RESUMO
This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC -with the carrier that forms a eutectic mixture with GSF -provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment's hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.
Assuntos
Griseofulvina , Sacarina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , SolubilidadeRESUMO
Enzymes are highly significant catalysts, essential to biological systems, and a source of inspiration for the design of artificial enzymes. Although many models have been developed describing enzymatic catalysis, a deeper understanding of these biocatalysts remains a major challenge. Herein we detail the formation, characterization, performance, and catalytic mechanisms of a series of bio-inspired supramolecular polymer/surfactant complexes acting as artificial enzymes. The supramolecular complexes were characterized and exhibited exceptional catalytic efficiency for the dephosphorylation of an activated phosphate diester, the reaction rate being highly responsive to: (a) pH, (b) surfactant concentration, and (c) the length of the hydrophobic chain of the surfactant. Under optimal conditions (at pH > 8 for the more hydrophobic systems and at pre-micellar concentrations), enzyme-like rate enhancements of up to 6.0 × 109-fold over the rate of the spontaneous hydrolysis reaction in water were verified. The catalytic performance is a consequence of synergy between the hydrophobicity of the aggregates and the catalytic functionalities of the polymer and the catalytic mechanism is modulated by the nature of the hydrophobic pockets of these catalysts, changing from a general base mechanism to a nucleophilic mechanism as the hydrophobicity increases. Taken as a whole, the present results provide fundamental insights, through an understandable model, which are highly relevant to the design of novel bioinspired enzyme surrogates with multifunctional potentialities for future practical applications.