FORMULATION DEVELOPMENT, CYTOTOXICITY ASSESSMENT AND PERMEABILITY STUDIES OF SEDDS CONTAINING LONG-CHAIN LIPIDS
Abstract
Lipid-based self-emulsifying drug delivery systems (SEDDS) present a viable approach to overcome poor aqueous solubility and thus improve oral drug bioavailability. However, limited lipid solubility of drugs, need of excessive co-solvents to achieve self-emulsification and higher drug-loading, excipient cytotoxicity, drug precipitation after dispersion and digestion pose challenges in development of SEDDS. In the first part of the current study, a systematic cytotoxicity evaluation of long-chain lipid-surfactant mixtures was done in Caco-2 cells of varying maturity using MTT assay. Long-chain lipids and their digestion products were well-tolerated up to as high as 5% v/v. Lipid-surfactant mixtures were better tolerated than neat surfactants. Cytotoxicity was affected by cell-maturity and formulation composition. Superior safety-profile of long-chain lipid-based SEDDS sparked interest for further exploration. Hence, in the second part of the study, digestion products of long-chain triglyceride (glyceryl trioleate), namely glyceryl monooleate (GMO) and oleic acid (OA) were used as the lipid phase to formulate SEDDS. Use of GMO and OA allowed higher drug-loading of weakly-basic drugs and could help overcome variability in performance of SEDDS due to triglyceride digestion. The optimized SEDDS contained 50% w/w mixture of GMO: OA (1:1.2 w/w) and 50% w/w mixture of Cremophor EL: Tween 80 (1:1 w/w). Cinnarizine (CZ) and Ritonavir (RTV) were used as weakly-basic model compounds. As low as 3mM sodium taurocholate remarkably improved the dispersibility and particle size of SEDDS. The optimized SEDDS showed no food effect in-vitro. No drug precipitation was observed throughout the in-vitro dispersion test period. The effect of developed SEDDS on permeation of a model poorly-water soluble Pgp-substrate dye Rhodamine 123 was tested in Caco-2 cells and it efficiently reduced the efflux-ratio of Rhodamine 123 from 5 (for control) to 0.6 at non-toxic concentration. Thus, fatty-acid in the formulation helped enhance the drug-loading of weakly-basic drugs, in-vivo solubilizers like bile-salts in physiologically relevant minimalistic concentration can help form microemulsion and aid complete dispersibility of SEDDS and thus excessive co-solvents may be avoided. The optimized SEDDS also helped enhance the permeation of Pgp-substrates like Rhodamine 123 in Caco-2 cells.