Studies On Honokiol Self-microemulsifying Drug Delivery System And Its Solidfication

Magnolia, a Chinese traditional medicine, has been used to cure avariety of diseases. Honokiol is one of its main active ingredients, but thereare no commercial products due to its poor water solubility.Self-microemulsifying drug delivery system (SMEDDS) consists ofsurfactant, co-surfactant, oil phase and drug, which forms finemicroemulsions spontaneously in water under mild agitation. SMEDDS cansignificantly increase the solubility of the insoluble drugs and improve theirabsorption in the gastrointestinal tract.We can combine SMEDDS with solid materials to form solidself-emulsifying tablets, pellets and microspheres by different ways andmeans. Compared with the traditional SMEDDS, solid self-microemulsionformulation is more convenient to carry, more stable and easier to beaccepted.In order to enhance the solubility and oral bioavailability of honokiol,we have prepared honokiol SMEDDS, investigated its optimizedprescription, evaluated its quality in vitro and pharmacokinetic behaviors invivo. Furthermore, we combined the polysaccharide polymer materials withSMEDDS to prepare solid preparation. Our research provided a theoretical basis for developing a novel honokiol SMEDDS in clinical applications.Specific studies included the following two parts:Part I Preparation and characterization of honokiolself-microemulsifying drug delivery system1The concentration of honokiol in vitro samples was determined byUV method. The maximum wavelength of honokiol was294nm in UVspectrophotometry. The calibration curve was given by the equation A=0.0292C-0.0038, with a correlation coefficient, r=0.9996, where theconcentration range of4.0~28.0μg/ml. Meanwhile, precision and recoveryrate were met the requirement of methodology.2The formulation of honokiol SMEDDS was screened by solubilityexperiment, compatibility test and pseudo-ternary phase diagrams. And thebest formulation was determined by the particle size and in vitro releaseevaluation. We selected MCT as oil phase, Cremophor RH40as surfactant,Transcutol P as co-surfactant, and the ratio of surfactant and co-surfactant(Km) was2. The components consisted of MCT (20.0%), Cremophor RH40(53.3%) and Transcutol P (26.7%).3We identified the microemulsion type by staining method,investigated the rate of self-emulsifying and preliminary stability ofhonokiol SMEDDS. The results showed that honokiol SMEDDS formed O/W microemulsion after emulsification and its stability was good.4The concentration of honokiol in vivo samples was determined by HPLC method. The calibration curve was given by the equation Y=0.3890C+0.0249, with a correlation coefficient, r=0.9996, where theconcentration range of0.0355~9.0909μg/ml. The method was accurate andreliable, specific and reproducible, which met the requirement of plasmaconcentration analysis. Honokiol SMEDDS and honokiol suspension wereorally administrated to rats and the bioavailability of the former was1.25times compared with that of the latter, which was efficient in improving thebioavailability of honokiol.Part Ⅱ Preparation and characterization of calcium-gellan beadscontaining honokiol self-microemulsifying drug delivery system1Calcium-gellan beads containing honokiol SMEDDS has beenprepared by ionotropic gelation. Polymer concentration, drug loading,CaCl2concentration and cross-linking time were selected as variables forsingle-factor experiments design. The entrapment efficiency of the resultantbeads has been studied. The optimal preparation method was decribed asfollows: gellan gum concentration was1.25%, CaCl2concentration was8%,the weight ratio of honokiol SMEDDS and gellan gum solution was0.15andcross-linking time was15min.2We studied the swelling and release characteristics of optimizedGB-HSMEDDS in pH1.2HCl solution and pH6.8PBS. The results showedthe swelling degree of GB-HSMEDDS in PBS was significantly greater thanthat in HCl solution (p＜0.01) and the cumulative release of honokiol was more than50%in HCl solution but less than20%in PBS at the time point of2h.