Development of a nanogel carrier system for oral antidepressant therapeutics

Abstract

Depression is mental disorder that is life threatening as well as a leading cause of disability globally and contributes greatly to the global burden of diseases. It is characterized by suicidal thoughts, persistent sadness, poor concentration, and a lack of interest in previously rewarding or enjoyable activities. According to World Health Organization (W.H.O) (study undertaken in 2021), more than 280 million people suffer from depression. The selective serotonin reuptake inhibitors (SSRI) remain the first line therapy. They come with drawbacks such as delayed therapeutic onset due to extensive first pass metabolism and other side effects such as weight gain. This results in reduced patients’ compliance, and they cannot be used under emergency conditions as it takes two or more weeks for therapeutic onset to be achieved. In the present research, an oral nanogel drug delivery platform was synthesised and loaded with paroxetine hydrochloride hemihydrate. Chitosan (CS) and methoxy polyethylene glycol (mPEG) were employed as the biopolymers and were ionically crosslinked with TPP to attain mPEG-CS nanogel carrier system. Paroxetine loaded mPEG-CS nanogel carrier system was synthesised to minimize the drawbacks, as the nano system exhibits characteristics that minimize the extensive first pass metabolism and to improve the solubility of paroxetine owing it the hydrophilicity properties of mPEG. The freeze-drying method was used to formulate the paroxetine loaded mPEG-CS nanogel carrier system bio-platform. A Box-Behnken experimental design was employed for optimizing the particle size and drug encapsulation efficiency (DEE). The chemical integrity and the thermal properties of the nanogel were determined using FTIR, TGA 1H NMR, XRD and DSC. The morphology and size of the nanoparticles were confirmed using the SEM and zeta sizer, respectively. The optimized paroxetine loaded mPEG-CS nanogel carrier system exhibited a release of 99 % over 24 hours and entrapment efficiency of 77.90 %. In vitro analysis and Franz diffusion studies were done using the UV vis and the in vitro cytotoxicity analysis was carried out using a PC12 cell line (neuronal cells) and Caco 2 cells (intestinal cells). The in vitro cytotoxicity studies proved that the nanoformulation showed acceptable cytotoxicity on PC12 (murine brainderived) cells. This study proved that paroxetine-loaded mPEG-CS nanogel carrier system improves the solubility of the drug and decreased the cytotoxic effect when compared to pure paroxetine. Hence, mPEG-CS nanogel carrier system may be considered for the delivery of paroxetine to treat depression.