Pilot plant scale up for erlotinib synthesis, formulation, physicochemical and cytotoxicity evaluation of erlotinib sustained release nanoparticles on lung cancer cell model

Abstract

Introduction: Erlotinib is a potent and selective tyrosine kinase inhibitor. The polymeric nanoparticles are prepared from biocompatible and biodegradable polymers with size ranged between 10 to 1000 nm. The most extensive pharmaceutical researches on the topic of nanoparticles have been focused in the area of oncology, because nanocarriers can concentrate preferentially in tumor masses by enhanced permeability and retention (EPR) effect on the vasculature. Therefore based on this effect passive targeting of nanoparticles to tumors is possible. Objective: The aim of this study was the synthesis of erlotinib hydrochloride via modified method and also synthesis of PCEC copolymers with controlled molecular weight and finally preparation, characterization and cytotoxicity evaluation of erlotinib loaded PCEC nanoparticles. Materials and Methods: Erlotinib hydrochloride was synthesized in seven steps starting from 3, 4-dihydroxy benzoic acid. The composition of copolymers was designed using full factorial methodology. Molecular weight of used PEG and weight ratio of epsilon-caprolactone/PEG were selected as independent variables. The PCEC copolymers were synthesized by ring opening polymerization. Formation of copolymers was confirmed by FT-IR spectroscopy as well as H-NMR. The Mn of PCEC copolymers was calculated from HNMR spectra. The thermal behavior of copolymers was characterized on differential scanning calorimeter. Erlotinib loaded nanoparticles were prepared by means of synthesized copolymers via solvent displacement method. Finally physicochemical properties and cytotoxicity of prepared nanoparticles were evaluated. Results and Discussion: Synthesis of erlotinib hydrochloride was completed in 7 steps with overall yield of 44%. In order to evaluate the effect of selected variables on the copolymers composition and Mw, a mathematical model for each response parameter with p-value less than 0.001 were obtained. Average percent error for prediction of total Mn of copolymers and Mn of CL blocks were 13.81% and 14.88% respectively. Physicochemical properties of obtained polymeric nanoparticles were dependent on composition of used copolymers. Size of particles was decreased with decreasing the PCL/PEG weight ratio in the used copolymers. Encapsulation efficiency of prepared formulations was declined by decreasing their particle size. Drug release behavior from the prepared nanoparticles exhibited a sustained pattern without a burst release. From the release profiles, it can be found that erlotinib release rate from polymeric nanoparticles is decreased by increase of CL/PEG weight ratio of prepared block copolymers. Based on MTT assay results, cell growth inhibition of erlotinib had a dose and time dependent pattern. After 72 hours of exposure, the 50% inhibitory concentration (IC50) of erlotinib hydrochloride was appeared to be 14.8 μM. Conclusion: From the results obtained it can be concluded that the prepared PCEC nanoparticles in this study might have the potential to be considered as delivery system for erlotinib.