日夜两用生长激素微针贴片的制备及体外评价

Microneedle Patch for Daytime and Nighttime Transdermal Delivery of Growth Hormone

关键词:  药物递送  生长激素  微针  经皮递送  日夜两用

Key words:  drug delivery  growth hormone  microneedle  transdermal delivery  daytime and nighttime dosing

摘要:

目的 制备日夜两用生长激素微针贴片，模拟人体生理状态下内源性生长激素分泌的昼夜差异，实现生长激素给药时间和用量的优化，同时有效减轻皮下注射给药疼痛感，提高患者使用依从性。方法 采用铸模法制备微针贴片，通过光学显微镜和扫描电子显微镜观察微针表面形貌。经体外释放试验确定含生长激素微针制备的最佳工艺条件，包括优化紫外交联时间和交联剂含量。通过微针力学强度测试和体外透皮试验验证微针贴片有效穿透皮肤的可行性，通过圆二色光谱测定药物的稳定性。通过调试负载不同剂量生长激素制备日用和夜用微针贴片。结果 在显微镜下观察到微针排列整齐，针体完整、尖锐，微针在药物释放前后形貌无明显差异。工艺优化结果表明，当紫外交联时间为7 min，交联剂用量为1.5%时，微针贴片可以有效穿透离体大鼠皮肤，同时实现了生长激素在12 h内稳定释放，且微针释放出的蛋白药物构象无明显变化。通过在针体中负载不同剂量生长激素，制备了日用和夜用生长激素微针贴片。结论 本研究制备的微针能够顺应在生理状态下生长激素分泌的日夜差异，实现了适宜时间释放适量生长激素的目标，未来可进一步优化微针药物负载量以满足不同患者的实际使用需求，以期实现个体化治疗。

Abstract:

OBJECTIVE To design microneedle patches for daytime and nighttime administration of growth hormone to stimulate the circadian rhythm of endogenous growth hormone secretion under human physiological state, effectively alleviate the pain of subcutaneous injection and improve the compliance of patients. METHODS Microneedle patches were prepared by the casting method. The surface morphology of microneedles was observed by the optical microscope and scanning electron microscope. The optimum process conditions for the preparation of microneedles were determined by in vitro release experiments, including optimizing the UV irradiation duration and the content of the crosslinking agent. The mechanical strength test and ex vivo penetration experiment were applied to verify whether the microneedles can effectively penetrate the skin and achieve transdermal drug delivery. The biostability of the protein drug was assessed by the circular dichroism spectroscopy. Two types of microneedle patches for daytime and nighttime administration respectively were prepared by loading different doses of growth hormone. RESULTS The microneedles were orderly arranged with the complete and sharp needles observed by the microscope, and there was insignificant morphology change after drug release. Through the optimization of process conditions, when the UV irradiation duration was 7 min and the content of the crosslinking agent was 1.5%, the microneedle patch could effectively penetrate the rat skin and realize the stable release of growth hormone within 12 h, and the conformational change in the released protein drug was insignificant. By loading different doses of growth hormone into the microneedle patches, daytime and nighttime dosing patches had been prepared. CONCLUSION In this study, the daytime and nighttime microneedle patches loading different dosages of growth hormone were prepared, which can comply with the circadian rhythm of growth hormone secretion in human physiological state, optimize the relationship between the administration time and dose of growth hormone, and realize on demanding releasing of growth hormone. In the future, the drug loading of microneedle patches can be further optimized to meet the personalized needs of people and realize individualized treatment.