Quercetin (QC) is a typical plant flavonoid, possesses diverse pharmacologic effects including antiinflammatory, antioxidant, anti-cancer, anti-anaphylaxis effects and against aging. However, the application of QC in pharmaceutical field is limited due to its poor solubility, low bioavailability, poor permeability and instability. To improve the bioavailability of QC, numerous approaches have been undertaken, involving the use of promising drug delivery systems such as inclusion complexes, liposomes, nanoparticles or micelles, which appear to provide higher solubility and bioavailability. Enhanced bioavailability of QC in the near future is likely to bring this product to the forefront of therapeutic agents for treatment of human disease.
In the present study, we prepared an inclusion complex of methotrexate (MTX) with β-cyclodextrin (β-CD) in order to decrease its photosensitivity and enhance its aqueous solubility. Then we incorporated this inclusion complex in a self-microemulsifying drug delivery system (SMEDDS) overall to increase its oral bioavailability. The inclusion complex has been prepared by freeze drying method and characterized by differential scanning calorimetry (DSC), ultraviolet (UV), and infrared (IR) spectroscopy assays. The proper molecular ratio of MTX/β-CD was found to be of 1:7, and the water-solubility of MTX was increased in an average of 10-fold. The photostability studies showed that the MTX became stable on exposure to light. Construction of pseudoternary diagrams were investigated to prepare a MTX/β-CD inclusion complex loaded SMEDDS which was characterized by measuring the particle size and the zeta-potential. The optimum formulation of SMEDDS was a system consisting of ethyl oleate, tween 80, and propylene glycol with a mean droplet size of 39.42 nm. In vitro drug release in different pH media showed that the release profile of MTX from the MTX/β-CD loaded SMEDDS was influenced by the pH of the release medium and presented the characteristics of a sustained release profile. Finally, in-vivo studies showed an enhancement of the bioavailability of MTX from the MTX/β-CD loaded SMEDDS form of 1.57-fold. We concluded that the β-CD inclusion complex loaded SMEDDS improved the chemical and physiological properties of MTX and could be a promising means for the delivery of MTX and other unstable and lipophilic drugs by oral route.
The purpose of this study was to develop a liquid self-assemble proliposome for quercetin oral delivery. This liquid proliposome was prepared by dissolving phospholipids, surfactants and drug in ethanol. There was only one step in the preparation process of this liquid self-assemble proliposome and no special devices were required. The mechanism about proliposome transformation was discussed. Quercetin proliposomes with different cremorphor RH40 concentrations (0%, 20%, 23%, 26%, 30%) were prepared. The particle size and polydispersity index decreased as cremorphor RH40 concentration increased. Meantime, the drug entrapped efficiency decreased slightly with an increase in cremorphor RH40 concentration. The in vitro drug release showed prolonged drug release in case of proliposome and the release of quercetin was slower when cremorphor RH40 concentration was higher. The absorption of quercetin and its in vivo bioavailability were significantly improved by proliposome, which was evidenced by the in situ intestinal absorption and pharmacokinetic study. Besides, the obtained quercetin proliposome was with good stability when stored at room temperature. In conclusion, quercetin liquid self-assemble proliposome was successfully prepared. It could transform into liposomal vesicle with satisfied particle size and polydispersity index instantly when cremorphor RH40 was added. Cremorphor RH40 concentration in the formulation should below 26% to get higher drug entrapped efficiency (>90%) and less irritation. The drug release was affected by the cremorphor RH40 concentration and the required drug release could be obtained by adjusting cremorphor RH40 content. The enhanced bioavailability showed liquid self-assemble proliposome could be a promising vehicle for the oral delivery of quercetin.
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