Study On Traditional Chinese Medicine Active Monomer Drug Delivery System Based On SBA-15 Mesoporous Molecular Sieve

Objectives:Owing to tanshinone IIA?TSN?poor water-solubility and insufficient dissolution rate,the oral bioavailability of TSN is still very low under the existing dosage forms and this problem limits the clinical application of TSN.The disadvantage of solubility can be solved by sodium tanshinone IIA sulfonate?STS?,which obtained by sulfonated treatment of TSN.However,the instability of STS injection leads to the occurrence of clinical adverse reactions.Berberine hydrochloride?BBH?is the main administration form of berberine in clinic.However,the low bioavailability of BBH that caused by some reasons,such as short half-life,poor oral absorption and short duration of effective plasma concentration,is quite low.Therefore,design and synthetize new drug delivery system of TSN,STS and BBH that can improve the oral bioavailability of these drugs have important research significance.There are some special physicochemical properties of SBA-15 mesoporous molecular sieve,which is a type of novel inorganic material,such as large pore size and pore volume,highly surface area and hydrothermal stability,highly drug loading,relatively low-cost and nontoxicity template.The drug release time can be prolonged and the dissolution rate of insoluble drugs can be improved by using SBA-15.The mesopores of SBA-15 can offer a helping hand to increase the drug stability.Accordingly,the SBA-15 is used to prolong the drug release time and improve the drug dissolution rate in this research.The preparation process of model drugs/SBA-15was conducted by methodological study;the analysis method of drug-loading systems in vitro was established;the cell pharmacodynamic evaluation of drug-loading systems in vitro was assessed.Methods:1.Preformulation studies:the determination methods of drug loading of three model drugs and the analysis methods of drug dissolution rate of STS and BBH were established by using ultraviolet spectrophotometry?UV method?;the analysis method of drug dissolution rate of TSN was established by using high performance liquid chromatography?HLPC method?.2.The synthesis of SBA-15:using hydrothermal crystallization method to synthesize SBA-15 and adjust pore size of SBA-15 by changing reaction temperature,stir speed,hydrothermal crystallization temperature and time.The characterization of morphology,mesostructure,pore size,pore volume and surface area of SBA-15 were performed by using Fourier-transform infrared?FT-IR?spectroscopy,small angle X-ray diffraction?SAXRD?,scanning electron microscopy?SEM?,transmission electron microscopy?TEM?,N₂ adsorption-desorption.3.Model drug loading:the processes of drug loading were using immersion method,stir method and incipient wetness impregnation method under vacuum condition.In addition,the preparation process was screened by single factor experiments.The characterization of drug-loading systems was achieved by above methods.4.The research of release behavior in vitro of drug-loading systems:the determination of drug dissolution rate were using rocking bed method and dialysis bags method in pH 1.2,4.5 and 6.8 dissolution medium.The kinetic release mechanisms of samples were investigated using Korsmeyer-Peppas release model.5.Cytotoxicity:human normal gastric epithelial GES-1 cells and human gastric cancer BGC-823 cells were chosen as cell pharmacodynamics models in vitro,the cytotoxicity evaluation of SBA-15 and drug-loading systems was using MTT method.Results:1.Preformulation studies:under the condition of the model drug determination methods established by UV method and HPLC method,the UV detection wavelengths of three model drugs are 268,271 and 265nm respectively.The concentration and the absorbance or peak area exhibit a good liner relationship?R>0.9999,n=6?.The precision,stability and recovery all met the requirements of the ChP?2015?.The equilibrium solubility of the three drugs was STS>BBH>TSN.The equilibrium solubility of TSN was not affected by the pH value of the solution.The solubility of STS in acid solution was the highest and the BBH was the lowest.2.The synthesis of SBA-15:the SBA-15 with four appropriate pore sizes were synthesized by changing the above factors.The results of characterization shown that these SBA-15 samples have a highly ordered hexagonal mesoporous structure?p6mm space group?,and the average pore sizes are 4.61,5.02,6.39 and 7.49nm.3.Model drug loading:In single factor experiments,the drug/carrier ratio,stirring time and the pore size of SBA-15 have positive correlation with drug loading until reached the drug equilibrium state.Immersion method benefited to the drug loading of STS,however,stirring method conduced to the drug loading of TSN and BBH.The drug loading can be targeted in 30%by using incipient wetness impregnation method under vacuum condition.The characterization of drug-loading systems shown that model drugs were homogeneously dispersed in the mesopores and surface of SBA-15.The molecular structure of model drugs and the mesostructure of SBA-15 were not destroyed during the process of drug loading.4.The research of release behavior in vitro of drug-loading systems:the release time of model drugs were clearly prolonged,which are 12h?TSN?,60h?STS?and 36h?BBH?respectively.The drug release time has a negative correlation with the pore size of SBA-15.The dissolution rate of TSN can be increased by SBA-15.It is three times higher than that of row powder in 0.5h of release time,and 1.6 times higher than that in 12h.The pH value of dissolution medium has influence on the dissolution rate of STS/SBA-15 and BBH/SBA-15.STS release time is lowest and BBH release time is highest in pH 1.2.The kinetic release mechanism of TSN/SBA-15 and BBH/SBA-15 related to Fickian diffusion and STS/SBA-15s followed non-Fickian transport.5.Cytotoxicity:SBA-15 and model drugs/SBA-15 are not show a strong inhibition on the cell viability of GES-1,and the cell viability of GES-1 in model drugs/SBA-15is higher than 100%in some conditions,which shown that drug-loading systems have potential function to repair the human normal gastric epithelial cell.SBA-15 has not a strong inhibition on the cell viability of BGC-823,however,the growth inhibition of model drugs/SBA-15 on BGC-823 in a time and dose all dependent.The cell viabilities of BGC-823 are 20.47%?TSN/SBA-15?b??,21.55%?STS/SBA-15?b??and26.97%?BBH/SBA-15?b??respectively in 60?g/ml and 48h condition.Conclusions:This study makes use of the special properties of SBA-15 mesoporous molecular sieve to fabricating and assessing three drug loading systems,which are TSN/SBA-15,STS/SBA-15 and BBH/SBA-15.The drug release time of these drugs is extended and the dissolution rate of TSN is clearly increased by TSN/SBA-15 system.All drug-loading systems have a strong inhibitory effect on the cell viability of human gastric cancer BGC-823 cells and have potential anti-gastric cancer efficacy.This study has achieved the expected experimental purposes,provided new ideas for the development of new dosage forms and new drug delivery systems of traditional Chinese medicines,and built the foundations for the development of traditional Chinese medicine nano-administrations.