马钱子碱双层聚合物可溶性微针的制备及其在不同载药方式下的体外经皮渗透性研究

Study on the Preparation of Brucine Bilayer Polymer Soluble Microneedle and Its in vitro Transdermal Permeability under Different Drug Loading Modes

目的:制备马钱子碱(Bru)双层聚合物可溶性微针,并考察其在不同载药方式下的体外经皮渗透特性。方法:以微针揭膜难易程度、阵列完整性、气泡量、针型、针尖硬度、背衬韧性等为考察指标分别筛选微针的针尖材料和背衬材料,并以微针形态为考察指标筛选基质溶胀方法和干燥方法,然后采用两步法制备双层聚合物可溶性微针,并进行表征和安全性评价。通过Franz扩散池法考察针尖载药、背衬载药、全载药Bru双层聚合物可溶性微针的体外经皮渗透特性,绘制体外透皮曲线并计算累积渗透量(Q)和累积渗透率。结果:优选的双层聚合物可溶性微针的制备工艺为以硫酸软骨素-聚乙烯吡咯烷酮K30(1∶1,m/m)作为针尖材料,15%聚乙烯醇作为背衬材料,在4℃冰箱静置1 h进行基质溶胀,干燥器室温干燥24 h。所制微针阵列完整,机械性能良好,能成功刺穿铝箔和大鼠皮肤,微针处理后皮肤在6 h内即可恢复到原来的状态。体外透皮试验结果显示,微针递药可大大提高Bru的经皮累积渗透量,针尖材料可在10 min内溶解并释放药物;针尖载药微针在8 h内基本释放完全,Q8 h为102.185μg/cm^2,累积渗透率达到94.05%;背衬载药、全载药微针在8 h内的药物累积渗透率均超过50%,48 h药物累积渗透率均超过90%,Q48 h分别为840.77、1156.73μg/cm^2,显示出缓释特性。结论:成功制备了针尖层硬、背衬层软的Bru双层聚合物可溶性微针,通过全载药的方式可实现药物的有效经皮递送并达到缓释效果。

OBJECTIVE:To prepare Brucine(shorted for"Bru")bilayer polymer soluble microneedles,and to investigate their in vitro transdermal permeation characteristics under different drug loading modes.METHODS:Taking the degree of difficulty of microneedle film uncovering,array integrity,bubble amount,needle shape,tip hardness and backing toughness as the indexes,tip and backing materials were screened.The swelling method and drying method of matrix were screened using the morphology of microneedles as index.The double-layer polymer soluble microneedle was prepared by two-step method,then it was characterized and evaluated in the safety.The in vitro transdermal permeation characteristics of tip-loaded,backing-loaded and full-loaded Bru bilayer polymer soluble microneedles were investigated by Franz diffusion cell.The in vitro skin penetration curve was drawn,and the cumulative permeability amount(Q)and cumulative permeability rate were calculated.RESULTS:The optimal preparation technology of bilayer polymer soluble microneedles included chondroitin sulfate(CS)and polyvinylpyrrolidone K30(PVP K30)(1∶1,m/m)as tip materials,15%polyvinyl alcohol(PVA)as backing material,matrix swelling in the refrigerator at 4℃for 1 h,and drying at room temperature for 24 h in dryer.Prepared microneedle array was complete and had good mechanical properties,and could successfully puncture aluminum foil and rat skin.After microneedle treatment,the skin could return to its original state within 6 h.The results of in vitro transdermal test showed that microneedle drug delivery could greatly increase the cumulative transdermal permeability amount of Bru,and the tip material could dissolve and release the drug within 10 min;the tip-loaded microneedle was basically released within 8 h,Q8 h was 102.185μg/cm^2 and the cumulative permeability rate reached 94.05%;the drug cumulative permeability rate of backing-loaded and full-loaded microneedles exceeded 50%within 8 h and exceeded 90%within 48 h;Q48 h were 840.77 and 1156.73μg/cm^2,showing sustained-release characteristics.CONCLUSIONS:Bru bilayer polymer soluble microneedles with hard tip and tough backing material are successfully prepared to achieve effective transdermal delivery and sustained release through full-loaded mode.