Purpose: Poor drug loading, recrystallization of drug and incomplete drug release from liquisolid formulation are major hurdles in the development of supersaturated self-nanoemulsifying drug delivery system. To address these issues, we have developed a dimethylacetamide (DMA) based lipid system and a novel co-processed excipient. Despite high solubilization capacity, DMA was never investigated as a co-solvent in self-emulsifying preparation. We hypothesize that co-processing with a hydrophilic polymer like PVA will facilitate the complete release and tabletability of superSNEP. The aim of this research work was to develop and characterize a solid supersaturated self-nanoemulsifying drug delivery system of fenofibrate (FB) for enhanced dissolution.
Methods: A supersaturated self-nanoemulsifying preconcentrate (superSNEP) of FB was prepared using dimethylacetamide (DMA), medium chain triglycerides (MCT) and kolliphor EL after screening various co-solvents and surfactants. Co-processed excipients (CPE) prepared using inorganic microporous silica (Neusilin US2, Florite 100 or Aerosil 200) and hydrophilic polymers (Polyvinyl alcohol, HPMC, and Kollidon VA64) were evaluated for flow property, BET surface area and adsorption capacity. A solid supersaturated self-nanoemulsifying preconcentrate (S-superSNEP) was prepared by adsorbing superSNEP on to the selected CPE. Lipophilic fluorescent probe (Coumarin-6) was used to investigate the extent of release/emulsification from the pores of the silicate after adsorption. S-superSNEP was successfully converted into a rapidly disintegrating tablet using recently developed microcrystalline cellulose (KG1000). The formulation was further characterized for solid state, precipitation kinetic, in-vitro cytotoxicity in colon carcinoma (caco-2) cells, in-vitro dissolution in a sink, non-sink, and biorelevant media was carried out and the release of FB from optimized S-superSNEP tablet was compared with the different marketed formulation. Currently, we are investigating the oral bioavailability of S-superSNEP in sprague dawley rats.
Results: The solubility of FB in DMA was found to be around 83 times and 11 times higher than commonly used co-solvents - PG and PEG, respectively. DMA based self-nanoemulsifying system was found to be non-toxic to colon carcinoma (Caco-2) cell even at very high concentration. Based on the powder characteristics, adsorption capacity and dissolution study, PVA-F100 was found to be the most suitable carrier for S-superSNEP. Optimized superSNEP with 20% w/v FB loading spontaneously forms nanoglobules of 40.5±2.7 nm. CPE prepared using PVA and Florite 100 (1:1 weight ratio) showed highest adsorption capacity (1 ml/gm) and complete release of oil as depicted by fluorescence study (Figure 1). DSC thermograms confirmed that the drug remained in the supersaturated solubilized state for 3 months. S-superSNEP showed significantly faster and higher dissolution FB in a sink (Figure 2) and non-sink condition compared plain API. The release of FB in biorelevant media increased in the following order FaSSGF
Conclusion: DMA and PVA-F100 based novel co-processed excipient could be a promising approach to prepare solid supersaturated self-nanoemulsifying drug delivery system for enhancing dissolution of lipophilic drugs.
Ketankumar Patel– Assistant Professor, St. John's university, Jamaica, New York