In a program aimed at the design and synthesis of novel azole inhibitors of C. albicans CYP51 (CA-CYP51), a series of azole 1,4-benzothiazines and 1,4-benzoxazines were recently synthesized. Among them a novel derivative, 2-butyl-6-{1-[(4-chlorobenzyl)oxy]-2-(1H-1-imidazoyl)ethyl}-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one, characterized by a very good MIC against C. albicans CA-6, showed a low water solubility that probably limits its in vivo activity. Therefore, the aim of the study was to assess the feasibility of using nanoemulsion technology to overcome the compound solubility issues. The nanoemulsion was characterized by dimensions of 189±55 nm and the formulation showed to be stable for at least 7 months even when diluted. The nanometric compound droplets should accelerate its in vivo solubilization with respect to the drug solution (DMSO:H2O, 1:4). In fact, it can be hypothesized that once injected, DMSO dilution or absorption may lead to drug phase separation and low effective surface available for dissolution. In addition to the improved solubility properties, this formulation allowed to eliminate the use of DMSO that should be preferably avoided in vivo. The preliminary results of in vivo experiments showed that the use nanoemulsion turned out to be a valuable strategy to overcome solubility problems encountered during early discovery and at the formulation stage as well.

Nanoemulsion formulation of a new Candida albicans CYP51 inhibitor

SCHOUBBEN, Aurelie Marie Madeleine;CENCI, Elio;SCHIAFFELLA, Fausto;BLASI, PAOLO;MILANESE, Lara;ROSSI, Carlo;VECCHIARELLI, Anna;RICCI, Maurizio;FRINGUELLI, Renata
2009

Abstract

In a program aimed at the design and synthesis of novel azole inhibitors of C. albicans CYP51 (CA-CYP51), a series of azole 1,4-benzothiazines and 1,4-benzoxazines were recently synthesized. Among them a novel derivative, 2-butyl-6-{1-[(4-chlorobenzyl)oxy]-2-(1H-1-imidazoyl)ethyl}-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one, characterized by a very good MIC against C. albicans CA-6, showed a low water solubility that probably limits its in vivo activity. Therefore, the aim of the study was to assess the feasibility of using nanoemulsion technology to overcome the compound solubility issues. The nanoemulsion was characterized by dimensions of 189±55 nm and the formulation showed to be stable for at least 7 months even when diluted. The nanometric compound droplets should accelerate its in vivo solubilization with respect to the drug solution (DMSO:H2O, 1:4). In fact, it can be hypothesized that once injected, DMSO dilution or absorption may lead to drug phase separation and low effective surface available for dissolution. In addition to the improved solubility properties, this formulation allowed to eliminate the use of DMSO that should be preferably avoided in vivo. The preliminary results of in vivo experiments showed that the use nanoemulsion turned out to be a valuable strategy to overcome solubility problems encountered during early discovery and at the formulation stage as well.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/42194
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