Design and assessment of pulsatile technology based chronomodulated delivery systems of nifedipine

Abstract

Nifedipine has poor aqueous solubility which limits its oral absorption as unit formulation. This limitation was acted through multiparticulate pulsatile systems for the treatment of angina pectoris. Initially, solid dispersions of nifedipine (NF) using sodium starch glycolate (SSG) and guar gum (GG) in 1:1 and 1:2 ratios were processed by kneading technique. Solution layering technique was employed to coat the solid dispersions on non-pareil sugar spheres (∼450 µm) to obtain immediate (NMP 1 and 2) and controlled release pellets (NMP-3 and 4). Controlled release pellets were further coated with Eudragit L100 and RS100 to achieve pulsatile pellets (NMPP-1 to 5). Pellets were subjected to saturation solubility, FTIR, DSC, micromeritics, SEM, drug content, drug release, pharmacokinetic and stability studies. By means of solid dispersions, solubility of NF was increased by 130-folds due to encompassing ordered interparticle mixing of NF and carriers. Significant interactions between NF and carriers were not demonstrated in FTIR spectra as well as in DSC thermograms. Fluidization process again proved its supremacy in producing defined spherical shaped pellets with desired micromeritics. Solution layering process resulted with high drug content (81–94.2%) and maximum drug was released by end of 12 h with 6 h lag phase. Suitable pharmacokinetic parameters were moderated by immediate (NMP) and pulsatile pellets (NMPP) as Cmax of 820 ng/mL for NMP-2 and 360.8 ng/mL for NMPP-5 at 5 and 16 h respectively. Increased pharmacokinetics and bioavailability were the result of linear increase in solubility of NF with solid dispersions. The pulsatile formulations were physicochemically intact over a period of time. Thus, multiparticulate systems of NF had demonstrated their applicability in chronotherapy of circadian based ailments. Keywords: Angina, Circadian, Multiparticulates, Non-pareil, Solid dispersion, Solution-layering