Hintzen Fabian, Perera Glen, Hauptstein Sabine, Müller Christiane, Laffleur Flavia, Bernkop-Schnürch Andreas
Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
Int J Pharm. 2014 Sep 10;472(1-2):20-6. doi: 10.1016/j.ijpharm.2014.05.047. Epub 2014 May 29.
The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for the model peptide drug leuprorelin to prove a protective effect against luminal enzymatic metabolism. In order to incorporate leuprorelin into microemulsion droplets (o/w), the commercially available hydrophilic leuprolide acetate was modified by hydrophobic ion paring with sodium oleate. The obtained hydrophobic leuprolide oleate was dissolved in the SMEDDS formulation (30% (m/m) Cremophor EL, 30% (m/m) Capmul MCM, 10% (m/m) propylene glycol and 30% (m/m) Captex 355) in a concentration of 4 mg/g showing a mean droplet size of 50.1 nm when dispersed in a concentration of 1% (m/v) in phosphate buffer pH 6.8. The microemulsion was able to shield leuprolide oleate from enzymatic degradation by trypsin and α-chymotrypsin, so that after 120 min 52.9% and 58.4%, respectively, of leuprolide oleate were still intact. Leuprolide acetate dissolved in an aqueous control solution was completely metabolized by trypsin within 60 min and by α-chymotrypsin within 5 min. Moreover, an in vivo study in rats showed a 17.2-fold improved oral bioavailability of leuprolide oleate SMEDDS compared to a leuprolide acetate control solution. This is the first time, to our knowledge, that hydrophobic ion pairing is utilized in order to incorporate a peptide drug in SMEDDS and evidence of a protective effect of oil-in-water (o/w) microemulsion droplets against enzymatic degradation of a peptide drug was provided. According to these results, the system could be likely a novel platform technology to improve the oral bioavailability of peptide drugs.
本研究的目的是为模型肽药物亮丙瑞林开发一种自微乳化药物递送系统（SMEDDS），以证明其对管腔内酶促代谢的保护作用。为了将亮丙瑞林纳入微乳液滴（油包水型），通过与油酸钠进行疏水离子对作用对市售的亲水性醋酸亮丙瑞林进行了改性。将得到的疏水性油酸亮丙瑞林以4 mg/g的浓度溶解在SMEDDS制剂（30%（m/m）聚氧乙烯蓖麻油EL、30%（m/m）辛酸癸酸甘油三酯、10%（m/m）丙二醇和30%（m/m）中链甘油三酸酯）中，当以1%（m/v）的浓度分散在pH 6.8的磷酸盐缓冲液中时，平均液滴尺寸为50.1 nm。该微乳液能够保护油酸亮丙瑞林免受胰蛋白酶和α-胰凝乳蛋白酶的酶促降解，因此在120分钟后，分别仍有52.9%和58.4%的油酸亮丙瑞林保持完整。溶解在水性对照溶液中的醋酸亮丙瑞林在60分钟内被胰蛋白酶完全代谢，在5分钟内被α-胰凝乳蛋白酶完全代谢。此外，在大鼠体内进行的一项研究表明，与醋酸亮丙瑞林对照溶液相比，油酸亮丙瑞林SMEDDS的口服生物利用度提高了17.2倍。据我们所知，这是首次利用疏水离子对将肽药物纳入SMEDDS，并提供了水包油（油包水型）微乳液滴对肽药物酶促降解具有保护作用的证据。根据这些结果，该系统可能是一种提高肽药物口服生物利用度的新型平台技术。
