Abstract

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (−18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ’s antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

 抽象的

Canagliflozin (CFZ) 是一种钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2)，可降低 2 型糖尿病患者以及心血管、肾脏和肝脏疾病患者的蛋白尿。 CFZ 在生物制药分类系统 (BCS) 中被归类为 IV 类，具有低渗透性、溶解度和生物利用度的特点，很可能归因于肝脏首过代谢。基于纳米晶体的舌下制剂是在癸酸钠存在下开发的，作为润湿剂和渗透性增强剂。该剂型适合儿童和成人，可增强溶解性、渗透性，并通过舌下粘膜吸收避免肠肝循环。在本研究中，通过Sono-homo辅助沉淀离子技术制备了含有各种表面活性剂（P237、P338、PVA和PVP K30）的制剂。用 PVP-K30 制备的优化配方显示出最小的粒径 (157 ± 0.32 nm)、Zeta 电位 (−18 ± 0.01) 和 TEM 分析的形态。随后将优化后的配方配制成含有 Pharmaburst-V® 的舌下片，崩解时间较短（51 秒），用于体内研究。与市场配方相比，所选舌下含片改善了组织学和生化标志物（血糖、肝肾功能）、AMP 激活蛋白激酶（AMPK）和蛋白激酶 B（AKT）途径，提高了 CFZ 对糖尿病兔的抗糖尿病效力，将生物利用度提高五倍，并产生更快的起效。这些发现表明 CFZ 纳米晶体舌下片可以成功治疗糖尿病。