Development of canagliflozin nanocrystals sublingual tablets in the presence of sodium caprate permeability enhancer: formulation optimization, characterization, in-vitro, in silico, and in-vivo study

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.

Keywords:

• Canagliflozin (CFZ)
• sublingual
• nanocrystal
• sodium-glucose cotransporter-2 inhibitor (SGLT2)
• diabetes mellitus (type II)
• streptozotocin
• BCS class IV
• sono-precipitation-technique
• PVP K30
• permeability enhancer
• sodium caprate (C10)

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval statement

Male New Zealand albino rabbits were provided from the Animal House of Cairo University’s Faculty of Pharmacy in Giza, Egypt. All animal procedures were carried out per the Regulations for the Care and use f Laboratory Animals unrestricted access to food and water. The rabbits’ handling was done in accordance with the Study Ethics Committee (REC), Faculty of Pharmacy, Cairo University rules, and according to the research procedures. All animal experiments were approved by Institutional Review Board (or Ethics Committee) of the Faculty of Pharmacy, Cairo University, Cairo, Egypt (protocol code PI 3185 and date of approval 15.01.2023). The ARRIVE criteria were followed in all animal experiments. All precautions were taken in order to minimize animal suffering during the experiments.

Data availability statement

The data that support the findings of this study are available from the corresponding author and first author QW upon reasonable request.