There are numerous modes of therapeutic administration, of which oral delivery is the most convenient and conventional as it involves administration of therapeutics in the form of liquids or solid capsules and tablets. However, this mode encounters several challenges, such as chemical processes within the gastrointestinal track and first pass metabolism which subsequently reduce the efficacy of the therapeutic drugs. To overcome these issues, transdermal drug administration in the form of hypodermic needles, topical creams, and transdermal patches have been employed. However, the effect of transdermal administration is limited due the stratum corneum layer of the skin, which acts as a lipophilic and hydrophobic barrier preventing external molecules from entering the skin. Therefore, hypodermic needles are used due to their sharp tip facilitating penetration through the stratum corneum to deposit the drug formulation into the skin, subcutaneous fat, or muscles layers. However, these needles induce needle-phobia and reduce patient compliance due to the complexity with administration and pain associated with injection. Microneedle devices have been developed to avoid these issues and provide enhanced transdermal therapeutic drug delivery in a minimally invasive manner to eliminate the first-pass metabolism and provide a sustained release. Unlike hypodermic needles injection, they do not cause pain and related fear or phobia in individuals, thereby improving compliance to the prescribed dosage regime. Till now different types of microneedles have been fabricated. These include, solid, coated, hollow and dissolvable, where each type has its own advantages and unique properties and designs. In this thesis, two novel methods utilising silicon etching processes, for the fabrication of both out-of-plane and in-plane silicon microneedles are presented. Hollow out-of-plane microneedles are manufactured through deep reactive-ion etching (DRIE) technology. The patented three-step process flow has been developed to produce multiple arrays of sharp bevelled tipped, hollow microneedles which facilitate easy insertion and controlled fluid injection into excised skin samples. The in-plane microneedles have been fabricated from simultaneous wet KOH etching of the front and reverse of (100) orientated silicon wafers. The characteristic 54.7˚ sidewall etch angle was utilised to form a sharp six-sided microneedle tip and hexagonal shaped shaft. Employing this method allowed fabrication of both solid and hollow microneedles with different geometries i.e., widths and heights of several µm, to determine the optimal MN height and width for effective penetration and transdermal drug delivery. All microneedles fabricated during the PhD studentship tenure have been characterised through histology, fluorescent studies, and delivery into ex-vivo porcine and human skin tissue (research ethics committee reference 08/WSE03/55) to demonstrate effective microneedle based transdermal therapeutic drug delivery. The transdermal delivery of insulin and hyaluronic acid has been successfully demonstrated by employing a simple poke and patch application technique, presenting a clinical improvement over traditional application such as creams and ointments.
Effect of oral pretreatment with indomethacin on the intestinal first-pass metabolism of salicylamide in rabbits.
