Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation.

A new technology was developed to form extended release hard gelatin capsules, based on the lipid matrix formation of Gelucire 50/13 and cetostearyl alcohol. Matrices were formed in situ by filling pulverised lipids, ethylcellulose and active ingredients such as diclofenac sodium, acetaminophen and metronidazol into capsules and heating at 63°C for 11 min. Effects of heating were investigated also on the brittleness of capsule shells. Inhibition of the evaporation of water reduced capsule damage. Dissolution tests and texture analysis were performed to discover the release and mechanical profiles of the matrices. Tests were repeated after 1 month storage and results were compared. Gelucire 50/13 alone prolonged drug release but cetostearyl alcohol slowed drug liberation even further. Drug release from all compositions was found to follow first-order kinetic. Significant softening of the matrices was detected during storage in composition containing only Gelucire 50/13, ethylcellulose and diclofenac sodium. Thermal analysis and IR tests were also performed to discover physicochemical interactions between active pharmaceutical ingredients and excipients. Thermal analysis confirmed a notable interaction between diclofenac sodium and Gelucire 50/13 which could be the cause of the observed softening. In conclusion, modified release hard gelatin capsules were developed by a simple and fast monolithic lipid matrix formation method.

Complexation with Random Methyl-ß-Cyclodextrin and (2-Hydroxypropyl)-ß-Cyclodextrin Promotes Chrysin Effect and Potential for Liver Fibrosis Therapy.

Liver fibrosis results from chronic liver injury and is characterized by the accumulation of extracellular matrix in excess driven by hepatic stellate cells (HSCs) activation. Chrysin (CHR) is a natural flavonoid that is limited by its low solubility to exert its anti-inflammatory, antioxidant and anti-fibrotic properties. The aim of this study was to investigate the biocompatibility of CHR complexes with two cyclodextrins (CDs)-(2-hydroxypropyl)-ß-cyclodextrin (HPBCD) and random methyl-ß-cyclodextrin (RAMEB), and their potential to induce anti-inflammatory, antioxidant and anti-fibrotic effects. Biocompatibility of the complexes was evaluated on Huh7 and LX2 cell lines: MTT and Live/Dead tests indicated the cell viability and an LDH test showed the cytotoxicity. Immunohistochemical staining of Nuclear Factor Kappa B (NF-κB) nuclear translocation was performed to evaluate the anti-inflammatory effect of the complexes. Oxygen Radical Absorbance assay, Superoxide Dismutase activity and Glutathione Peroxidase (GPx) assays indicated the antioxidant properties of the chrysin complexes. Finally, the complexes' anti-fibrotic potential was evaluated at the protein and gene level of α-sma. In HSCs, CDs induced higher cytotoxicity correlated with lower cell viability than CHR-CD. The 1:1 CHR-RAMEB pretreatment avoided p65 translocation. The 1:2 CHR-RAMEB complex increased ORAC values, improved SOD activity and produced the highest stimulation of GPx activity. CHR-RAMEB reduced α-sma expression at lower concentration than CHR-HPBCD, proving to be more efficient. In conclusion, both CHR-CD complexes proved to be biocompatible, but CHR-RAMEB showed improved anti-inflammatory, antioxidant and anti-fibrotic effects that could recommend its further use in liver fibrosis treatment.

Cyclodextrin Complexation Improves the Solubility and Caco-2 Permeability of Chrysin.

Chrysin is a bioflavonoid that can be found in natural products such as honey and propolis, and it possesses several biological effects such as antioxidant, anti-inflammatory, and anti-cancer activity. However, it is poorly soluble in water, and its bioavailability is limited. The aim of this research is to investigate the chrysin solubilization capacity of different ß-cylcodextrin derivatives and compare their biological activities. Chrysin was complexed with ß-cyclodextrin (ßCD), hydroxypropyl-ß-, (HPBCD) sulfobutylether-ß-, (SBECD), and randomly-methylated-ß-cyclodextrin (RAMEB) by the lyophilization method in 1:1 and 1:2 molar ratios. The solubilities of the chrysin-cyclodextrin complexes were tested, and the solubilization abilities of cyclodextrins were studied by phase solubility experiments. The cytotoxicity of the complexes was measured by the MTT method, and the permeability enhancement was tested on Caco-2 monolayers. The solubility study showed that the complexes formed with RAMEB had the highest solubility in water. The phase solubility experiments confirmed the strongest interaction between RAMEB and chrysin. In the viability test, none of the complexes showed cytotoxicity up to 100 µM concentration. The permeability study revealed that both at 1:1 and 1:2 ratios, the RAMEB complexes were the most effective to enhance chrysin permeability through the Caco-2 monolayers. In conclusion, cyclodextrins, especially RAMEB, are suitable for improving chrysin solubility and absorption.