Improved Dissolution and Oral Bioavailability of Valsartan Using a Solidified Supersaturable Self-Microemulsifying Drug Delivery System Containing Gelucire® 44/14.

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.

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

Gastroprotective effects of the isopropanol extract of Artemisia princeps and its gastroretentive floating tablets on gastric mucosal injury.

In this study, we investigated the gastroprotective effect of an isopropanol extract from the aerial parts of Artemisia princeps (IPAP) and developed a gastroretentive floating tablet of IPAP (IPAP-FR) for maximized local gastroprotective effects. Pre-treatment with IPAP ameliorated the gastric mucosal hemorrhagic lesions in ethanol/HCl- or indomethacin- treated rats. IPAP decreased mucosal hemorrhage of gastric ulcers induced by ethanol or indomethacin plus pyloric ligation in rats. The optimized floating tablet, IPAP-FR, floated on medium surface with more sustained eupatilin release compared to the non-floating control tablet. X-ray photographs in beagle dogs showed that IPAPFR was retained for > 2 h in the stomach. In the ethanol-induced gastric ulcer rat model, the gastric hemorrhagic lesion was improved more substantially with IPAP-FR compared to the non-floating control tablet. Based on these data, our data suggest that IPAP-FR has an improved therapeutic potential for the treatment of gastric ulcer.

Formulation of controlled-release pelubiprofen tablet using Kollidon(®) SR.

To develop a matrix-type, controlled-release tablet formulation of pelubiprofen (PLB), a recently developed non-steroidal anti-inflammatory drug, polymeric excipients including hypromellose, hydroxypropylcellulose, Eudragit(®) RS PO, and Kollidon(®) SR were screened. A formulation containing 12.4% w/w Kollidon(®) SR (K2 tablet) was found to be the most promising and stable for 6 months in an accelerated stability test. PLB release from K2 tablet was limited at pH 1.2, but gradually increased at pH 6.8 with a surface-erosion, resulting in the best fit to Hixson-Crowell equation. Comparative human PK studies were performed using a randomized, 2-way crossover design. LC-MS/MS assay revealed that the plasma level of PLB-transOH, an active metabolite, was significantly higher than that of PLB. After multiple dosing of immediate-release tablet (R) and K2 tablet (T), the T/R ratios of AUC were 1.02 and 1.04 for PLB and PLB-transOH, respectively. Level A in vitro-in vivo correlation was established for the K2 tablet-administered group. PK profile of PLB-transOH was not influenced by food intake, while that of PLB was altered. We suggest that K2 tablet could be administered twice a day without being affected by food intake, thereby enhancing patient compliance.

The ameliorative effect of 23-hydroxytormentic acid isolated from Rubus coreanus on cisplatin-induced nephrotoxicity in rats.

Previously, the authors demonstrated that the triterpenoid glycoside niga-ichigoside F1 (NIF1) and its aglycone 23-hydroxytormentic acid (23-HTA) isolated from the unripe fruits of Rubus coreanus (Rosaceae) ameliorate cisplatin-induced toxicity in renal epithelial LLC-PK1 cells. In the present study, the nephroprotective effects of NIF1 and 23-HTA were investigated in Sprague-Dawley rats with acute renal injury induced by a single intraperitoneal (i.p.) injection of cisplatin (7 mg/kg). Pretreatment with 23-HTA (10 mg/kg/d, per os (p.o.)) significantly reduced cisplatin-induced elevations in blood urea nitrogen (BUN) and serum creatinine level, whereas NIF1 (10 mg/kg, p.o.) slightly reduced these levels. In addition, pretreatment with 23-HTA prevented cisplatin-induced hydroxyl radical generation, malondialdehyde (MDA) production, glutathione (GSH) depletion, and cisplatin-induced changes in the activities of oxidant and antioxidant enzymes in rat renal tissues. In addition, histopathological examinations showed that 23-HTA pretreatment reduced cisplatin-induced acute tubular necrosis and histological changes. In contrast, NIF1 was found to have a slight or no influence on cisplatin-induced oxidative enzymes and acute tubular necrosis. Taken together, these results suggest that protective effect of 23-HTA pretreatment on cisplatin-induced renal damage is associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.

Anti-inflammatory effect of pelubiprofen, 2-[4-(oxocyclohexylidenemethyl)-phenyl]propionic acid, mediated by dual suppression of COX activity and LPS-induced inflammatory gene expression via NF-κB inactivation.

Pelubiprofen is a non-steroidal anti-inflammatory drugs (NSAIDs) that is related both structurally and pharmacologically to ibuprofen. Anti-inflammatory properties of ibuprofen are due to its ability to both decrease prostaglandin synthesis by inhibiting the activities of cyclooxygenases (COXs) and IκB kinase-ß (IKK-ß). However, the exact mechanisms that accounts for the anti-inflammatory effects of pelubiprofen are not reported. In this study, we investigated the molecular mechanisms how pelubiprofen modulates the inflammatory mediators in LPS-induced macrophages and carrageenan-induced acute inflammatory rat model. Pelubiprofen potently diminished PGE(2) productions through inhibition of COX enzyme activity (IC(50) values for COX-1 and COX-2 are 10.66 ± 0.99 and 2.88 ± 1.01 µM, respectively), but also reduced the expressions of COX-2, inducible nitric oxide (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 at transcriptional level in LPS-induced RAW 264.7 cells. In addition, pelubiprofen attenuated the LPS-induced transcription activity and the DNA binding activity of NF-κB, which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa B-α (IκB-α) and consequently by decreased nuclear translocation of NF-κB. Furthermore, pelubipofen inhibited the LPS-induced phosphorylation of IKK-ß and transforming growth factor-ß activated kinase-1 (TAK1). In acute inflammatory rat model, pretreatment with pelubiprofen inhibited carrageenan-induce edema, neutrophil migration, PGE(2) production, and p65, a subunit of NF-κB, nuclear translocation in inflamed paw. Taken together, our data indicated that pelubiprofen is involved in the dual inhibition of COX activity and TAK1-IKK-NF-κB pathway, revealing molecular basis for the anti-inflammatory properties of pelubiprofen.