Skin structure and drug permeation

The transdermal drug delivery is an innovative and non-invasive route of drug administration through the skin, which circumvents the first-pass metabolism in the liver, offers higher patient compliance and reduces adverse effects when compared with the more traditional routes of drug delivery. Nevertheless, its applications are limited by the skin high resistance to the transport of drugs. The skin is not just another simple biological membrane. Instead, it is about 100 times less permeable than the other biological membranes, remarkably selective and has a powerful imune system that readly reacts to any agression. Therefore, the aim of this work is to investigate the structural organization of the outer layer of the skin, the stratum corneum (SC), as well as the development of a novel transdermal drug delivery system. In Chapter I it is given a general introduction to all the main concepts that are needed for the development of the work and are explored throughout the thesis. Considering the importance of the thermal analysis for the understanding of the SC and SC lipids molecular structure and their role in the selective permeability of the skin, the present work has been initiated by the investigation of the phase transitions induced by temperature in the both SC and SC lipids (Chapter II). The results have shown that at least eight transitions are detected in the SC from room temperature to ca. 120oC, instead of the usual four described in literature. Also, it has been confirmed the existence of low temperature transitions that are likely to affect the SC permeability at physiological temperatures. These results indicate that human SC Skin Structure and Drug Permeation VI lipids are organized heterogeneously, with coexisting phases at physiological and non-physiological temperatures. The SC is subjected to several different gradients such as water level, temperature and pH that influence its functions and permeability. After studying the influence of temperature and with the knowledge that the SC permeability has a non-linear response to variations in the degree of hydration, it was considered relevant to investigate the phase behavior of the SC and SC components at different water contents under isothermal conditions (Chapter III). A substancial swelling of the SC and SC components and the presence of lipids in a fluid phase in both extracted lipids and intact SC was observed, even at remarkably low water contents. Three new exothermic phase transitions were detected in the SC lipids at RH=91-94% that may be related to the non-linear response of SC permeability to hydration. After increasing the understanding of the structure and physicochemical nature of the skin, novel chitosan based polyelectrolyte complexes (PEC) were developed and optimized in order to obtain films possessing the optimal functional properties (flexibility, resistance, water vapour transmission rate and bioadhesion) to be applied on skin (Chapter IV). The interaction between chitosan and two polyacrylic acid polymers was maximized by pH control. Glycerol was the plasticizer with the best influence in the film functional properties at 30%. The application of a pressure sensitive adhesive significantly improved the films bioadhesion properties, with only a negligible effect in their resistance and flexibility. The optimized film exhibited very good properties for application in the skin and represented a very promising formulation for further incorporation of drugs for topical and transdermal drug administration. In order to evaluate the drug delivering potential through the skin of the optimized chitosan based films, four drugs (paracetamol, ibuprofen, galantamine HBr, galantamine free base) with different physicochemical properties were incorporated in the films and the drug release as well as the skin permeation were evaluated. A second purpose of the work presented in Chapter V was the in vivo evaluation of the bioadhesive properties and irritation potential of the placebo film. The films