| At present,most of the new drugs or compounds obtained by combinatorial chemistry and high-throughput screening are poorly soluble drugs,and their poor water solubility leads to low bio availability.Therefore,for poorly soluble drugs,in order to improve their bioavailability,the necessary preparation methods have important research significance.SBA-15 mesoporous silica is a kind of inorganic porous material with excellent performance.It has high specific surface area and pore volume,uniform and adjustable mesoporous size,no biological activity,no toxicity,etc.It is suitable as a drug carrier to improve the dissolution rate of poorly soluble drugs.In this paper,on the basis of the synthesis of conventional SBA-15,the large mesoporous SBA-15(L-SBA-15)was prepared by adding a pore expander.The insoluble drug Fenofibrate(FNB)and Anirracetam(ANI)were model drugs,and a series of drug-loading complexes are synthesized using different drug-loading processes.The preparation process,drug-loading process,drug release performance and mesoporous structure of the carrier were studied.The mechanism of carrier materials to improve the dissolution of poorly soluble drugs was also discussed.The main research contents are as follows:(1)SBA-15 mesoporous silica was synthesized by hydrothermal synthesis method with poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)(P123)as the template,tetraethyl orthosilicate(TEOS)as the silicon source and high-temperature calcination of template.The effects of the crystallization temperature and crystallization time of the reaction system on the preparation of SBA-15 carrier were studied,and the preparation process conditions were optimized.SBA-15 drug-loaded comp lex was prepared by impregnation of FNB into the pores.The process parameters such as drug-loading solvent,drug-loading concentration,drug-loading time,and carrier input amount were optimized to obtain the best drug-loading process which were ethyl acetate as the drug loading solvent,the drug loading concentration of 100 mg/mL,the drug loading time of 24 h,the carrier input of 0.15g,and the corresponding drug loading was 29.49%.(2)On the basis of synthesizing SBA-15,the pore expansion L-SBA-15 was synthesized by adding 1,3,5-trimethylbenzene(TMB)as pore expander and the influence of the concentration of hydrochloric acid and the amount of TMB added on the pore size was studied.The results showed that the main factor affecting the pore size was the amount of pore expander TMB,and the concentration of hydrochloric acid had little effect on it.The pore size is related to mTMB/mP123.With the increase of the ratio,the pore size will expand first and then decrease.The largest pore size was 11.92 nm when the ratio was 2,while the pore size of the unexpanded carrier was only 5.04 nm.Dissolution experiments were performed on L-SBA15 drug-loaded complexes with different pore diameters.The dissolution rate of all drugloaded complexes was higher than that of the bulk drug.Considering the dissolution rate and drug loading capacity,the optimal pore expansion condition was obtained as mTMB/mP 123=2.Its release rate was faster with the drug loading of 20.88%.(3)In vitro analysis methods for aqueous solutions and different pH dissolution media(pH 1.2,pH 4.0,pH 6.8,pH 7.4)was established to investigate the dissolution behavior of SBA-15 and L-SBA-15 loaded with two model drugs(FNB and ANI).The results showed that dissolution rate of the drug-loaded complexs were significantly increased in different dissolution media,compared with the bulk drug,and L-SBA-15 drug-loaded complex showed even faster dissolution rate.(4)Fourier infrared spectroscopy(FT-IR),scanning electron microscope(SEM),high resolution transmission electron microscope(HRTEM),X-ray diffraction(XRD),N2 adsorption-desorption isotherm,thermogravimetric-differential thermal analysis and so on were used to characterize the morphology,framework structure,specific surface area,pore volume,and pore diameter of the two carrier materials before and after drug loading.The SBA-15 sample had a two-dimensional hexagonal phase mesoporous structure.After expansion,the morphology of L-SBA-15 changed from the original short rod shape to a sheetlike stack,with local foam appearing.The mesoporous pore size,pore volume and the specific surface area of SBA-15were 5.04 nm,0.62 cm3/g,683.28 m2/g,respectively and those of LSBA-15 were 11.92 nm,1.58 cm3/g,674.99 m2/g,respectively.The loaded drug was dispersed into the mesoporous pores in an amorphous state without affecting the amorphous framework structure of the mesoporous silica.The framework structure of the two carriers were complete before and after pore expansion.(5)The relationship between the mesoporous structure of the material and the drug re lease performance was analyzed based on the material characterization and dissolution results.Enlarging the pore size of mesoporous silica will reduce its specific surface area,resulting in a decrease in drug adsorption sites,and a slight decrease in the drug loading of L-SBA-15.Compared with the bulk drug,the drug loaded in SBA-15 and L-SBA-15 were filled in an amorphous non-crystalline form,which changed the crystalline state of the original drug,thereby increasing the dissolution rate of the drug.In addition,the high specific surface area and pore volume of thetwo carrier materials was favorable of high dispersion and dissolution of the drug.Compared with SBA-15,L-SBA-15 had a larger pore size and pore volume,and a smaller steric hindrance,which was more conducive to the diffusion and release of drug molecules from the pores into the dissolution medium,so it had a higher dissolution rate.The two types of SBA-15 carrier materials prepared in this research have improved the dissolution of the insoluble drugs FNB and ANI.This provides some reference for expansion of new inorganic mesoporous materials in pharmaceutical application and the development of new dosage forms and new technologies based on mesoporous materials. |
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