Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery

Abstract

Cigarette smoking has become one of the leading causes of preventable deaths all over the world, causing a serious threat to human wellbeing and a tremendous economic burden to governments. The currently available treatment options for smoking cessation are not efficient. The pulmonary delivery of drugs by methods such as dry powder inhaler (DPI) has been recognized as one of the most efficient routes of drug delivery to the targeted area. The lung delivery of nicotine in this way would be expected to mimic the effects of tobacco smoking and could significantly reduce the negative health effects of smoking that result from nicotine addiction.The aim of this study is to develop nanoparticles with controlled physicochemical properties using biodegradable polymer of chitosan (CS) loaded with nicotine salt for pulmonary delivery as DPI formulations. The outcomes of this project are expected to be a safe and effective CS-based nicotine formulation for pulmonary delivery to treat nicotine dependence. This thesis specially addresses the research questions: (1) how to develop a feasible process to manufacture the nanoparticles suitable for pulmonary drug delivery using biodegradable polymer of CS containing nicotine salt; (2) how to develop an animal model for pulmonary drug delivery from DPI formulation using a nose-only inhalation device.The current therapeutic options for treatment of smoking addiction have been reviewed, and current advancements of technology in pulmonary drug delivery are summarised. Buccal administration of drugs exhibits a low oral bioavailability, and sublingual tablets and chewing gums can be swallowed before being absorbed.Although nasal spray of nicotine is a fast way to deliver nicotine into the bloodstream, Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery iii the rate of absorption is still not as rapid as cigarette smoking. Therefore, it is proposed that delivery of nicotine with sustained drug release profile direct into the deep lung is likely to more effectively mimic the rapid effects of cigarette smoking on a physiological level, which could eliminate patient craving and allow the tapering of nicotine level over time to improve patients' compliance.Water in oil (w/o) emulsion crosslinking method has been used to fabricate nicotine hydrogen tartrate (NHT)-loaded CS nanoparticles which separate as solid microaggregates. The physicochemical properties of particles are characterized by a series of techniques. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) shows that the prepared particles are spherical in morphology with rough surface after loading CS particles with NHT. Dynamic Light Scattering (DLS)by Zetasizer determined nanoparticle size ranging from 167.6 nm to 411 nm, while DLS by Mastersizer demonstrated that the microaggregates of these nanoparticles are in the respirable range (<5µm). The surface positive charge as measured by zeta potential tends to decrease with increase of mass ratios of NHT to CS, which is in contr...

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