In this study, a core-shell lipid/polymer nanoparticle (NP) was prepared to deliver Isotretinoin drug with pH sensitive and controllable drug release property for oral administration usage. Chitosan was cross-linked to tripolyphosphate to form the core of the NP using the ionic gelation technique and coated with glycerol monostearate lipid as a shell by applying a two-step approach. Response surface methodology was used to investigate the effects of various parameters on particle size and drug entrapment efficiency of the nanoparticles. Optimal nanoparticles with lower particle size and higher entrapment efficiency had a diameter of 100 nm based on TEM analysis and 64% drug entrapment efficiency. Coating NPs surface with lipid changed the NPs charge, hydrophilicity and swelling property. Lipid coating NPs changed release rate from 6 to 4% after 2 h in simulated gastric fluid (SGF), 9 to 16% after 6 h in simulated intestine fluid (SIF) and 21 to 71% after 7 days in blood medium. Kinetic modeling of drug release confirmed Fickian diffusion based on Higuchi model in SIF and blood media where swelling and dissolution of polymer network were negligible, while drug dissolution due to polymer swelling in SGF media was the dominant mechanism for drug release.

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