Immediate release tablet formulation of varenicline salicylate and comparative pharmacokinetic study in human volunteers

Abstract

Purpose

To develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference.

Materials and methods

The characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug–excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared.

Results

VRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m ²/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing f ₂ values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (T _max), maximum plasma concentration (C _max), and area under the curve from 0 to infinity (AUC _inf), were compared. The values of 90% CI were 0.972–1.035 for C _max and 0.982–1.075 for AUC _inf, which was indicative of the bioequivalence of both products.

Conclusion

VRC-S–containing F4 tablet might be a good candidate for smoking cessation treatment.