Amphotericin B Loaded Nanostructured Lipid Carriers for Parenteral Delivery: Characterization, Antifungal and In vitro Toxicity Assessment

Abstract

Background: Amphotericin B (AmB) is important for the treatment of systemic fungal infections. Nowadays, only intravenous administration (IV) of AmB has been available due to its low aqueous solubility. Two forms of AmB are available. The first is Fungizone®, a mixture of AmB and sodium deoxcycholate that produces severe nephrotoxicity. The second are lipid-based formulations that reduce nephrotoxicity, but they are costly and require higher dose than Fungizone®. Thus, a cheaper delivery system with reduced AmB toxicity is required. Objective: To develop and characterize AmB loaded-nanostructured lipid carriers (AmB-loaded NLCs) for IV administration to reduce AmB toxicity. Methods: AmB-loaded NLCs with different solid lipids were prepared by the high-pressure homogenization technique. Their physicochemical properties and the drug release profile were examined. The molecular structure of AmB, antifungal and hemolysis activities of developed AmB-loaded NLCs were also evaluated. Results: AmB-loaded NLCs ~110 to ~140 nm in diameter were successfully produced with a zeta potential of ~-19 mV and entrapment efficiency of ~75%. In vitro release showed fast release characteristics. AmB-loaded NLCs could reduce the AmB molecular aggregation as evident from the absorbance ratio of the first to the fourth peak showing a partial aggregation of AmB. This result suggested that AmB-loaded NLCs could offer less nephrotoxicity compared to Fungizone®. In vitro antifungal activity of AmB-loaded NLCs showed a minimum inhibitory concentration of 0.25 µgmL-1. Conclusion: AmB-loaded NLCs present high potential carriers for effective IV treatment with prolonged circulation time and reduced toxicity.

Relationship and improvement strategies between drug nanocarrier characteristics and hemocompatibility: What can we learn from the literature

“…The hemolytic effect of NLCs loaded with AmB was significantly reduced. The low hemolysis of AmB when formulated in NLCs can be attributed to the association of drugs and lipid compounds, which may cause structural changes in the drugs without molecular aggregation [89] . The low hemolytic activity of NLCs is entirely reasonable, because hemolytic agents (oil at the core and surfactant at the interface) are restricted at the lipophilic core and the interface, thus hindering Initial contact with RBCs membrane [90] .…”

“…This may explain the tendency of the smallest size to be combined with the RBC membrane. Therefore, most of the partially aggregated AmB in the myristic acid-NLCs located on the surface of the particles has more opportunities to destroy RBC [89] . In addition, unlike micelles, NLCs with different alkyl chain lengths (solid phase) do not necessarily exhibit the same trend of hemolytic as alkyl chain lengths [90] .…”