Poor encapsulation and high initial burst were two major obstacles for the water-soluble peptide drug loaded microspheres preparation using the industrial emulsification method. In the present study, we hypothesized that the hydrophobic ion-pairing (HIP) complex strategy with a further healing of the pores within the microspheres may improve drug encapsulation and initial burst release. DSS was chosen as the most suitable one among the three test ion-pairing agents (SDS, DSS and STC) due to its high binding efficiency with drug and reversible dissociation capacity in presence of counter ions. The formation of HIP complex between octreotide acetate and DSS successfully reversed the highly water-soluble nature of the drug. A specific S/O/W method was adopted to encapsulate such drug containing HIP complex. The encapsulation efficiency of the drug was greatly improved compared with the conventional W1/O/W2 method (from 44% to 90%). Under the optimal healing conditions (the healing time 6 h, temperature 40 °C and 4% DEP content), the pores within the microspheres were effectively healed. Initial burst amount of octreotide acetate in S/O/W microspheres decreased to 3.56%. The pore healing effect was further confirmed by the scanning electron microscopy and fluorescence microscopy results. In the process of testing the drug release performance of such new strategy in vitro and in vivo, a more satisfactory single phase release profile with sustained and steady drug release was observed. These results suggested that the modified HIP strategy could be a promising platform for water-soluble peptide encapsulation with high encapsulation efficiency, low initial burst and stable drug release mechanism.

包封不良和高初始破裂是使用工业乳化方法制备水溶性肽药物的微球制备的两个主要障碍。在本研究中，我们假设疏水离子对（HIP）复杂的策略与微球中的孔的进一步愈合可能会改善药物封装和初始爆发释放。DSS被选为三种测试离子对试剂（SDS，DSS和STC）中最合适的一种，因为它与药物的结合效率高，并且在存在抗衡离子的情况下具有可逆的解离能力。醋酸奥曲肽和DSS之间HIP复合物的形成成功逆转了该药物的高度水溶性。采用一种特殊的S / O / W方法来封装这种含有HIP复合物的药物。与传统的W1 / O / W2方法相比，药物的封装效率得到了极大的提高（从44％到90％）。在最佳愈合条件下（愈合时间为6小时，温度为40°C，DEP含量为4％），微球内的孔得到了有效愈合。S / O / W微球中醋酸奥曲肽的初始爆破量降至3.56％。通过扫描电子显微镜和荧光显微镜结果进一步证实了毛孔愈合作用。在体外和体内测试这种新策略的药物释放性能的过程中，观察到具有持续和稳定药物释放的更令人满意的单相释放曲线。这些结果表明，改良的HIP策略可能是具有高包封效率的水溶性肽包封的有前途的平台，