Comparative studies of the effects of novel excipients amino acids with cyclodextrins on enhancement of dissolution and oral bioavailability of the non-ionizable drug carbamazepine

Abstract

Despite significant innovations in pharmaceutical industries, low water solubility is still a common biopharmaceutics-related problem that encounters 40% of marketed pharmaceutical products and results in erratic oral absorption and low bioavailability. Poorly soluble non-ionizable drugs pose additional challenges for enhancing solubility of this class of drugs. The effects of small molecular weight carriers such as amino acids (glycine, L-threonine; L-lysine and aspartic acid) on solubilization and enhancing bioavailability of Carbamazepine (Car) were investigated and compared to the more known excipients cyclodextrins (β-CD, HPβ-CD and γ-CD). Drug-carrier PM and Coppt in 1:1 molar ratio were prepared; characterized for docking, solubility, DSC, FTIR, XRD and dissolution rate; and evaluated for their oral bioavailability. Molecular docking calculations, spectral and thermal analysis confirmed Car-Amino acids ion pair complexes and Car-CDs inclusion complexes. While dissolution rate enhancement factors recorded for both CDs and amino acids were up to 12-times; additional permeation enhancing mechanism could explain superior relative bioavailability by approximately 170% for Car: Amino acid complexes and 166% for Car: CDs compared with Car alone. This study warrants the use of amino acids as a promising small molecular weight and versatile water-soluble carrier for enhancing solubility/permeability and bioavailability for this non-ionizable drug. This might endow the formulator flexibility in the design and dosage form with less bulky economic and more patient friendly solid platform for those epileptic patients and/or elderly patients that can experience difficulty in swallowing and need rapid onset of action.