A promising codrug of nicotinic acid and ibuprofen for managing dyslipidemia. I: Synthesis and in vitro evaluation

Abstract

Nicotinic acid is therapeutically the optimum antihyperlipidemic agent, yet its intolerable cutaneous flushing hinders its wide clinical implication. The codrug of nicotinic acid and ibuprofen (IBP) was synthesized in the aim of overcoming the troublesome side effect of nicotinic acid by blockade of prostaglandin synthesis through released IBP, thus enhance patient’s compliance. The physico-chemical properties of codrug namely solubility, partition coefficient, and pKa were determined. Its solubility in aqueous and organic solvents was highest in 0.1 M HCl and isopropanol, respectively. The kinetics of hydrolysis of the codrug and IBP 2-hydroxyethyl ester was studied in aqueous phosphate buffer solution in pH 1.2, 6.8, and 7.4 at 70°C, 80°C, and 90°C. The hydrolysis was found to be pH dependent and followed Arrhenius equation. The half-life of codrug and IBP 2-hydroxyethyl ester at 25°C in pH 7.4 was 218 days and 3 years, respectively. In vitro enzymatic hydrolysis of codrug and IBP 2-hydroxyethyl ester was studied in human plasma and rat liver homogenate. Codrug and IBP 2-hydroxyethyl ester exhibited faster in vitro enzymatic hydrolysis than in vitro chemical hydrolysis. The pseudo-first-order rate constants were 0.0113, 0.177 min⁻¹ for codrug and 0.0006, 0.0569 min⁻¹ for IBP 2-hydroxyethyl ester in human plasma and rat liver homogenate, respectively. Thus, nicotinic acid will be rapidly released from codrug to manage dyslipidemia, followed by the later release of IBP from IBP 2-hydroxyethyl ester to alleviate nicotinic acid cutaneous flushing.

Keywords::

• Dyslipidemia
• codrug
• nicotinic acid
• ibuprofen
• chemical hydrolysis
• enzymatic hydrolysis