Birro Büşra Arpaç, Pesce Cristiano, Tognetti Francesco, Fragassi Agnese, Casagrande Lisa, Garofalo Mariangela, Salmaso Stefano, Caliceti Paolo
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Int J Pharm. 2025 Jun 10;678:125686. doi: 10.1016/j.ijpharm.2025.125686. Epub 2025 May 10.
Exenatide, a first-in-class GLP-1 receptor agonist, is used to control glycaemic levels in type 2 diabetes. There are two approved injectable formulations: one solution for immediate action and one dispersion for prolonged action. Oral exenatide has low bioavailability due to poor gastrointestinal stability and absorption. To address these obstacles, we designed Solid Lipid Nanoparticles (SLN) including DOTAP in the formulation to yield high exenatide encapsulation by hydrophobic ion pairing and DSPE-PEG to convey colloidal stability and mucus diffusivity. The microfluidic production of SLN yielded 9.7 % exenatide encapsulation and 94.2 % loading efficiency. SLN exhibited solid cored-spherical morphology with sizes of about 120 nm and zeta potential of + 53 mV. The SLN surface charge was modulated by DSPE-PEG coating; 10 and 30 w/w% DSPE-PEG /lipid ratios yielded slightly positive and neutral zeta potentials, respectively. All SLN formulations provided exenatide protection from proteolytic enzymes. The non-PEGylated SLN resulted in a twofold increase of exenatide delivery across Caco-2 cell monolayers compared to the peptide solution. The 10 w/w% SLN PEGylation reduced the exenatide delivery compared to non-PEGylated SLN through Caco-2 cell monolayers. However, the exenatide delivery with 10 w/w% PEGylated SLN across mucus-producing Caco-2/HT29-MTX coculture layer was 2-fold higher compared to the unformulated peptide, and 1.5 higher than non-PEGylated SLN. The 30 w/w% SLN PEGylation did not improve the peptide transport neither through Caco-2 cell monolayers nor through Caco-2/HT29-MTX coculture layer.
艾塞那肽是首个获批的胰高血糖素样肽-1（GLP-1）受体激动剂，用于控制2型糖尿病患者的血糖水平。目前有两种已获批的注射用制剂：一种是速效溶液剂，另一种是长效分散剂。由于胃肠道稳定性和吸收性较差，口服艾塞那肽的生物利用度较低。为克服这些障碍，我们设计了包含二油酰基三甲基氯化铵（DOTAP）的固体脂质纳米粒（SLN）制剂，通过疏水离子对作用实现艾塞那肽的高包封率，并使用二硬脂酰基磷脂酰乙醇胺-聚乙二醇（DSPE-PEG）来确保胶体稳定性和黏液扩散性。通过微流控技术制备的SLN实现了9.7%的艾塞那肽包封率和94.2%的载药效率。SLN呈现出实心球形形态，粒径约为120nm，ζ电位为+53mV。SLN的表面电荷通过DSPE-PEG包衣进行调节；DSPE-PEG与脂质的比例分别为10%和30%（w/w）时，ζ电位分别呈轻微正值和中性。所有SLN制剂均能保护艾塞那肽免受蛋白水解酶的降解。与肽溶液相比，未聚乙二醇化的SLN使艾塞那肽透过Caco-2细胞单层的递送量增加了两倍。与未聚乙二醇化的SLN相比，10%（w/w）聚乙二醇化的SLN通过Caco-2细胞单层时，艾塞那肽的递送量减少。然而，10%（w/w）聚乙二醇化的SLN通过分泌黏液的Caco-2/HT29-MTX共培养层时，艾塞那肽的递送量比未制剂化的肽高2倍，比未聚乙二醇化的SLN高1.5倍。30%（w/w）聚乙二醇化的SLN无论是通过Caco-2细胞单层还是通过Caco-2/HT29-MTX共培养层，均未改善肽的转运。
