在本研究中,各种表面活性剂与胰岛素(INS)组合,牛血清白蛋白(BSA)和辣根过氧化物酶(HRP)通过疏水离子配对来增加亲脂性并促进掺入自乳化药物递送系统(SEDDS)。模型蛋白的亲脂性成功增加,实现对数正丁醇/水值高达3.5(INS),3.2(BSA)和1.2(HRP)。特此,确定了导致复合物形成的关键因素。特别是,支链烷基链或链长大于C12的表面活性剂对疏水离子对(HIP)具有良好的性能。此外,碳链的柔韧性导致更高的亲脂性,表面活性剂的极性头基对HIP的适用性在磺酸盐>磺基琥珀酸盐>磷酸盐=硫酸盐>碳酸盐>膦酸=磺基甜菜碱的等级上降低。在各种胃肠液中进行形成的HIP复合物的稳定性研究,并在常用的SEDDS赋形剂中确定其溶解度。形成的复合物在模拟的胃肠液中稳定,可以掺入SEDDS制剂中(C1:10%辛丙酰基聚氧乙烯-8甘油酯,20%PEG-40氢化蓖麻油,20%中链甘油三酯,50%正丁醇;C2:10%辛酸聚氧乙烯-8甘油酯,20%PEG-40氢化蓖麻油,20%中链甘油三酯,40%正丁醇,10%1,2-丁二醇),导致胰岛素的合适有效载荷高达11.9mg/ml,对于BSA为1.0mg/ml,对于HRP为1.6mg/ml。
In the present study, various surfactants were combined with insulin (INS), bovine serum albumin (BSA) and horseradish peroxidase (HRP) via hydrophobic ion pairing to increase lipophilicity and facilitate incorporation into self-emulsifying drug delivery systems (SEDDS). Lipophilicity of model proteins was successfully increased, achieving log Dn-butanol/water values up to 3.5 (INS), 3.2 (BSA) and 1.2 (HRP). Hereby, key factors responsible for complex formation were identified. In particular, surfactants with branched alkyl chains or chain lengths greater than C12 showed favorable properties for hydrophobic ion pairs (HIP). Furthermore, flexibility of the carbon chain resulted in higher lipophilicity and suitability of polar head groups of surfactants for HIP decreased in the rank order sulfonate > sulfosuccinate > phosphate = sulfate > carbonate > phosphonic acids = sulfobetaines. Stability studies of formed HIP complexes were performed in various gastrointestinal fluids and their solubility was determined in commonly used SEDDS excipients. Formed complexes were stable in simulated gastrointestinal fluids and could be incorporated into SEDDS formulations (C1: 10% caprylocaproyl polyoxyl-8 glycerides, 20% PEG-40 hydrogenated castor oil, 20% medium-chain triglycerides, 50% n-butanol; C2: 10% caprylocaproyl polyoxyl-8 glycerides, 20% PEG-40 hydrogenated castor oil, 20% medium-chain triglycerides, 40% n-butanol, 10% 1,2-butanediol), resulting in suitable payloads of up to 11.9 mg/ml for INS, 1.0 mg/ml for BSA and 1.6 mg/ml for HRP.