The use of polymeric biomaterials such as Hydrogels has been very significant and the diffusion-controlled mechanism for transport of water and drugs has played an important role in the application and development of controlled release drug delivery systems.
The first objective of this project was to investigate the diffusion and drug release kinetics of HEMA homopolymer, its copolymers with THFMA and copolymers that were gelled with PEM powder. A comparative study for diffusion and drug release kinetics in distilled water and simulated body fluid, SBF, were carried out to observe the change and impact of the different ionic species in SBF on the polymer system. The effect of the polymer composition, temperature, a range of drug loadings, the size and nature of the drugs on the diffusion and drug release kinetics were studied, and the drug release kinetics were correlated with the penetrant uptake rates. The second major aim of this project was to compliment the mass uptake studies with NMR imaging studies to obtain real-time and spatial information about the diffusion front and later to correlate these results with the results obtained from macroscopic sorption experiments.
The water transport in the initially glassy polymers of pure PHEMA and PHEMA with two loaded drugs (vitamin B12 and aspirin) at two different drug loadings (5 wt.% and 10 wt.%) were studied at different temperatures (25 °C, 37 °C 0, and 45 C) and were found to be controlled by Fickian diffusion. PHEMA-B12 systems show a higher water uptake than pure PHEMA and PHEMA-aspirin systems show lower water uptake than pure PHEMA at equilibrium. The activation energies for water diffusion were found to be very similar for all the PHEMA-drugs systems including the pure PHEMA, which indicates that the diffusion mechanisms were similar for sorption of water. Aspirin plays an important role in plasticising the polymers while B12 acts as an antiplasticiser to some extent.
The drug diffusion coefficients for the PHEMA-aspirin systems at all the temperatures studied are similar to the diffusion coefficients for water sorption at the corresponding temperature while the drug diffusion coefficients for the PHEMA-B12 systems are much lower than the diffusion coefficients for the sorption of water. The drug release kinetics for all of the PHEMA-drug systems were found to be controlled by a Fickian diffusion mechanism over the release ranges studied.
The water transport into glassy copolymers of HEMA and THFMA initially loaded with drugs (B12 and aspirin) was found to be controlled by a Fickian diffusion mechanism. The equilibrium water uptakes for the copolymer-B12 systems were higher and the water uptakes for the copolymer-aspirin systems were lower than that for the corresponding pure copolymers without any drug loading. The water diffusion coefficients and the EWC decrease as the amount of hydrophobic THFMA in the copolymer increases. The drug release profiles for both aspirin and B12 are similar and follow a Fickian-type diffusion mechanism. However, most of the B12 remained in the copolymer matrix over the sorption times studied while most of the loaded aspirin was released out of the matrix.
The solvent diffusion of DW and SBF into the glassy copolymers of HEMA and THFMA loaded with drugs (aspirin and B12) follow a Fickian mechanism. A second stage sorption was evident in some systems, which was attributed to the ductility of the THFMA component of the copolymers. An overshoot phenomenon was observed in the copolymers with high HEMA contents. The diffusion coefficients for both copolymer-drug systems in SBF are lower for the copolymers with high HEMA content than the values obtained for DW. The EWC and volume change was always higher in SBF compared to DW for both copolymer-drug systems.
The drug release profiles for both copolymer-drug systems were similar in DW and SBF As the THFMA content in the copolymer increases, the release rates of both drugs were reduced. The matrix crack formation has a similar effect on the drug release kinetics in DW and SBF. In the swelling media of SBF, there is a significant increase of release for the two model drugs (aspirin and B12) from the same polymer matrices compared to the media of DW The drug release kinetics for both drugs in both swelling media (DW and SBF) follow a Fickian-type diffusion mechanism over the release periods studied.
The water-concentration profile in the MRI show two features; an underlying Fickian profile and an inner feature resulting from water with a relatively high T2, over the linear region of the relative mass uptake versus t1/2 curve for the polymers. The high T2 value can be attributed to water residing in cracks.
The underlying MRI diffusion front profiles in the PHEMA-B12 systems appear consistent and fitted well to the Fickian diffusion model, while for PHEMA-aspirin systems the fits of the Fickian curves were not as good, compared to PHEMAB12 systems. However, at longer sorption times, after the glassy core has disappeared, the profiles for the PHEMA-aspirin systems are clearly Fickian in shape. The best-fit values of diffusion coefficient (D) obtained from MRI for both PHEMA-B12 and PHEMA-aspirin systems were found to be in reasonable agreement with the corresponding values of D from the mass uptake measurements. The vitamin B12 systems with the copolymers of HEMA and THFMA could be described by the Fickian diffusion mechanism with the values of the diffusion coefficients obtained from the gravimetric measurements. The MRI profiles for the copolymer-aspirin systems were found to be inconsistent with the predictions of the Fickian model with a value of the diffusion constant equal to that found from the gravimetric measurements. However, the profiles obtained were Fickian-like in their shape. The origin of the deviations between the predicted and experimental water concentration profiles may lie in the T2 of the water protons in these systems, and/or in distortions of the profiles due to some crack formation in the glassy core region.
The copolymer-B12 systems that were rich in HEMA displayed extensive crack formation in the glassy core during water sorption. This was attributed to the antiplasticisation effect of the B12 on the polymers. The image profiles for the copolymer-B12 systems with high HEMA contents were distorted by the presence of water in cracks formed as a result of the swelling stress generated in the glassy core during water sorption. On the other hand, there was no visible evidence for extensive crack formation in the glassy core of the swelling cylinders when aspirin was present. This was attributed to the plasticisation of the polymers by the aspirin.
From the MRI images it was revealed that low signal-to-noise ratios were observed, particularly for the copolymer-aspirin systems with THFMA contents greater than 20 percent. This is believed to be principally due to a reduction of the spin-spin relaxation time, T2, of the polymers through interactions between the water, aspirin and the copolymer. The confounding effects of the aspirin on the water relaxation dynamics in these copolymers may distort the water concentration profiles.
In polymer-B12 and polymer-aspirin systems secondary sorption processes were observed with water diffusion front profiles which were characterised by a non-uniform water concentration across the cylinder during sorption in this regime. In the copolymer-aspirin systems with intermediate composition there was also evidence for the formation of surface fissures.
From the MRI profiles, crack formation is evident in most of the polymers with high HEMA contents when the polymers were prepared using the room temperature polymerisation technique and gelled with PEM powder. Crack formation is not evident in the PEM/THFMA systems. The presence of the cracks leads to a distortion of the water concentration profiles, making it difficult to curve-fit the profiles to the Fickian diffusion model in the early stages of water sorption. For the polymer systems with high THFMA contents the MRI images reveal the presence of a second stage diffusion mechanism.
A low signal-to-noise ratio was observed for the copolymers with high THFMA contents in the early stages of water sorption, especially those loaded with aspirin. The use of different DMPT concentrations in preparing the polymers (1% and 2.5%) does not show any significant impact on the water diffusion coefficients or the shapes of the MRI profiles. In PEM/THFMA systems, sharp features were found to be developed at the surface during the diffusion process, which were attributed to the water protons in these regions having higher T2 values, consistent with the formation of fissures in the surfaces of the cylinders and the formation of resident pools of water. The water in these features distort the T2-weighted MRI images.
The copolymers (PEM/HEMA:THFMA) having different compositions of HEMA and THFMA show a behaviour intermediate between those for PEM/HEMA and PEM/THFMA. The underlying profiles for PEM/copolymer-drug systems could be fitted reasonably well to the Fickian diffusion model. However, the poor signal-to-noise ratios for the images for the systems containing aspirin made the assessment of the diffusion coefficient somewhat uncertain, but the signal-to-noise ratios for the chlorhexidine systems were much better than those for copolymer-aspirin systems.
All of the polymers prepared by the room temperature polymerisation method and gelled with PEM powder, with and without loaded drugs, show Fickian type water diffusion behaviour in the early stages of the diffusion process.