1 School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute , Dublin 2, Ireland .
J Aerosol Med Pulm Drug Deliv. 2014 Feb;27(1):1-11. doi: 10.1089/jamp.2013.1049. Epub 2013 Nov 19.
Salmon calcitonin (sCT) is approved for the short-term treatment of Paget's disease and hypercalcemia. As pulmonary delivery might improve the drug's efficacy, a variety of liposomal sCT formulations for inhalation were prepared and characterized with the intention of developing a controlled release formulation.
The influence of pH of the loading buffer, charge of the vesicular surface, and membrane rigidity on particle size, ζ-potential, and sCT encapsulation efficiency of formulations was studied. The most promising systems were investigated for their ability to withstand nebulization stresses using an Aeroneb(®) vibrating mesh device. In vitro studies were carried out to determine sCT release from the vesicles and the bioactivity of the peptide post nebulization. Lastly, pharmacokinetics of sCT liposomes following intratracheal aerosolization in an experimental rat model were investigated and compared with intravenous injection.
Liposomes prepared with acidic loading buffer and comprising rigid lipid membranes showed an optimal compromise between small particle size, high encapsulation efficiency, and sCT stability. Polyethylene glycol (PEG) liposomes showed the highest encapsulation efficiency overall, regardless of the ζ-potential of the vesicles. Positive surface charge, however, yielded higher entrapment in non-PEGylated liposomes. All liposomes tested were stable during nebulization. The bioactivity of sCT after formulation into liposomes was 52-55%. Intratracheal nebulization in rats revealed that the bioavailability and other pharmacokinetic parameters were not enhanced by liposomes, when compared with sCT solution. Following intravenous administration, however, liposomes showed significantly higher bioavailability and AUCinf (area under the curve to the infinity time point) than controls.
The developed liposomal formulations were not optimal carriers for pulmonary delivery of sCT. Due to the low amounts of peptide released from the vesicles, enzymatic digestion by peptidases in the airspace reduced the bioavailability significantly. Liposomal encapsulation of sCT, nevertheless, resulted in improved pharmacokinetics following injection.
鲑鱼降钙素（sCT）被批准用于治疗 Pagets 病和高钙血症的短期治疗。由于肺部给药可能会提高药物的疗效，因此制备了各种用于吸入的脂质体 sCT 制剂，并对其进行了表征，旨在开发一种控释制剂。
研究了装载缓冲液的 pH 值、囊泡表面的电荷和膜刚性对制剂粒径、ζ-电位和 sCT 包封效率的影响。使用 Aeroneb（®）振动网装置研究了最有前途的系统抵抗雾化应激的能力。进行了体外研究以确定囊泡中 sCT 的释放以及肽雾化后的生物活性。最后，在实验大鼠模型中通过气管内气溶胶化研究了 sCT 脂质体的药代动力学，并与静脉注射进行了比较。
用酸性装载缓冲液制备并包含刚性脂质膜的脂质体在小粒径、高包封效率和 sCT 稳定性之间表现出最佳折衷。聚乙二醇（PEG）脂质体无论囊泡的 ζ-电位如何，总体上显示出最高的包封效率。然而，正表面电荷导致非 PEG 化脂质体中的包封效率更高。所有测试的脂质体在雾化过程中均稳定。包封成脂质体后的 sCT 生物活性为 52-55%。在大鼠中进行气管内雾化表明，与 sCT 溶液相比，脂质体并未增强生物利用度和其他药代动力学参数。然而，静脉给药后，脂质体的生物利用度和 AUCinf（至无穷时间点的曲线下面积）明显高于对照。
所开发的脂质体制剂不是 sCT 肺部给药的理想载体。由于从囊泡中释放的肽量少，气腔中的肽酶的酶解显着降低了生物利用度。然而，sCT 的脂质体包封导致注射后的药代动力学得到改善。
