蛋白药物相转化微针的浸泡吸附制备法

Phase-transition Microneedle Patches Loaded with Protein Drugs via Impregnation

微针透皮贴片已被证实是目前最有可能实现生物药高效非注射给药的在研制剂。目前多采用预载药物的方式制备微针,但由于存在于微针根部及中心部分的药物的扩散距离要大于位于尖端及外侧的药物,会造成释放延迟,甚至相对分子质量较大的蛋白难以通过微针的水凝胶网状基质而被释放出来。针对这一难题,本研究拟采用浸泡吸附法担载蛋白药物。处方设计上,为兼顾微针强度和溶胀释药的要求,以聚乙烯醇作为微针的主体材料,并添加羧甲纤维素钠和葡聚糖作为辅料。之后用封口膜和铝箔对相转化水凝胶微针贴片进行包裹并使针尖露出。分别以猪胰岛素和异硫氰酸荧光素标记牛血清白蛋白为模型药物,将包裹后的微针贴片浸入药液中,通过分析猪胰岛素的载入量和体外释放情况,证明了这一方法用于微针担载蛋白药物的可行性。结果表明,在释放初期(0~2 h),70%~90%的猪胰岛素被很快释出,最终90%~95%的药物得以释出。通过分析共聚焦显微镜拍摄的荧光照片可见,经由浸泡吸附法担载的药物可充分进入微针的针尖处,随着接近背衬层针体直径的加粗,大部分药物则分布于针体表层和浅表处。

Microneedle patches have proven to be the most developed agents for non-injectable delivery system in recent years. Currently, most drugs are suspended in polymer solution during microneedle preparation, while some drugs are kept in the root and the central part of the microneedles, whose diffusion distances are farther than those at the tip and surface, leading to the delay in release. And proteins with high molecular weight are difficult to pass the hydrogel network. Therefore, this study aimed to utilize impregnation method for drug loading. In formulation design, since both the mechanical straight and swelling ratio should be taken into account, we decided to use polyvinyl alcohol(PVA) to form the matrix, with sodium carboxymethylcellulose(CMC-Na) and dextran being added. The microneedle patches were then wrapped with Parafilm and aluminum foil, and each microneedle tip was exposed. For test, we chose porcine insulin and bovine serum albumin fluorescein(BSA-FITC) as model drugs. The wrapped microneedle patches were then immersed in drug solution, followed by drying method. After analyzing the loading amount and the in vitro release curves of porcine insulin, the feasibility of impregnation was proved. The results also showed that most of the loaded porcine insulin(70%-90%) could be released quickly in the early stage(0-2 h) of release, and 90%-95% of the drug can be released finally. By observing the images obtained by confocal microscope, we could get the conclusion that drug loaded by impregnation method could fully enter the microneedle tip. While the diameter of the needle close to the backing layer was thickened, most drugs were distributed at the surface.