值表明这些尺寸适合用于吸入器。发现纯AmB会使RBC溶血，并且对肺泡巨噬细胞毒性很大，当AmB浓度从1μg/mL增加到8μg/mL时，其活力从93%迅速下降到56%。与AmB相比，SDS-AmB制剂的毒性显著降低。结果清楚地表明，基于SDS的脂质纳米颗粒有潜力作为Fungizone®的替代选择，用于制备吸入用AmB制剂。
