Ruggiero, Flavia (2016) An engineered driving plate for the electro-drawing of polymer microneedles with internal microstructure based on multiphase system templating. [Tesi di dottorato]

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To date, transdermal delivery is recognized as a successful route for the administration of active compounds, overcoming most of the drawbacks affecting the traditional oral and parenteral routes. Patches made up of microscopic needles, namely microneedles, fabricated by means of several kinds of polymers, including biodegradable, biocompatible and water-soluble polymers, have been, in the last decade, developed and tested as effective and non-invasive devices for delivering therapeutic macromolecules across the skin. Anyway, some limitations associated to the fabrication techniques of biodegradable and dissolvable microneedles, such as stamp-based multistep processes or high working temperatures, not suitable for encapsulating thermo-labile drugs, have prevented their spreading on pharmaceutical market. Recently, a mold-free and mild temperature Electro-Drawing (ED) technique, has been proposed as viable route for the fabrication of biodegradable microneedles: it is based on the single-step deformation of sessile drops of polymer solution, undergoing an electrohydrodynamic (EHD) action generated from the electric field arising from a pyroelectric crystal, punctually and thermally stimulated. In the thesis work a novel ED set up, based on the control of the pyro-EHD action by means of an electric circuit directly patterned onto the crystal is presented. This solution allows the heating of an extended surface area of the crystal, in order to activate a uniform electric field, and therefore a homogeneous EHD action, on a two-dimensional array of polymer solution drops. In this way the ED advantages are extended to the in parallel fabrication of microneedles in an array configuration, in a single drawing step. In addition, microneedle shape modulation, in terms of indenting cone height and tip radius of curvature, can be achieved. This optimized shape, joint to a rapid dissolvable layer interposed between the microneedles and their substrate, allows the release of microneedles from the patch few minutes after its application. Several strategies for tuning the microneedle internal morphology, in order to modulate the drug release kinetics, are also presented. In particular, it is shown how, by electro-drawing drops of emulsions, it is possible to obtain microneedles with closed disperse compartments, which features can be controlled through the emulsion formulation, especially the inner phase composition. On the contrary, interconnected porosities can be obtained by means of a Thermally Induced Phase Separation (TIPS) process on the just shaped microneedles. A strategy based on Isothermal Titration Calorimetry (ITC) and Monte Carlo modeling has also been developed to study thermodynamics of binary or ternary systems, in order to gain information useful for controlling the morphologies of porous polymer structures obtained from phase separation processes.

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