Nanogel-based carriers for topical delivery.

This thesis investigated the potential of multiple stimuli-responsive nanogels as carriers in topical drug administration, with a view to developing a multi-responsive topical delivery system. Firstly, temperature-responsive N-isopropylacrylamide (NIPAM) was co-polymerised with a butyl acrylate monomer to yield poly(NIPAM-co- BA), which was loaded with a model permeant, methotrexate. An in vitro study of the loaded nanogel showed that it was capable of delivering methotrexate across the epidermis in levels that significantly reduce the biosynthesis of prostaglandin E2 (PGE2), a key inflammation mediator. Moreover, reduced lag time and enhanced delivery by the addition of sodium carbonate to the nanogel were observed. However, Western blotting for cyclooxygenase-2 (COX-2) in ex vivo skin, found the nanogel to be pro-inflammatory thus the observed reduced level of PGE2 was due to the enhanced delivery of methotrexate, which overwhelmed the inflammatory effect produced by the nanogel. Next, a temperature- and pH-responsive polyNIPAM copolymerised with acrylic acid known as poly(NIPAM-co-AAc) (5%) nanogel was synthesised. An in vitro migration study demonstrated that particles of the poly(NIPAM-co-AAc)(5%) were capable of penetrating the porcine skin and migrating across the epidermis, as shown by the presence of the particulates in the diffusion cell receptor phases. Furthermore, the nanogels were shown to enhance the delivery of loaded drugs across the epidermis in comparison to saturated solutions of the corresponding drugs. Western blotting for COX-2 demonstrated that the nanogel did not induce significant inflammatory reactions post-topical application, suggesting its compatibility with skin. A preliminary investigation examined a single-compartment system comprised of poly(NIPAM-co-AAc) (5%) nanogel and pH modulator-containing liposome, designed to remain stable until its application onto the skin. However, the composite system proved unsuccessful, primarily due to the liposome instability. Overall, this novel smart topical drug delivery system is within reach, provided the pH modulator-loaded liposome can be adequately stabilised