pH-independent controlled release tablets containing nanonizing valsartan solid dispersions for less variable bioavailability in humans

Abstract

The aims of this work were to design pH-independent controlled release (CR) tablet containing nanonizing solid dispersion (SD) adsorbed on hydrophilic silica (Aeroperl® 300/30). Valsartan (VAL) was chosen to simultaneously modulate solubility and release rate due to its poor water solubility in low pH condition and short elimination half-life. Based on extensive equilibrium solubility and compatibility studies, poloxamer 407 was selected as a SD carrier. The melted mixtures of drug and poloxamer 407 were adsorbed onto hydrophilic fumed silica (Aeroperl® 300/30). Ternary SD system changed crystalline drug into an amorphous state and had intermolecular hydrogen bonding as confirmed by FT-IR with poloxamer 407. The dissolution rate of SD system was markedly enhanced as compared with pure VAL or commercial Diovan® tablet in simulated gastric fluid (pH 1.2). Interestingly, the particle size of SD system was gradually nanonized for 2 hr, ranging from 600 nm to 150 nm during dissolution process. The SD-loaded CR (SD-CR) tablets using hydroxypropylmethylcellulose (HPMC 4000) showed pH-independent zero-order release and good stability at accelerated conditions for six months. The SD-CR tablet showed minimized inter-subject variation of maximum plasma concentration as compared with commercial Diovan® tablets in healthy human volunteers.