Biopharmaceutical Process of Diclofenac Multiparticulate Systems for Chronotherapy of Rheumatoid Arthritis

Objective: Diclofenac exhibits limited solubility, low bioabsorption and gastric toxicity. The objective is to address above limitations and to design multiparticulate formulation for chronotherapy of Rheumatoid arthritis (RA).
Materials and methods: Solid dispersions of diclofenac (DC) with sodium starch glycolate (SSG) and guar gum (GG) were prepared. Uniform sized (~400 µm) non-pariel seeds were coated with solid dispersions to produce immediate release pellets (DMP-1 and DMP-2) and controlled release pellets (DMP-3 and DMP-4). The resultant controlled release pellets were further layered with methaacrylate polymers to obtain pulsatile release pellets (DMPP). Solubility, FTIR, DSC, micromeritics, SEM, drug content, drug release, pharmacokinetics and stability studies were performed for DMPP.
Results: Solubility of DC was improved by 164-folds due to presence of hydrophilic carries in the solid dispersions. No chemical and physical interactions were noticed in FTIR spectra and also in thermograms. Fluidized bed processor facilitated the production of high-quality, circular and regular pellets with angle of repose less than 19.5º and DC content in between 95.18-98.87%. Maximum drug was released from DMPP at the end of 12 hours. DMP-1 and DMP-2 pellets had 2 hrs of drug release and pulsatile controlled release pellets had 6 hrs lag phase followed by 12 hrs controlled release. Both DMP-1 and DMP-2 immediate had shown first-order release followed by Hixson-Crowell kinetics whereas DMPP pellets followed zero order release with Higuchi’s kinetics. Maximum concentration of DC in plasma was recognized as 400.8 ng/ml at 5 hr for DMP-2 and 381.1 ng/ml at 14 hr for DMPP-5. The solubility of DC was increased with the application of solid dispersion technique and in turn increased the pharmacokinetics. The pellets were plausibly stable above a time period. Thus, multiparticulate pulsatile systems of DC were as effective as chronotherapeutics in the treatment of circadian rhythm based ailments like RA.