A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul^® MCM, 45% Tween^® 20, and 45% Transcutol^® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate.

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.

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability

To improve the dissolution behavior of telmisartan (TMS), a poorly water-soluble angiotensin II receptor blocker, TMS-phospholipid complex (TPC) was prepared by solvent evaporation method and characterized by differential scanning calorimetry and powder X-ray diffractometry. The crystalline structure of TMS was transited into an amorphous state by TPC formation. The equilibrium solubility of TPC (1.3–6.1 mg/mL) in various vehicles was about 100 times higher than that of TMS (0.009–0.058 mg/mL). TPC-loaded self-microemulsifying drug delivery system (SMEDDS) formulation was optimized using the D-optimal mixture design with the composition of 14% Capryol 90 (oil; X₁), 59.9% tween 80 (surfactant; X₂), and 26.1% tetraglycol (cosurfactant; X₃) as independent variables, which resulted in a droplet size of 22.17 nm (Y₁), TMS solubilization of 4.06 mg/mL (Y₂), and 99.4% drug release in 15 min (Y₃) as response factors. The desirability function value was 0.854, indicating the reliability and accuracy of optimization; in addition, good agreement was found between the model prediction and experimental values of Y₁, Y₂, and Y₃. Dissolution of raw TMS was poor and pH-dependent, where it had extremely low dissolution (< 1% for 2 h) in water, pH 4, and pH 6.8 media; however, it showed fast and high dissolution (> 90% in 5 min) in pH 1.2 medium. In contrast, the dissolution of the optimized TPC-loaded SMEDDS was pH-independent and reached over 90% within 5 min in all the media tested. Thus, we suggested that phospholipid complex formation and SMEDDS formulation using the experimental design method might be a promising approach to enhance the dissolution of poorly soluble drugs.