| Honokiol (HNK), a bioactive lignanoid extracted from the well knownChinese herb Magnolia officinalis or from other species of theMagnoliaceae family, has a large number of pharmacological propertiessuch as anti-cancer effects, anti-infammatory effects, anti-oxidant actions,and anti-anxiety effects. However, the poor aqueous solubility of honokiolhas seriously hindered its clinical application and further study. To improvethe solubility of HNK, several drug delivery systems have beeninvestigated, including self-assembled micelles, nanoparticles, andmicroparticles. To improve the solubility and bioavailability of HNK,hydroxy-propyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin havebeen used to prepare inclusion complex. After these inclusion complexshave been prepared, the solubility and the bioavailability of HNK has beenimproved. It has met very well to the requirement of clinical applicationand further study.The main contents of this study were listed below:1. An effective andprecise UV spectrophotometric analytical method was developed to detecting the content of honokiol and investigated the solubility ofhonokiol in HPCD solution;2. A reasonable preparation method waschosen from stirring method, ultrasonic method and grinding method forHNK-HPCD. The formulation and processing parameters were optimizedby central composite design based on the inclusion efficiency;3.HNK-HPCD validation and its in vitro release behavior;4. HNK-HPCDpharmacokinetic studies in rats;5. Preparation of HNK-SBECD andoptimized by central composite design;6. HNK-SBECD characterisationand its in vitro release behavior;7. pharmacokinetic study of HNK-SBECDin rats.An UV spectrophotometric method for the determination of HNK wasestablished. The solubility of honokiol in HPCD solution was investigatedby phase-solubility experiments at different temperatures. A reasonablepreparation method was chosen from stirring method, ultrasonic methodand grinding method for HNK-HPCD. The formulation and processingparameters were optimized by central composite design based on theinclusion efficiency. Taking into account the ultrasonic method andgrinding method was not conducive to industrial production, and thestirring method with better stability and repeatability, so the stirring methodwas chosen to be the prepare method. The formulation and processingparameters were optimized by central composite design based on theinclusion efficiency. HNK-HPCD and HNK-SBECD inclusion complex solution wereprepared by stirring method, and the inclusion complex in solid state wereobtained by a freeze drying method. HNK-HPCD and HNK-SBECD werecharacterized by X-ray diffraction (XPD), differential scanning calorimetry(DSC) or Fourier transform infrared spectroscopy (FT-IR). The in vitrodrug release studies were evaluated using the dialysis membrane methodand model fitting were systematically explored and evaluated.Pharmacokinetics studies of HNK-HPCD, HNK-SBECD, and HNKsuspension were performed using Sprague-Dawley male rats. Particularly,HNK-HPCD and HNK-SBECD solution were prepared using stirringmethod, pharmacokinetic behaviors were evaluated after oraladministration in rats. HNK suspension was dealt with the same processas control. Furthermore, the pharmacokinetics of HNK-HPCD andHNK-SBECD following intravenous injection in rats were alsoinvestigated. An RP-HPLC method of evodiamine as an internal standardwas established to detecting the content of HNK in plasma, the meanplasma concentration-time profiles were analyzed by non-compartmentalmodel. The results indicated that HPCD and SBECD significantlyincreased the solubility and absorption of HNK. In detail, the AUC0-tofHNK-HPCD and HNK-SBECD were2.13and1.58folds higher than thoseof HNK suspension, respectively.Series of experiments in this paper show that the method of preparation was simple but also effectiveness. After HNK-HPCD andHNK-SBECD have been prepared, the apparent solubility of HNK weresignificantly increased and also improved the bioavailability of HNK. |
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