Experimental and computational insight of the supramolecular complexes of Irbesartan with β-cyclodextrin based nanosponges

Abstract

Irbesartan (IRB), one of the extensively prescribed drugs, for treatment of hypertension has limited therapeutic potential attributed to its poor water solubility, slow dissolution rate and poor bioavailability. Cyclodextrin-based nanosponges (NSs) are novel nanosized delivery systems comprised of hyper-crosslinked solid nanoparticles with nanosized cavities. Nanosponges are widely explored to increase water solubility of active drug moieties, to protect labile actives, to achieve prolonged or sustained release and site-specific targeting. The aim of the study was to investigate enhancement of solubility of Irbesartan by its complexation with β-cyclodextrin (β–CD) based nanosponges (NS). Blank NSs were fabricated by reacting β–CD, with pyromellitic dianhydride (PMDA) and diphenyl carbonate (DPC) as cross linkers, in various molar ratios of 1:2, 1:4, 1:6 and 1:8. Solubility studies were performed to select drug nanosponge stoichiometric complex with highest degree of saturation solubilization. Irbesartan loaded nanosponges namely PMDA-CDNS and DPC–CDNS were prepared and characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powdered X-ray diffraction, scanning electron microscopy and nuclear magnetic resonance studies, to confirm the complexation of Irbesartan with nanosponges. PXRD studies revealed the shift from crystalline nature of Irbesartan to amorphous form in nanoponges. The average particle sizes of IRB–PMDA-CDNS and IRB-DPC-CDNS were 471.5 nm and 382.7 nm respectively. Zeta Potential values were 34.9 mV and −29mV for IRB–PMDA-CDNS and IRB- DPC-CDNS respectively. Entrapment efficiency varied from 9 to 38% w/w and 17 to 33%w/w for IRB–PMDA-CDNS and IRB-DPC-CDNS respectively. Complexation of IRB with β-cyclodextrin based nanosponges, as IRB-PMDA-CDNS and IRB-DPC-CDNS, resulted in significant enhancement of 81.86 and 23.35 folds, in its water solubility and 1.91- and 1.96-folds enhancement in its percent dissolution efficiency (% D.E.) respectively. Molecular docking calculations of IRB with DPC-CDNS and PMDA-CDNS have exhibited binding affinities of −8.97 and −9.51 kcal/mol respectively. Molecular dynamics simulations have revealed that IRB with PMDA-CDNS is more stable and efficient nanocarrier.