Abstract
To improve the dissolution and oral bioavailability of valsartan (VST), we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMED) composed of Capmul® MCM (oil), Tween® 80 (surfactant), Transcutol® P (cosurfactant), and Poloxamer 407 (precipitation inhibitor) but encountered a stability problem (Transcutol® P-induced weight loss in storage) after solidification. In the present study, replacing Transcutol® P with Gelucire® 44/14 resulted in a novel SuSMED formulation, wherein the total amount of surfactant/cosurfactant was less than that of the previous formulation. Solidified SuSMED (S-SuSMED) granules were prepared by blending VST-containing SuSMED with selective solid carriers, L-HPC and Florite® PS-10, wherein VST existed in an amorphous state. S-SuSMED tablets fabricated by direct compression with additional excipients were sufficiently stable in terms of drug content and impurity changes after 6 months of storage at accelerated conditions (40 ± 2 °C and 75 ± 5% relative humidity). Consequently, enhanced dissolution was obtained (pH 1.2, 2 h): 6-fold for S-SuSMED granules against raw VST; 2.3-fold for S-SuSMED tablets against Diovan® (reference tablet). S-SuSMED tablets increased oral bioavailability in rats (10 mg/kg VST dose): approximately 177–198% versus raw VST and Diovan®. Therefore, VST-loaded S-SuSMED formulations might be good candidates for practical development in the pharmaceutical industry.
Highlights
Valsartan (VST), a selective blocker for the type I angiotensin II receptor, has been used for the treatment of cardiac diseases [1]
Tween® 80 was selected as a surfactant because of greater solubility (232.6 ± 20.9 mg/mL) than that of Cremophor® EL or Labrasol®
GPhEarLmaecxeuhtiibcsi2te01d8,a10g,rxeFaOtlRyPiEnEcRreRaEsVeIdEWsolubility (688.7 ± 20.7 mg/mL), which was over 2-fold gre7aotfe1r9 than that of other cosurfactants (152.5–328.2 mg/mL on average)
Summary
Valsartan (VST), a selective blocker for the type I angiotensin II receptor, has been used for the treatment of cardiac diseases [1]. VST belongs to class II of the biopharmaceutical classification system (BCS) and has a low oral bioavailability (BA) because of its limited solubility in water and acidic pH environments [2] To solve this problem, various techniques including cyclodextrin complexation, solid dispersion, microemulsification, micelles, and nanosuspension have been widely introduced [3,4,5,6]. Gelucire® 44/14 (lauroyl polyoxyl-32 glycerides; GEL) is an inert semi-solid waxy material with a melting point of 44 ◦C and an HLB value of 14 It was recently introduced as a self-emulsifying non-ionic surfactant, and is frequently used in type III lipid-based formulations including SMEDDS [10,11]. As GEL contains a well-balanced proportion of short-, medium-, and long-chain fatty acid esters, it forms an exceptionally stable, fine dispersion when in contact with the GI fluids at body temperature
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