Development of Canagliflozin Nanocrystals Sublingual Tablets in the Presence of Sodium Caprate Permeability Enhancer: Formulation Optimization, Characterization

Authors

Sammar Fathy Elhabal
Mohamed A El-Nabarawi
Nashwa Abdelaal
Mohamed Fathi Mohamed Elrefai
Shrouk A Ghaffar
Mohamed Mansour Khalifa
Passant M Mohie
Dania S Waggas
Ahmed Mohsen Elsaid Hamdan
Samar Zuhair Alshawwa
Essa M Saied
Nahla A Elzohairy
Tayseer Elnawawy
Rania A Gad
Nehal Elfar
Hanaa Mohammed
Mohammad Ahmad Khasawneh

Publication Date

12-1-2023

Journal

Drug Delivery

DOI

10.1080/10717544.2023.2241665

PMID

37537858

PMCID

PMC10946264

PubMedCentral® Posted Date

8-3-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Rabbits, Canagliflozin, Diabetes Mellitus, Type 2, Sodium-Glucose Transporter 2 Inhibitors, Tablets, Solubility, Povidone, Permeability, Nanoparticles, 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)

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.