Abstract: Octreotide (OCT) is widely used for the treatment of acromegaly, neuroendocrine tumors such as gastrinoma, and ruptured esophagogastric variceal bleeding in clinical. However, due to the short half-life of octreotide, the patients need frequent dosing in the treatment of diseases requiring long-term medication such as acromegaly, which leads to poor compliance. Therefore, it is urgent to develop a long-acting sustained-release formulation that can improve patient compliance. And since octreotide is a small molecule peptide drug that is extremely soluble in water, it tends to escape to the external aqueous phase during the preparation of microspheres, resulting in low drug loading and encapsulation efficiency. In this study, HIP-OCT complexes were prepared by hydrophobic ion-pairing (HIP) method. The effects of charge ratio, pH value, and temperature on the binding efficiency of the complexes were investigated, and the water solubility and dissociation of the complexes were observed. The sodium dodecyl sulfate-octreotide (SDS-OCT) with 93.77% binding efficiency, 9.31% water solubility, and 92.10% dissociation was screened as the optimal complex from the four HIP-OCT complexes. Due to the formation of HIP complexes, the hydrophilicity of OCT was changed and the difficulty of OCT encapsulation in double emulsion method was overcome. The SDS-OCT complex microspheres were prepared by the O1/O2/W double emulsion method combined with the premix membrane emulsification technique. Finally, the uniform SDS-OCT microspheres with particle size of 28.02 μm, Span value of 0.776, drug loading efficiency of 6.51%, and encapsulation efficiency of 72.00% were prepared under the negative pressure solidification, drug concentration of 80 mg/mL and poly(D,L-lactic-co-glycolic acid) (PLGA) concentration of 200 mg/mL. The in vitro accelerated release of the prepared SDS-OCT complex microspheres was basically in line with the trend of zero-level release, and the cumulative release was close to 100%. In vivo pharmacodynamic experiments showed that the microspheres had stable and long-term sustained release within one month.

Key words: Hydrophobic ion-pairing, octreotide, premix membrane emulsification, O1/O2/W double emulsion method, encapsulation efficiency

摘要： 奥曲肽(OCT)在临床上常被用于治疗肢端肥大症、胃泌素瘤等神经内分泌肿瘤以及食管胃底静脉曲张破裂出血等疾病，应用广泛。由于OCT半衰期较短，对于治疗肢端肥大症等需要长期用药的疾病，患者需要频繁给药，这导致顺应性差，因此亟须开发一种能够提高病人依从性的长效缓释制剂。此外，奥曲肽是极易溶于水的小分子多肽药物，在制备微球的过程中易逃逸至外水相，导致微球载药量和包埋率低。本工作采用疏水离子配对(HIP)法制备了HIP-OCT复合物，考察了电荷比、pH值、温度对复合物结合率的影响，并对复合物的水溶性、解离率进行检测，从四种复合物中筛选出结合率93.77%，水溶性9.31%，解离率92.10%的十二烷基硫酸钠-奥曲肽(SDS-OCT)为最优复合物。该复合物改变了OCT的亲水性，克服了OCT在传统复乳法中包埋率低的难点。采用O1/O2/W复乳法结合快速膜乳化技术，在抽负压固化、药物浓度80 mg/mL、聚乳酸-羟基乙酸共聚物(PLGA)浓度200 mg/mL的条件下制备了均一SDS-OCT复合物PLGA微球，粒径为28.02 μm，Span值为0.776，载药量为6.51%，包埋率为72.00%。制备的SDS-OCT复合物微球体外加速释放基本符合零级释放的趋势，累计释放度接近100%；体内药效实验表明该微球在一个月内具有稳定的长效缓释作用。

关键词: 疏水离子配对, 奥曲肽, 快速膜乳化, O1/O2/W复乳法, 包埋率