Interaction pattern and in vitro, in vivo release behavior of simvastatin-loaded chitosan nanoformulation.

Objective and methods: This study predicted the nature of chitosan interactions and effects of this interaction on drug release mechanism in simvastatin-loaded chitosan nanoformulation using molecular docking, spectroscopic and thermal analysis. Significance: This work explains in depth the molecular mechanism of simvastatin and chitosan bond formation in nanoformulation. Results: The effective encapsulation and sustain release properties of chitosan were indicated by increase in melting endotherm of simvastatin. Intermolecular hydrogen bond between third hydroxyl group pyranone ring of simvastatin and amino group of chitosan represented the stability of active lactone moiety that was not cleaved during formulation which is prerequisite for biological activity. UV-vis spectroscopic characterization, shift in infrared vibration wavenumber of simvastatin and chitosan, ligand titration, 1HNMR and 13C-NMR analyses confirmed this interaction pattern. The pharmacokinetic evaluation in mouse model revealed the sustain release property of nanoformulation. Conclusion: Thus formation of intermolecular hydrogen bond in nanoformulation contributed to modified physicochemical properties and improved in vivo performance of simvastatin.

Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation.

Busulfan-mediated endothelial damage is believed to be a common mechanism in a variety of vascular disorders that occur during haematopoietic stem cell transplantation. The alkylating capacity of busulfan is compromised in vivo by enzymatic conjugation with glutathione, principally catalysed by glutathione S-transferase alpha (GST alpha). We investigated whether the susceptibility of endothelial cells to busulfan-mediated damage is related to their intrinsic deficiency in GST alpha expression. We tested for the expression of GST alpha mRNA by real-time quantitative PCR and the GST protein by enzyme-linked immunosorbent assay in various independently derived endothelial cell types (human bone marrow-derived endothelial cell line and endothelial cells from human vein umbilical cord ) and in a control hepatic cell line, HepG2. We demonstrate that endothelial cells, contrary to hepatic cells do not express GST alpha either at mRNA or protein levels and hence are potentially susceptible to busulfan-mediated cytotoxic damage.

The multifunctional synergistic effect of chitosan on simvastatin loaded nanoparticulate drug delivery system.

The present study reported design and evaluation of nanoformulations of Simvastatin using different polymers. The study emphasizes upon the synergistic activity of the drug and the polymers owing to the reported anti- hyperlipidemic activity of the selected polymers. Preliminary studies advocated for chitosan formulations due to the expected particle size (543±26nm) among the three polymer formulations. Four formulations (F1-F4) were prepared varying chitosan ratio. F4 demonstrated optimal characteristics (particle size - 549±23.43nm, narrow size distribution - 0.515±0.06) and qualified for further investigation. The formulation parameters modified the intrinsic properties of chitosan. Formation of low M. wt chitosan (70,000±10,000Da) enhanced swelling & mucoadhesive properties. These influenced the drug properties in which amorphization of drug increased solubility and decreased partition coefficient. This led to better absorption at intestine sustaining the drug release up to 66.18±1.26% in SIF during the in vitro study. Better absorption was confirmed by reduction in lipid profile with several fold reduced dose in mouse model. The in vitro bile binding property of chitosan in formulation demonstrated the enhancement of hypolipidemic activity of Simvastatin. The outcomes of the study showed a successful preparation of optimum nanoformulations and also revealed possible synergistic functionalities of chitosan and the Simvastatin as potential hypolipidaemic modality without any toxic manifestations.