| Objective:In recent years,researchers have taken advantages of the large specific surface area and rigid pores of mesoporous silica carriers to limit the crystallization of drugs,which are primarily delivered in an immediate manner through improving the dissolution rate of poorly soluble drugs or via surface functionalization to construct more sophisticated drug carriers to modulate drug release and adsorption characteristics.However,the interactions between mesoporous silica and drugs for regulating drug release were less reported.Therefore it's a meaningful work to investigate the factors affecting drug release and the interactions between mesoporous silica and model drugs for drug release behaviors.Methods:In this work,a five-level four-factor central composite design?CCD?was carried out to investigate the influences of the four factors including hydrogen bond acceptor?HBA?count?X1?,MCF pore size?X2?,drug loading degree?X3?and dissolution stirring rate?X4?as well as their cross-interactions for drug release behaviors.The factors were chosen from all drug release aspects consisting of drug,carrier,formulation and dissolution,respectively.And cumulative release over 1 h?Y1?,cumulative release over24 h?Y2?and rate constant k?Y3?were selected as dependent response variables.The sol-gel method was adopted to synthesize the MCFs with P123 as the soft template.The influences of trimethylbenzene?TMB?,ammonium fluoride,reaction temperature and hydrothermal reaction for the pore diameters of MCFs were investigated by single factor experiments.Then,a series of MCFs with various pore diameters?4 nm,7 nm,12 nm,17 nm,22 nm?were prepared,and the morphologies,internal structures and pore size distributions were systematically analyzed by SEM,TEM and BET methods.Five of BCS II drugs including disulfiram,loratadine,celecoxib,metronidazole and nimodipine were selected as model drugs possessing different numbers of HBAs?0,2,3,4 and 6?respectively.A solvent deposition method was applied to load the model drugs into MCF carriers.The drug-loaded samples were characterized by the DSC and XRD methods.In addition,the actual drug loading degrees were assayed.The drug release behavior was examined by in vitro dissolution.Interactions between the model drugs and the MCFs for drug release behavior were analyzed in detail using response surface plots.The influences of HBA count,MCF pore size,drug loading degree and dissolution stirring rate as well as their cross-interactions for drug release behaviors based on MCF carrier were investigated.Results:In this context,4MCF,7MCF,12MCF,17MCF and 22MCF were successfully synthesized.The BET method indicated that the pore size of all prepared MCFs met the requirements of 4.24 nm,7.71 nm,11.42 nm,15.68 nm and 22.92 nm,respectively.SEM and TEM results showed that the morphologies transformed from long tube particles to irregular and spherical agglomerated particles which seemed like a cauliflower,the channel morphologies changed from 1D channel parallel to the axial of the rod structures to 3D mesocellular foams as the pore size increased.The drug loaded samples were successfully prepared by solvent evaporation method and their drug loading degrees were all in accordance with the results in design.The DSC and XRD indicated that model drugs not existed endothermic peaks and characteristic diffraction peaks,but when the drug loading degree increasing to 40%,DSC exsited melt point endothermic peak and XRD showed characteristic diffraction peaks of the model drugs.The in vitro release assays showed that the samples of disulfiram,loratadine,celecoxib,metronidazole and nimodipine loaded in various MCFs all cumulative release were close to the complete release in 30 min.However,the samples derived from celecoxib interestingly displayed a controllable and sustained release manner.In particular,when celecoxib was loaded in 12MCF with a highly loading degree of 50%,the cumulative release was generally increased and the process completely finished until 24 h achieving to 100%.Moreover,the drug release behaviors during the first 30 min is in accordance with the Higuchi model as the maximum R2,so the rate constant k was calculated by the Higuchi model.Conclusion:?1?The results of the single factor experiments demonstrated that the pore diameters presented a tendency of firstly increase via decrease and then increase along with the increase of TMB doses;the reaction temperature showed a positive correlation with the pore size;ammonium fluoride and the hydrothermal reaction could enlarge the pore size of MCF.?2?A series of MCFs?4MCF,7MCF,12MCF,17MCF and 22MCF?was successfully synthesized and characterized.?3?A drug release model between the mesocellular foam silica?MCF?carrier and the BCS II drugs was successfully constructed by CCD.CCD results demonstrated that HBA counts?X1?,MCF pore sizes?X2?,and drug loading degrees?X3?greatly affected the cumulative release over 1 h and the effective order was X2>X3>X1,when a drug own the medium number of hydrogen bond acceptors loaded into the MCF own a larger pore size with a higher drug loading degree,a lower cumulative release over 1 h was obtained.The cumulative release over 24 h?Y2?was primarily influenced by X1 and X2.Furthermore,the pore diameter?X2?was the most significant factor.It was found that the larger pore sizes corresponding to smaller or larger numbers of HBAs and smaller pore diameters corresponding to intermediate numbers of HBAs may contribute to achieving complete release over 24 h.The rate constant k is affected by X1 and X3 and X3>X1.When the drug loading is larger and the HBAs count is at an intermediate level,the smaller rate constant k was achieved.The result is consistent with the results of 1 h cumulative release. |
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