| Objective:Considering the advantages of drug preparations made from drug abuse prevention materials,including low solubility and easily inflated in organic solutions,difficult to be extracted,and poor chewiness by oral medication,polyacrylic resin Ⅳ can be dissolved be dissolved only under acidic conditions with a p H of less than 5,which can not be used in injections directly.Based on these conditions,this research tried to form a quaternary ammonium crosslinking process to modify the polymer’s performances in mechanical strength,toughness and solvent resistance and find an optimal cross-linking ratio for the application in drug delivery and controlled release drugs and provide new strategies for drug abuse prevention.Methods:1.Based on the principle of quaternization reaction,polyacrylic resin Ⅳ is used as the raw material to provide tertiary amine groups,and a crosslinking agent is quaternized to obtain a quaternized polyacrylic resin Ⅳ containing latent crosslinking groups.The quaternization process was established and the gradients of the reaction solvent,crosslinker chain length,crosslinking ratio and sample drying temperature in the process conditions were investigated and optimized and the conversion rate and gelation time were used as the detection criteria to determine the optimal preparation conditions.The final prepared quaternized polyacrylic resin Ⅳ was characterized by FTIR,~1HNMR and GPC.2.The potential crosslinking group was used to obtain a crosslinked polyacrylic resin Ⅳ film after heating treatment,and the effects of drying temperature and drying time on the swelling properties of the film were studied.The structure of the finally prepared cross-linked polyacrylic resin Ⅳ was characterized by FTIR,TGA and DSC to explore the basic structure of the self-made cross-linked polyacrylic resin Ⅳ,providing relevant theoretical basis in anti-solvent extraction and drug delivery applications.3.The non-steroidal anti-inflammatory and analgesic alcohol-soluble drug aspirin was selected as the model drug,and the quaternized cross-linked polyacrylic resin Ⅳ was used as the skeleton material.The cross-linked polyacrylic resin Ⅳ-based matrix sheet was prepared through different process conditions,and its anti-abuse performance and drug release performance were preliminarily studied.4.In order to study the drug release mechanism of cross-linked polyacrylic acid resin Ⅳ-based matrix tablets,the commonly used zero-order kinetic model,first-order kinetic model,Higiuch equation and Ritger-pepas equation was used to simulate the drug dissolution curve in gastrointestinal fluid for fitting,these framework sheets were prepared by different curing temperatures.Results:1.The optimal condition for quaternary ammonium modification to synthesize a primary product with better fluidity was:N-Propanol as the reaction solvent.1,4-dichlorobutane as the crosslinking agent.The mole ratio of polypropylene resin Ⅳ to 1,4-dichlorobutane is 30:1,with a drying temperature of 40°C.2.The chlorine atom in the latent cross-linking agent1,4-dichlorobutane and the tertiary amine group in the quaternized polyacrylic resin Ⅳ occurd a quaternized cross-linking reaction after heating which greatly improves solvent resistance of polyacrylic resin Ⅳ.Also,with the extension of the thermal curing temperature and time,the swelling performance of the resin in ethanol increases first and then decreased.3.Different temperatures and durations was used to cure tablets and prepare cross-linked polyacrylic resin Ⅳ-based matrix tablets.When the curing temperature was 50℃,60℃ and 70℃,the extraction rate of the drug in ethanol within 60 min was only 2.68–5.82% for the intact tablet with a fixed cure time.However,the extraction rate in ethanol was slightly higher than that of the intact tablet,and the extraction rate of the drug within 60 minutes was 4.02–65.80% for the crushed tablets.Fixed curing temperature,when the curing time was 0.5h,1h and 1.5h,the extraction rate of the drug in ethanol within 60min was 4.24–8.03% for intact tablets,and the extraction rate of the drug within 60 minutes came to 4.02–11.07% for crushed tablets,.The cross-linked polyacrylic resin Ⅳ-based matrix tablets prepared by curing at different temperatures have a cumulative drug release of 11.04–27.35% in simulated gastric juice within 2 hours.In the simulated intestinal fluid,the cumulative release of the drug could reach 80% within 6 hours,which revealed it could be released almost completely in the intestinal juice.4.Research on drug release mechanism showed that the release of cross-linked polyacrylic resin Ⅳ matrix tablets in simulated gastric juice conformed to the zero-order kinetic equation.As the curing temperature increases during the release process,the release mechanism was transformed from matrix erosion to the synergistic effect of matrix erosion and drug diffusion.The release in the simulated intestinal fluid could be better fitted with Higuchi equation.The drug release mechanism was mainly drug diffusion,and the value of n did not change with the increase of curing temperature.Conclusion:An optimal preparation process of quaternized polyacrylic resin Ⅳ was established;after cross-linking with latent cross-linking groups,polyacrylic resin Ⅳ with cross-linked structure could be prepared,which has solvent resistance;Preliminary evaluation of the anti-abuse performance of the cross-linked polyacrylic resin Ⅳ-based frame sheet has the potential as an anti-abuse material.At the same time,the cross-linked polyacrylic resin Ⅳ matrix tablets could well resist the erosion of gastric acid,showing the potential advantages of drug-loaded drugs with greater gastric irritation;The research results of the in vitro drug release mechanism of cross-linked polyacrylic acid resin Ⅳ matrix tablets show that in simulated gastric juice,the release mechanism is the synergistic effect of drug diffusion and matrix erosion,and in simulated intestinal juice,the drug release mechanism is drug diffusion. |
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