[发明专利]一种加速聚乙烯醇可溶性微针成型和速溶给药的方法及制备的微针

说明书

本发明公开一种加速聚乙烯醇可溶性微针成型和速溶给药的方法及制备的微针。本发明首先公开了加速聚乙烯醇可溶性微针成型和速溶给药的方法包括将至少一种水溶性二价无机盐或其水合物，或海藻酸钠与聚乙烯醇组合使用。本发明还提供了上述方法制备的微针。本发明在制备聚乙烯醇可溶性微针时通过在聚乙烯醇中添加至少一种水溶性二价无机盐或其水合物或海藻酸钠，使得聚乙烯醇结晶度降低，结构规整性被破坏，聚乙烯醇链段活性增强，从而加速聚乙烯醇可溶性微针成型、实现速溶给药以及提高针体耐湿稳定性，同时保持了良好的微针基底柔韧性及针尖机械强度。另外，本发明方法简单、快速，便于大规模生产，拓宽了聚乙烯醇在可溶性微针领域的应用。

技术领域

本发明涉及医药技术领域。更具体地，涉及一种加速聚乙烯醇可溶性微针成型和速溶给药的方法及制备的微针。

背景技术

聚乙烯醇(PVA)是一种生物可降解的合成高分子材料，具有良好的水溶性、生物相容性、成膜性、热稳定性以及机械性能，被广泛应用于可溶性微针的制备。

聚乙烯醇分子链中存在大量的亲水性羟基基团，易交联形成分子链内、间氢键，使得聚乙烯醇结晶度较高，具有明显的结构规整性，1)使得聚乙烯醇溶液中水分子的流动性减弱，水蒸气渗透性能不佳(Hongguang Dai,Juan Wang,Lirong Wang.Preparation andProperties of PVA Films Using Hydroxyalkylformamides as the Plasticizers[J].Polymer Engineering and Science,2018，58:145-150.)，表现为聚乙烯醇溶液在微针成针过程中干燥时间较长，常需在室温、吹风条件下干燥一整晚(Evin A.Allen,Conor O’Mahony,Michael Cronin,et al.Dissolvable microneedle fabrication usingpiezoelectric dispensing technology[J].International Journal ofPharmaceutics,2016,500:1-10；BoZhi Chen,Mohammad Ashfaq,XiaoPeng Zhang,etal.In vitro and in vivo assessment of polymer microneedles for controlledtransdermal drug delivery[J].Journal of Drug Targeting,2018,26(8):720-729.)或在真空干燥箱(30-40℃)条件下干燥24小时(Sejal Amodwala,Praveen Kumar,HetalP.Thakkar.Statistically optimized fast dissolving microneedle transdermalpatch of meloxicam:A patient friendly approach to manage arthritis[J].European Journal of Pharmaceutical Sciences,2017,104:114-123；Mei-Chin Chen,Kuan-Ying Lai,Ming-Hung Ling,et al.Enhancing immunogenicity of antigensthrough sustained intradermal delivery using chitosan microneedles with apatch-dissolvable design[J].Acta Biomaterialia,2018,65:66-75.)方能干透，降低了聚乙烯醇微针的生产效率，不适用于规模化生产，且干燥中长时间的暴露，极易导致微针中药物活性的降低；2)相关文献报道，聚乙烯醇可溶性微针的稳定性较差，极易吸收空气中水蒸气发生溶解，导致微针机械强度降低，丧失皮肤穿刺性，研究表明在40％的湿度条件下，微针放置10分钟便失去皮肤穿刺性(QiLei Wang,JiaWei Ren,Bozhi Chen,et al.Effectof humidity on mechanical properties of dissolving microneedles fortransdermal drug delivery[J].Journal of Industrial and Engineering Chemistry,2018,59:251-258.)，这给聚乙烯醇微针的生产、储存以及使用过程带来了极大的不便；3)此外，聚乙烯醇微针成形过程中，随着溶液中水分子的蒸发，聚乙烯醇分子链内、间羟基进一步交联形成强的氢键相互作用，导致聚乙烯醇微针的皮内溶解速度较慢，无法实现速释给药(Shinying Lau,Jie Fei,Haoran Liu,et al.Multilayered pyramidal dissolvingmicroneedle patches with flexible pedestals for improving effective drugdelivery[J].Journal of Controlled Relaese,2017,265:113-119.)，针对该问题，已有相关文献报道通过添加聚乙烯吡咯烷酮(PVP)等亲水性材料实现聚乙烯醇微针的加速溶解(Shubhmita Bhatnagar,Amala Saju,Krishna Deepthi Cheerla,et al.Cornealdelivery of besifloxacin using rapidly dissolving polymeric microneedles[J].Drug Delivery and Translational Research,2017；Sejal Amodwala,Praveen Kumar,Hetal P.Thakkar.Statistically optimized fast dissolving microneedletransdermal patch of meloxicam:A patient friendly approach to managearthritis[J].European Journal of Pharmaceutical Sciences,2017,104:114-123；Mei-Chin Chen,Ming-Hung Ling,Setiawan Jati Kusuma.Poly-γ-glutamic acidmicroneedles with a supporting structure design as a potential tool fortransdermal delivery of insulin[J].Acta Biomaterialia,2015,24:106-116.)，但聚乙烯吡咯烷酮的加入，使得聚乙烯醇微针机械强度降低，皮肤穿刺效果变差(I.-Chi Lee,Jheng-Siou He,Meng-Tsan Tsai,et al.Fabrication of a novel partiallydissolving polymer microneedle patch for transdermal drug delivery[J].Journalof Materials Chemistry B,2015,3:276-285)。以上三点严重制约了聚乙烯醇可溶性微针的产业化发展。