| New approach to increase Magnolol’s poor water solubility and to enhance its low oral bioavailability is a constant interest of formulators in the pharmaceutical research area. In this paper, solvent evaporation method was adopted to prepare magnolol-phospholipid complex, aimed to achieve an increase in oral absorption and to improve its bioavailability.(1) A method to evaluate the binding percentage of magnolol and phospholipid (the binding efficiency) was established. Then the responses of the solvent, the feed ratio of magnolol and phospholipid, reactant concentration, reaction time and reaction temperature were examined and the preparation process was validated. The results indicated that the reaction solvent and the feed ratio of the two reactants were the crucial factors and the manufacture conditions were obtained as following:the feed ratio of phospholopid and magnolol was3:1, reacted in the tetrahydrofuran for3h under40℃.(2) An RP-HPLC method was developed and validated to determine the content of magnolol in its phospholipid complex. The validated results showed that the method’s sensitivity, accuracy, repeatability and durability were in compliance with the requirement for the assay of the magnolol-phospholipid complex.(3) Ultraviolet spectroscopy, scanning calorimetry, X-ray powder diffraction, infrared spectroscopy and nuclear magnetic resonance were used to study the physicochemical. properties of the complex; and its formation mechanism was discussed. The results revealed that magnolol was in an amorphous state and was homogeneously dispersed in the phospholipid molecules instead of maintaining its crystal characteristics after the formation of the phospholipid complex. The changes in the corresponding infrared signals indicated that the binding site could occur between the magnolol’s benzene group or its phenolic hydroxyl group and the phospholipid’s polar base. The’H-NMR spectrum showed that the H-signals’strength of magnolol-phospholipid complex was attenuated, which was probably caused by the fixation effect generated from the combination of the sites mentioned above of the magnolol and the phospholipid. Stability study showed that thermostablity of magnolol could be enhanced when the phospholipid complex formed, which might be explained by the barrier effect of fatty acid chain of the phosphlipid.(4) The water solubility study showed that both the magnolol phospholipid mixture and their complex could improve the magnolol’s apparent solubility in aqueous solution, but the mixture can increase more than that of complex. Such difference might be caused by the formation of the inter-molecular forces in the magnolol-phospholipid complex. Insignificant changes in the apparent solubility of each group in the dissolution media of pH1.2～8.0indicated that the aqueous solubility of magnolol was pH-independent under the physiological conditions, and the dissolution media of different pH without surfactant had no significant influence on the dissolution rate for each group. The stirring rate in the dissolution test had an obvious effect on the dissolution rate of magnolol-phospholipid complex, for that the mechanic force could overcome its inter-molecular forces to increase the diffusion of the complex to the media.(5) The pharmacokinetic study in Spragu-Dawley rats was conducted by testing plasma concentration of magnolol after oral administration of an equivalent dose of magnolol, magnolol phospholipid mixture and their complex respectively. The results indicated that the pharmacokinetic character of magnolol-phospholipid complex was different from that of the magnolol and its phospholipid mixture. The main pharmacokinetic parameters such as Cmax, Tmax, AUC and MRT changed obviously with a tendency of sustained release and the relative oral bioavailability increased by97%compared to the magnolol. The in vivo study revealed that magnolol-phospholipid complex could assist the magnolol to disperse in aqueous solution; however, due to its lipophilic property of magnolol, the phospholipid could decrease its rate of diffusion from complex to the cell membrane.(6) Both the convolution and the deconvolution methods were used to study the in vitro-in vivo correlation of magnolol-phospholipid complex, based on the data of accumulated release rate in vitro study, and on the data of the plasma drug concentration in vivo study. The convolution method could have a higher simulation degree compared to the deconvolution method in the case of fluctuations in the experimental data. By comparing in vitro and in vivo drug release profiles, an optimized condition with the dissolution media of1000mL1%SDS at the stirring rate of100r-min-1for in vitro release assay was suggested in order to establish indicators of the quality control of magnolol-phospholipid complex.In summary, this paper involves the following five points of innovative research and exploration:(1) It was the first to report in this paper to prepare the phospholipid complex made of magnolol;(2) The physicochemical properties of magnolol-phospholipid complex were studied and their formation mechanism was discussed in this work.(3) Pharmacokinetic study found that, the formation of phospholipid complex of magnolol showed a sustained release tendency; (4) Both the convolution/deconvolution methods were compared for in vitro-in vivo correlation study of magnolol-phospholipid complex, and a corrector based on the AUC ratio was put forward to adjust the calculation.(5) Consequently, an approach to determine the condition of the in vitro release measurement was studied based on the IVIVC study. |
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