艾塞那肽相转化微针的制备及处方优化

Preparation and Formulation Optimization of the Exenatide Phase-transition Microneedle Tips

艾塞那肽作为第一个治疗2型糖尿病的胰高血糖素样肽-1(GLP-1)受体激动药,得到了市场的广泛认可。本研究计划将艾塞那肽开发成相转化微针透皮贴剂,以其微创、无痛、可通过揭去而中止给药的特性,为患者提供一个理想的制剂选择。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(PVA)和透明质酸(HA)作为微针的基质材料。试验表明,采用相对分子质量400 000的HA时,既可有效促进微针溶胀释药,又可维持足够的微针强度。HA含量为5.0%的微针在15 min时的溶胀率即达250%,且在90 min时达到350%;HA含量为8.7%的微针在体外释放试验中24 h时艾塞那肽的累积释放率达90%。试验还表明,微针浇铸制备时PVA的含量也与微针溶胀释药的速率相关,且随着PVA含量的增加,艾塞那肽的累积释放率逐渐减少。当PVA含量为63.3%时既能保证微针成型,又能实现较高的药物释放速率。艾塞那肽的载药量对其体外释放的释放速度和累积释放率影响不大。

Exenatide, the first commercialized glucagon-like peptide-1 （GLP-1） receptor agonist for treatment of type 2 diabetes, has received quite positive market responses due to its blood sugar responsive efficacy, the freedom of hypoglycemia concerns. This present study was aimed to formulate exenatide into phase-transition microneedle tips to meet the needs of the patients who required such tolerance training with a minimal invasive, painless, and flexible for on-and-off dosage form. Phase-transition microneedles could penetrate skin with enough high mechanical strength at dry state. Upon piercing into the skin, the microneedles would present soft hydrogel states and offer sufficient cross- skin permeability to hydrophilic agents by absorbing body fluid and swelling from the tips to the supporting plate of the entire microneedle tip, thus opening up diffusion channels for the transdermal delivery of hydrophilic macromolecules. In terms of formulation design, since both the mechanical straight and the in-skin swelling ratio of the microneedle tips should be taken into account, we decided to use polyvinyl alcohol （PVA） and hyaluronic acid （HA） to form the matrix of the microneedles of targeted properties. By adjusting the ratio of the two polymeric components, we found that the required needle straight and drug release rate were met simultaneously when HA with Mr of 400 000 was adopted. The water swelling ratio of the microneedle tips with HA amount of 5.0 % reached 250 % for 15 min emerging, and 350 % for 90 rain emerging. An in vitro release assay showed that 90 % of the drug load was released from the tips with HA amount of 8.7% within 24 h. We also found that the content of PVA played an important role to affect the drug release rate of microneedles. Experiments confirmed that the cumulative release of exenatide decreased with the increase of PVA content and PVA content of 63.3 % was optimal for achieving required mechanic straight and drug release rate. It was slightly unexpected that exenatide loading had little effects on the rate and cumulative amount of the drug release.