Singh Dilpreet, Tiwary Ashok K, Kang Tejwant Singh, Bedi Neena
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab,India.
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab,India.
Curr Drug Deliv. 2021;18(9):1352-1367. doi: 10.2174/1567201818666210217155909.
The present investigation attempts to optimize Supersaturable lipid based formulation (SS SMEDDS) of Biopharmaceutical Classification System (BCS) class IV drug canagliflozin (CFZ) and evaluating the oral bioavailability of the formulation.
Preliminary screening revealed Poloxamer 188 to most effectively inhibit precipitation of CFZ after dispersion during in vitro supersaturation studies. Box Behnken Design was employed for designing different formulations, and various statistical analyses were done to select an appropriate mathematical model. The optimized formulation (OSS 1) was evaluated for in vitro drug release and ex vivo permeation studies to evaluate drug release and permeation rate. Pharmacokinetic studies have been carried out according to standard methodologies.
The optimized formulation (OSS 1) containing 781.1 mg SS SMEDDS and 2.24% w/w Poloxamer 188 was developed at a temperature of 60°C, which revealed nano-globule size with negligible aggregation. Isothermal titration calorimetry revealed the thermodynamic state of formed microemulsion with negative ΔG. The optimized formulation was observed to possess physical stability under different stress conditions and acceptable drug content. In vitro dissolution of optimized SS SMEDDS revealed a higher dissolution rate of CFZ as compared to native forms of CFZ. The permeability of CFZ from optimized SS SMEDDS across various excised segments of rat intestine was observed to be multifold higher as manifested by 2.05-fold higher Cmax and 5.64- fold higher AUC0-36h following oral administration to Wistar rats.
The results could be attributed to substantial lymphatic uptake and P-glycoprotein substrate affinity of CFZ in SS SMEDDS investigated through chylomicron and P-glycoprotein inhibition approach, respectively.
本研究旨在优化生物药剂学分类系统（BCS）IV类药物卡格列净（CFZ）的超饱和脂质体制剂（SS SMEDDS），并评估该制剂的口服生物利用度。
初步筛选显示，泊洛沙姆188在体外超饱和研究中能最有效地抑制CFZ分散后的沉淀。采用Box Behnken设计来设计不同的制剂，并进行各种统计分析以选择合适的数学模型。对优化后的制剂（OSS 1）进行体外药物释放和离体渗透研究，以评估药物释放和渗透速率。按照标准方法进行了药代动力学研究。
在60°C的温度下制备了含有781.1 mg SS SMEDDS和2.24% w/w泊洛沙姆188的优化制剂（OSS 1），该制剂显示出纳米球粒大小且聚集可忽略不计。等温滴定量热法显示形成的微乳液的热力学状态具有负的ΔG。观察到优化后的制剂在不同应激条件下具有物理稳定性且药物含量可接受。与CFZ的天然形式相比，优化后的SS SMEDDS的体外溶出显示CFZ的溶出速率更高。给Wistar大鼠口服后，观察到CFZ从优化后的SS SMEDDS穿过大鼠肠道各切除段的渗透率提高了数倍，表现为Cmax高2.05倍，AUC0 - 36h高5.64倍。
这些结果可分别归因于通过乳糜微粒和P - 糖蛋白抑制方法研究的SS SMEDDS中CFZ大量的淋巴吸收和P - 糖蛋白底物亲和力。
