Colon Targeting of Naringin for Enhanced Cytoprotection Against Indomethacin-Induced Colitis in Rabbits.

BACKGROUND: Naringin is a promising anti-inflammatory drug against various disorders including ulcerative colitis. However, its oral bioavailability is low (8%) possibly due to cleavage at the upper gut. Consequently, colon targeting would be necessary for drug protection at the upper gut, enhanced oral bioavailability and potentiated cytoprotection against colitis. METHODOLOGY: This study involved the formulation of compression-coated tablets of naringin employing mixtures of pH-sensitive Eudragit L100-55 (EUD-L100-55) and different time-dependent polymers including ethyl cellulose (EC), sodium alginate (ALG) and sodium carboxymethyl cellulose (SCMC). Drug-polymer interaction during release was assessed using Fourier transform-infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Tablets were evaluated in vitro. Surface morphology of the optimized tablets either before or after exposure to the different release media was examined employing scanning electron microscopy (SEM). Cytoprotection potential of the optimized tablets against indomethacin-induced colitis in rabbits was screened and compared to core tablets through a histopathological examination of colon, measurement of serum perinuclear antineutrophil cytoplasmic antibodies (pANCA) and immunohistochemical localization of tumor necrosis factor-alpha (TNF-α). RESULTS: FT-IR and DSC results may indicate drug-polymers interaction during release. Release retardation could be related to polymer swelling that was in the order of SCMC > ALG > EC. SEM examination indicated more porous coats at the buffers relative to the acidic medium. Colon targeting was expected in case of coats of 5% ALG, 5% SCMC and 10% EC (w/w) in combination with EUD-L100-55; thus, they were selected for in vivo evaluation. Effective cytoprotection of selected tablets against indomethacin-induced colitis was indicated by a significant (P<0.05) reduction in mucosal damage, serum levels of pANCA and TNF-α expression compared to untreated colitis and core-pretreated groups. Compared to EC, higher cytoprotection potential of ALG- and SCMC-based tablets was reflected by lower concentration (5% w/w) to provide cytoprotection against indomethacin-induced colitis.

Potential use of iontophoresis for transdermal delivery of NF-kappaB decoy oligonucleotides.

Topical application of nuclear factor-kappaB (NF-kappaB) decoy appears to provide a novel therapeutic potency in the treatment of inflammation and atopic dermatitis. However, it is difficult to deliver NF-kappaB decoy oligonucleotides (ODN) into the skin by conventional methods based on passive diffusion because of its hydrophilicity and high molecular weight. In this study, we evaluated the in vitro transdermal delivery of fluorescein isothiocyanate (FITC)-NF-kappaB decoy ODN using a pulse depolarization (PDP) iontophoresis. In vitro iontophoretic experiments were performed on isolated C57BL/6 mice skin using a horizontal diffusion cell. The apparent flux values of FITC-NF-kappaB decoy ODN were enhanced with increasing the current density and NF-kappaB decoy ODN concentration by iontophoresis. Accumulation of FITC-NF-kappaB decoy ODN was observed at the epidermis and upper dermis by iontophoresis. In mouse model of skin inflammation, iontophoretic delivery of NF-kappaB decoy ODN significantly reduced the increase in ear thickness caused by phorbol ester as well as the protein and mRNA expression levels of tumor necrosis factor-alpha (TNF-alpha) in the mice ears. These results suggest that iontophoresis is a useful and promising enhancement technique for transdermal delivery of NF-kappaB decoy ODN.

Potential use of gamma-cyclodextrin polypseudorotaxane hydrogels as an injectable sustained release system for insulin.

The development of injectable hydrogels for protein delivery is a major challenge. In this study, insulin/alpha-cyclodextrin (alpha-CyD) and gamma-CyD polypseudorotaxane (PPRX) hydrogels were prepared through inclusion complexation between high molecular weight poly(ethylene glycol) (PEG) and CyDs. The alpha-CyD and gamma-CyD PPRX hydrogels were formed by inserting one PEG chain in the alpha-CyD cavity and two PEG chains in the gamma-CyD cavity. Insulin/CyD PPRX hydrogel formation was based on physical crosslinking induced by self-assembling without chemical crosslinking reagent. The supramolecular structures of insulin/CyD PPRX hydrogels were confirmed with (1)H nuclear magnetic resonance ((1)H NMR), X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release study showed that the release rate of insulin from the CyDs PPRX hydrogels decreased in the order of gamma-CyD PPRX hydrogel>alpha-CyD PPRX hydrogel. This decrease was controlled by the addition of CyDs to the medium. The serum insulin level after subcutaneous administration of gamma-CyD PPRX hydrogel to rats was significantly prolonged, accompanying with an increase in the area under serum concentration-time curve, which was clearly reflected in the prolonged hypoglycemic effect. In conclusion, these results suggest the potential use of gamma-CyD PPRX hydrogel as an injectable sustained release system for insulin.

Comparison of different perrmeation enhancers on topical ketoconazole formulations.

The clinical efficacy of five ketoconazole (CAS 65277-42-1) topical formulations (three gels and two creams) was evaluated in 50 patients suffering from fungal infections in an open uncontrolled pilot study. Each formulation contained selected permeation enhancers providing high permeability in vitro. The patients were randomly divided into five groups each of ten persons. Each group was assigned to a selected topical formula which was applied to the diseased skin twice daily for four weeks or until complete clinical improvement. The clinical evaluation of treatment effects was based on the following criteria: size of lesion, erythema, scaling and severity of itching (four grades each). The patients were considered cured after the disappearance of these clinical symptoms and negative potassium hydroxide and Wood's light examination tests during the follow-up period. The results showed that the overall therapeutic response to the treatment was 96.7% and 93% for the hydroxypropylmethyl cellulose gel containing menthol and sodium carboxymethyl cellulose gel containing isopropyl myristate, respectively. Creams (w/o and o/w) achieved 90% and 87% improvement after 2.5 weeks, respectively. The lowest clinical response (86.5% improvement) with the longest duration of treatment (3 weeks) was observed with sodium carboxymethyl cellulose gel containing oleic acid.