| Liquid crystalline is a thermodynamic stable system having definite shape and structure, which is assembled by lipid bilayer. The lipid bilayer is spontaneously formed in water by a certain concentration amphipathic lipid. The liquid crystalline has unique three dimensional and bicontinuous grid structure, which contains hydrophilic channels linking each other. The special structure can solubilize and disperse different polarities and particles drug molecules. Meanwhile, the biocompatibility of liquid crystalline is so good that it can promote drugs to penetrate biomembrane. As a drug delivery system, liquid crystalline has been paied general attention in recent years.Because of its special mechanism of action, liquid crystalline can be used as carrier for drugs with low oral absorption. Liquid crystalline has been a new way to improve the bioavailability of insoluble drugs. According to previous study, it is reasonable to think that GMO/P407 liquid crystalline matrices (GMO/P407 LCMs) can transfer to cubic gel after encountering water, then the cubic gel is dispersed as cubic nanoparticles under the effect of lipase, bile salt as well as gastrointestinal peristalsis. Silymarin was chosen as model drug in this project. The GMO/P407 LCMs were prepared by melting/congealing method. In vitro characterizations with DSC and powder X-ray diffractometry were performed to identify the physical state of silymarin in the lipid matrix. The release and lipolysis process in vitro were also studied. Finally, the oral bioavailability of silymarin was evaluated in beagle dogs.In the first part, GMO/P407 LCMs were prepared by melting/congealing method. Factors which might influence the formation of LCMs were studied, including P407/GMO ratio, drug/carriers ratio and several parameters such as the melting temperature of carriers, the melting time of carriers, the solvent of dissolving drugs, rotary evaporation time as well as congealed time. The response was no drug precipitation and forming of transparent gel after encountering water. Results indicated that, the forming of LCMs was mainly influenced by P407/GMO ratio and drug/carriers ratio. Based on the drug-loading rate and the results reported before, the optimum formulation was as follows: P407/GMO (w/w) 0.06/0.5, SM/(P407+GMO) (w/w)<10%.In the second part, three formulations (SM/(P407+GMO),2%(F1),4%(F2), 8%(F3)) of LCMs were prepared. The release characteristics, lipid digestion and stability were investigated. The results of micropolariscope indicated that the three formulations after encountering water were isotropic. The characteristic is one of the typical features liquid crystalline possesses. The differential scanning calorimetry and X-ray diffraction showed that silymarin was amorphous in GMO/P407 LCMs. The release results showed that the cumulative percent dissolution of LCMs was less 5% in 12h which was so little compared with the 20% of silymarin crude drug. The obviously retarded release suggested increased affinity of silymarin with the liquid crystalline matrices. GMO was digested rapidly and digestion completed at about 40 min. After centrifugation, the mixture was separated into an aqueous phase and a pellet phase. No oil phase was observed.In the third part, oral bioavailabilities of SM LCM, SM cubic gel and Legalon(?), a commercial silymarin product, were compared in Beagle dogs (at a dose of 14.4mg/kg calculated as silybin). Single dose of silymarin was given to 6 beagle dogs in a cross-over experimental design. The drug levels in plasma were assayed by a validated HPLC method. Pharmacokinetic analysis was performed by means of statistical monents using DAS 2.1.1 computer program. Results showed that there was a 3.46-fold increase in bioavailability for SM LCM compared with Legalon(?). It is indicated that SM LCM prepared by the method of melting/congealing can improve the SM oral bioavailability.
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