Pulsatile Drug Delivery by Thermoresponsive Polymer Films with Mathematical Model and Evaluation of Thermoresponsive Properties of Block Copolymers

Abstract

In this thesis, a new controlled thermoresponsive drug delivery system based on UV crosslinkable copolymer films was fabricated and characterised. The characterisation of the drug loaded films has shown an even drug distribution inside of the film which has a smooth surface (Ra = 8.3 nm). The kinetic study has shown that the release of two model drugs can be controlled by the thickness of the films, the initial drug concentration, and the solubility of the drug molecules. This controlled drug delivery system, fabricated from a thermoresponsive polymer, was designed to obtain a pulsatile release profile which is triggered by altering the temperature of the dissolution medium. Two stages of release behaviour were observed: fast release for the swollen state and slow (yet significant and non-negligible) release for the collapsed state. A mathematical model was developed to evaluate the feasibility of an in vivo implanted drug delivery system. The delivery device consists of a cooling material coated by a drug-loaded thermoresponsive polymer film. Drug release is initiated by remotely dropping the temperature of the cooling material sufficiently, so that the temperature throughout the polymer coating drops below its lower critical solution temperature (LCST), causing the polymer to swell and release the drug. Drug release switches off again when heat conduction from an external fluid medium raises the polymer temperature to above the LCST causing the polymer to collapse. The model was developed based on Fick's law which describes pulsatile release mathematically for the first time. Diffusion coefficients at different temperatures (including temperatures corresponding to both the fully swollen and collapsed states) were estimated by fitting the experimental data with the theoretical release profile given by this model. The effect of temperature on the diffusion coefficient was studied. The LCST of a series of poly(N -isopropylacrylamide) (poly(NIPAm)) block copolymers were measured using the cloud point method. This study has found the hydrophobicity of a segment in a copolymer, and the length of the poly(NIPAm) segment affects the LCST. The poly(acrylic acid) (poly(AA))block supplies the pH sensitivity in the block copolymer. These block copolymers can self assemble into particles which show no cytotoxicity towards 3T3 mouse fibroblast cells.