Colon-targeted delivery of solubilized bisacodyl by doubly enteric-coated multiple-unit tablet.

A doubly enteric-coated multiple-unit tablet (DET) of bisacodyl (BD) was formulated to selectively deliver the stimulant laxative to the large intestine. Solubilized BD in surfactants was adsorbed into the porous carrier and primarily coated with different combinations of pH-sensitive polymers (Eudragit S and Eudragit L) and time-dependent release polymer (Eudragit RS). BD-loaded granules were compressed into tablets and coated again with pH-sensitive polymers (Eudragit S:Eudragit L=1:1). The multiple-unit tablet was optimized with respect to the granular coating compositions (Eudragit S:Eudragit L:Eudragit RS=5:1:4) and coating level (12.5%), and coating level on the tablet (25%), by evaluating in vitro release profile in continuous dissolution medium. Drug release from the optimized tablet was effectively retarded in the simulated gastric and small intestinal fluids (below 7%), but profound drug liberation was attained in the colonic fluid (over 50%). On the other hand, drug release from the marketed product (Dulcolax®, Boehringer Ingelheim Pharma), a reference drug, in the gastric and small intestinal fluids was reached to 30%, while that in the colonic fluid was only 7%. In an in vivo efficacy study in loperamide-induced constipated rabbits, a remarkable recovery in fecal secretion was observed in the DET-treated group 24h post-dosing, compared to vehicle-treated (p<0.05) and the marketed product-treated groups (p<0.05). Moreover, pharmacokinetic evaluation in the constipated rabbits revealed that the DET system significantly lowered the systemic exposure compared with the marketed product (p<0.05), by hindering drug release in the upper intestine, a preferential absorption site. Therefore, the novel colon-targeted delivery system may be an alternative for boosting pharmacological responses in the colon, while diminishing the intestinal irritation and/or systemic adverse effect of the stimulant laxative.

Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.

The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA.

Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction.

Lymphatic remodeling in inflammation has been found in tracheal mycoplasma infection, human kidney transplant, skin inflammation, peritonitis, and corneal inflammation. Here we investigated lymphangiogenesis in fibrotic area in unilateral ureteral obstruction, a model of progressive renal fibrosis, and evaluated the roles of vascular endothelial growth factor (VEGF)-C and -D in the obstructed kidney. Compared to sham-operated mice, the number of LYVE-1-positive lymphatic vessels, the proliferation of LYVE-1-positive lymphatic endothelial cells, along with VEGF-C and -D mRNA expression were all significantly increased following ureteral obstruction. Depletion of macrophages with clodronate decreased lymphangiogenesis in the obstructed kidney. VEGF-C expression was higher in M2- than in M1-polarized macrophages from bone marrow-derived macrophages, and also increased in Raw 264.7 or renal proximal tubule cells by stimulation with TGF-ß1 or TNF-α. VEGF-D reversed the inhibitory effect of TGF-ß1 on VEGF-C-induced migration, capillary-like tube formation, and proliferation of human lymphatic endothelial cells. Additionally, the blockade of VEGF-C and VEGF-D signaling decreased obstruction-induced lymphangiogenesis. Thus, VEGF-C and VEGF-D are associated with lymphangiogenesis in the fibrotic kidney in a mouse model of ureteral obstruction.

In situ intestinal permeability and in vivo absorption characteristics of olmesartan medoxomil in self-microemulsifying drug delivery system.

To characterize the intestinal absorption behavior of olmesartan medoxomil (OLM) and to evaluate the absorption-improving potential of a self-microemulsifying drug delivery system (SMEDDS), we performed in situ single-pass intestinal perfusion (SPIP) and in vivo pharmacokinetic studies in rats. The SPIP study revealed that OLM is absorbed throughout whole intestinal regions, favoring proximal segments, at drug levels of 10-90 µM. The greatest value for effective permeability coefficient (P(eff)) was 11.4 × 10(-6) cm/s in the duodenum (90 µM); the lowest value was 2.9 × 10(-6) cm/s in the ileum (10 µM). A SMEDDS formulation consisting of Capryol 90, Labrasol, and Transcutol, which has a droplet size of 200 nm and self-dispersion time of 21 s, doubled upper intestinal permeability of OLM. The SMEDDS also improved oral bioavailability of OLM in vivo: a 2.7-fold increase in the area under the curve (AUC) with elevated maximum plasma concentration (C(max)) and shortened peak time (T(max)) compared to an OLM suspension. A strong correlation (r(2) = 0.955) was also found between the in situ jejunal P(eff) and the in vivo AUC values. Our study illustrates that the SMEDDS formulation holds great potential as an alternative to increased oral absorption of OLM.

Design of a Pep-1 peptide-modified liposomal nanocarrier system for intracellular drug delivery: Conformational characterization and cellular uptake evaluation.

In order to facilitate the intracellular delivery of macromolecules, Pep-1 peptide-modified liposomal (Pep1-Lipo) nanocarriers were designed and examined for their in vitro cell translocation capability. Pep-1 peptides were coupled via thiol-maleimide linkage to small unilamellar vesicles composed of phosphatidylcholine, Tween 80, and N-[4-(p-maleimidophenyl)butyryl]-phosphatidylethanolamine (MPB-PE). The amount of Pep-1 peptide conjugated to the vesicle was effectively controlled by the amounts of maleimide groups on the vesicular surface, ranging from 70 to 700 molecules per vesicle. Systems were evaluated for cell uptake capacity by monitoring entrapped fluorescence-labeled bevacizumab, a model protein for poorly permeable macromolecule, using confocal microscopy. The novel carriers rapidly bound to the cell membrane and migrated into the cells within 1 h, exhibiting better translocation of macromolecules compared to that of conventional liposomes. Cellular uptake of Pep1-Lipo was proportional to the amount of Pep-1 peptide on the liposomal surface. In conclusion, we found that the Pep1-Lipo formulation was a promising nanocarrier system for intracellular delivery of macromolecules.