Purpose

The current investigation explores the enhanced biopharmaceutical attributes of solid supersaturable self-microemulsifying drug delivery system (Solid SS SMEDDS) for poorly water soluble drug canagliflozin (CFZ).

Methods

Solid SS SMEDD formulation was prepared by spray drying using Neusilin US2 as an adsorbent. The developed SS SMEDDS were characterized for physicochemical and solid state characterizations. Theoretical molecular simulations were performed by in silico docking. BET measurements were done for evaluating surface area topography. In vitro dissolution, ex vivo permeation, and pharmacokinetics studies were performed to determine release rate, permeability, and absorption behavior, respectively. Anti-diabetic studies and histopathology were done as per standard protocols.

Results

The solid SS SMEDD formulation containing 320 mg Lauroglycol FCC, 1200 mg Tween 80, 480 mg Transcutol-P, and 2.24% w/v Poloxamer 188 as polymer-based precipitation inhibitor (PPI) was optimized. The solid state attributes of CFZ in solid SS SMEDDS revealed its molecularly dispersed state. The prepared formulation demonstrated uniform flow properties, nanoparticulate size distribution, and acceptable drug content. Theoretical simulations revealed strong intermolecular hydrogen bonding with a docking score of − 5.184 kJ/mol. In vitro dissolution studies depicted enhanced release of CFZ from solid SS SMEDDS in various dissolution media. Remarkable improvement in ex vivo permeability was observed across the jejunum segment of rat intestine. These studies revealed enhanced absorption of CFZ in rats following oral administration of solid SS SMEDDS, as compared with that of pure drug and marketed product. Pharmacological evaluation of optimized solid SS SMEDDS also revealed enhanced anti-diabetic activity, as evident from urinary glucose excretion studies and SGLT II protein expression in rat kidneys. Accelerated stability study confirmed the stability of the formulation up to 6 months storage period.

Conclusion

The designed delivery system indicated promising results in developing an effective formulation of CFZ for diabetes mellitus.

中文翻译：

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Canagliflozin的基于聚合物沉淀抑制剂的固态过饱和SMEDD配方：改善的生物利用度和抗糖尿病活性

目的

当前的研究探索了水溶性较差的药物卡格列净（CFZ）的固体超饱和自微乳化药物递送系统（Solid SS SMEDDS）增强的生物制药属性。

方法

使用Neusilin US2作为吸附剂，通过喷雾干燥制备了固态SS SMEDD制剂。对已开发的SS SMEDDS进行了物理化学和固态表征。通过计算机对接进行理论分子模拟。进行BET测量以评价表面积形貌。进行了体外溶出，离体渗透和药代动力学研究，分别测定了释放速率，渗透性和吸收行为。按照标准方案进行抗糖尿病研究和组织病理学检查。

结果

固态SS SMEDD配方，包含320 mg月桂醇FCC，1200 mg Tween 80、480 mg Transcutol-P和2.24％w / v优化了基于聚合物的沉淀抑制剂（PPI）的泊洛沙姆188。固态SS SMEDDS中CFZ的固态属性显示了其分子分散状态。制备的制剂表现出均匀的流动性能，纳米颗粒尺寸分布和可接受的药物含量。理论模拟表明分子间氢键很强，对接得分为-5.184 kJ / mol。体外溶出研究表明，在各种溶出介质中，CFZ从固态SS SMEDDS释放的增强。在大鼠肠的空肠段观察到离体通透性的显着改善。这些研究表明，与纯药物和市售产品相比，口服固态SS SMEDDS后大鼠对CFZ的吸收增强。优化的固态SS SMEDDS的药理学评估也显示出增强的抗糖尿病活性，从大鼠肾脏中的尿葡萄糖排泄研究和SGLT II蛋白表达可以明显看出。加速的稳定性研究证实了制剂在长达6个月的储存期中的稳定性。

结论

设计的给药系统在开发有效的糖尿病CFZ制剂中显示出令人鼓舞的结果。