Eid Rania K, Arafa Mona F, El Maghraby Gamal M
Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Department of pharmaceutics, Faculty of pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
Drug Deliv Transl Res. 2025 Feb;15(2):596-608. doi: 10.1007/s13346-024-01613-x. Epub 2024 May 13.
Linagliptin is hydrophilic antidiabetic with poor oral bioavailability due to poor permeability and pre-systemic metabolism. The objective was to assess w/o microemulsion for enhanced oral bioavailability of linagliptin. Nigella oil was used as oily phase based on its reported antidiabetic effect. Isopropyl myristate (IPM) or capryol were combined with nigella oil to impart intestinal membrane permeabilizing abilities. Pseudoternary phase diagrams were constructed utilizing nigella oil in presence and absence of isopropyl myristate or capryol as oily phase using Tween 60 as surfactant. W/O microemulsion formulations were selected from the constructed phase diagrams and linagliptin was loaded in the internal aqueous phase at a concentration of 0.5 mg/ml. The prepared formulations were physically evaluated and linagliptin in vitro release was monitored. Eventually, the in vivo hypoglycemic effect was assessed using diabetic rats. The developed microemulsions were of w/o type and exhibited Newtonian flow behavior with nigella/capryol microemulsion recording the lowest viscosity. The recorded droplet size values were 104.9, 121.2 and 86.4 nm for nigella, nigella/IPM and nigella/capryol microemulsions, respectively. All microemulsion formulations showed slower drug release rate compared with aqueous suspension with nigella/capryol microemulsion showing the highest release rate compared to other microemulsions. Release data from microemulsion best fitted to Higuchi model. In vivo oral hypoglycemic activity measurement reflected a more intensified hypoglycemic effect with rapid onset after oral ingestion of microemulsion compared to linagliptin dispersion. Nigella oil/IPM-based microemulsion was ranked as the most effective. The investigation highlighted the feasibility of w/o microemulsion for enhanced oral bioavailability of hydrophilic drugs like linagliptin.
利那格列汀是一种亲水性抗糖尿病药物，由于渗透性差和首过代谢，口服生物利用度较低。目的是评估油包水型微乳剂以提高利那格列汀的口服生物利用度。基于其已报道的抗糖尿病作用，黑种草油被用作油相。肉豆蔻酸异丙酯（IPM）或辛酸癸酸甘油三酯与黑种草油混合以赋予肠道膜通透能力。以吐温60为表面活性剂，在有和没有肉豆蔻酸异丙酯或辛酸癸酸甘油三酯作为油相的情况下，利用黑种草油构建伪三元相图。从构建的相图中选择油包水型微乳剂配方，并将利那格列汀以0.5mg/ml的浓度载入内部水相。对制备的配方进行物理评估，并监测利那格列汀的体外释放。最终，使用糖尿病大鼠评估体内降血糖作用。所制备的微乳剂为油包水型，表现出牛顿流体行为，其中黑种草油/辛酸癸酸甘油三酯微乳剂的粘度最低。黑种草油、黑种草油/IPM和黑种草油/辛酸癸酸甘油三酯微乳剂的液滴尺寸记录值分别为104.9、121.2和86.4nm。与水悬浮液相比，所有微乳剂配方的药物释放速率均较慢，其中黑种草油/辛酸癸酸甘油三酯微乳剂的释放速率高于其他微乳剂。微乳剂的释放数据最符合Higuchi模型。体内口服降血糖活性测量结果表明，与利那格列汀分散体相比，口服微乳剂后起效更快，降血糖作用更强。基于黑种草油/IPM的微乳剂被评为最有效。该研究突出了油包水型微乳剂提高利那格列汀等亲水性药物口服生物利用度的可行性。
