Environmental Stimuli-Responsive Composite System For Controlled-Release

Recently, controlled-release drug delivery systems have attracted more and more attentions. Especially, environmental stimuli-responsive controlled-release systems are capable of controlling or adjusting the release rate of drug in response to physical or chemical changes in environmental conditions (such as temperature, pH, ionic strength, chemical agents, electric field, magnetic field, and light). As a result the drug delivery can be rate-, site- and time-programmed with long-effect, high performance, and low side-effect. Unfortunately, the current two types of environmental stimuli-responsive controlled-release systems are accompanied by some inherent disadvantages or limitations. For example, there is a hidden trouble of drug security in reservoir-type systems such as gating membranes and microcapsules if the membranes rupture. In addition, the reservoir-type systems encounter the limitation of the maximum release rate of drugs by concentration-driven diffusion. For the matrix-type systems, e.g. hydrogels, the poor mechanical strength is a major problem. These inherent weaknesses restrict the applications of the current controlled-release systems to a certain extent. To solve these problems, a novel temperature-responsive composite system based on temperature-responsive hydrogel and temperature-responsive gating membrane is proposed in this thesis. The temperature-responsive characteristics of the release of model drugs from the composite system in a dynamic state were experimentally investigated, and the results were compared with those of other current controlled-release systems. A novel micron-sized pH-responsive composite system based on pH-responsive microgel and pH-responsive microcapsule is also proposed in this study. The preparation parameters, pH-responsivity and pH-stability of the cationic pH-responsive microgels were systematically examined. The design and preparation of a micron-sized pH-responsive composite system for controlled-release were preliminarily discussed. Some exciting results were obtained.In this study, cross-linked poly(N-isopropylacrylamide) (PNIPAM) hydrogels were synthesized by thermo-induced free radical polymerization. The prepared PNIPAM hydrogels exhibited excellent temperature-responsivity, and reversibly and sharply swelled or shrank when the environmental temperature changed across its lower critical solution temperature (LCST). Under the experimental conditions, decrease of cross-linker dosage and increase of monomer concentration increased the swelling ratio of PNIPAM hydrogels at low temperatures. For a static state with no change of temperature, the release rates of drug from PNIPAM hydrogels at low temperatures were larger than those at high temperatures. However, for a dynamic state with uninterrupted increase of temperature, the release rate of drug from PNIPAM hydrogels exhibited burst release at LCST. The larger the swelling ratio of PNIPAM hydrogels, the more remarkable the burst release of drug. When the environmental temperature was uninterruptedly decreased, the release rate of drug from PNIPAM hydrogels was very low and the release amount of drug was quite small. The results showed that the operation of loading drug into PNIPAM hydrogels was unsuitable to be carried out at temperatures higher than LCST.PNIPAM chains were grafted onto the porous polyvinylidene fluoride (PVDF) membrane substrates by plasma-induced pore-filling grafting polymerization and the PNIPAM-g-PVDF gating membranes were successfully prepared. The temperature-responsive characteristics of the release of drug through PVDF membrane substrate and PNIPAM-g-PVDF gating membrane in a dynamic state were examined. The results showed that the controlled effect of the gating membrane with grafting yield of 7.02 % was appreciably superior to that of the membrane substrate, and the gating membrane with grafting yield of 18.82 % exhibited "negative" gating effect. The proposed composite system, composed of both PNIPAM-g-PVDF gating membrane and PNIPAM hydrogels, presented low controlled effect of NaCl molecules. However, the controlled effect of VB₁₂ (with larger molecular weight) by the proposed composite system was significant and the controlled factor was as large as 2.26. The proposed composite system showed better performance for temperature-responsive controlled-release than gating membrane system and simple composite system. Furthermore, the proposed composite system can overcome the mechanical strength problem of hydrogel system and the drug security problem of membrane system.Monodisperse and micron-sized poly(N,N'-dimethylamino ethyl methacrylate) (PDMAEMA) microgels were successfully prepared by dispersion polymerization. The microgels diameter increased and size distribution broadened with an increase of ethanol/water ratio, as well as an increase of cross-linker concentration. Stable and monodisperse microgels were not obtained at both low and high monomer concentration. Increase of concentration or molecular weight of stabilizer decreased the diameter of microgels and remarkably narrowed their size distribution. PDMAEMA microgels exhibited excellent pH-responsivity and significantly swelled at low pH values. The microgels with different original diameters had different maximum ratios of volume change as a function of pH, and the microgels with intermediate diameter had larger maximum ratio of pH-dependent volume change than others. When the environmental pH value was around pH 6 (near the isoelectric point), PDMAEMA microgels were partially or totally aggregated. However, at both low (≤pH 5) and high (≥pH 7) pH values, the microgels were of stabilization and dispersed in the water.Based on the microfluidic technique and emulsion-diffusion method, the preparation route to micron-sized pH-responsive composite system for improved controlled-release was preliminarily designed. The content provided valuable guidance for further developing micron-sized pH-responsive composite system for enhanced controlled-release.