Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Int J Nanomedicine. 2020 Feb 18;15:1129-1148. doi: 10.2147/IJN.S235290. eCollection 2020.
Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism.
Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control.
SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study.
The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.
固体脂质纳米粒（SLNs）被认为是一种很有前途的系统，可提高水溶性差的药物的口服生物利用度；由于其内在的增加溶解度的能力，以及保护所载药物免受广泛代谢的能力。
利用这些特性，开发了载有格列齐特（GLZ）的 SLNs，以期提高 GLZ 的口服生物利用度和抗糖尿病作用，并延长其作用时间，以更好地控制血糖。
采用超声技术制备 SLNs，以甘油硬脂酸酯（Compritol888 ATO）为脂质基质，泊洛沙姆 188（PLX）为稳定剂。采用 2*3 不对称析因设计，研究不同稳定剂浓度和不同超声时间对颗粒形态、粒径、PDI 和载药量的影响。选择最佳处方，然后用海藻糖二水合物作为冷冻保护剂，在不同比例下与甘油硬脂酸酯浓度一起进行冷冻干燥。冷冻干燥后，对制剂进行体外药物释放、药代动力学和药效学测试。在进行亚急性毒性研究后，确定了所选配方的安全性。
析因设计实验得到了编码为 10F2（150mgPLX/10min 超声）的最佳配方。扫描电子显微镜显示，球形颗粒表面光滑，而保护剂与脂质的最佳比例为 2:1，粒径为 245.9±26.2nm，多分散指数为 0.482±0.026，具有双相体外释放，初始突释效应后为持续释放阶段。另一方面，与 GLZ 商业速释（IR）片剂（Diamicron）相比，所选 SLNs 显示出延长的药物释放。在糖尿病大鼠模型中的药效学研究证实，与 GLZ 原粉相比，载有 GLZ 的 SLNs 的抗糖尿病作用更好。亚急性毒性研究表明，重复口服 SLNs 是安全的。
